Conditions: Metastatic Pancreatic Adenocarcinoma
Keywords: Nivolumab APX005M previously untreated metastatic pancreatic adenocarcinoma Gemcitabine nab-Paclitaxel
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 129
Healthy volunteers: no

Brief summary:
The main purposes of this study are to learn how effective the study drug combinations are in treating patients with metastatic pancreatic adenocarcinoma. The drug combinations are APX005M+Nivolumab+Gemcitabine+nab-Paclitaxel, or APX005M+Gemcitabine+nab-Paclitaxel.

Detailed description:

Arms:
arm 1: Gemcitabine+Nab-Paclitaxel+nivolumab arm 2: Gemcitabine+Nab-Paclitaxel+APX005M arm 3: Gemcitabine+Nab-Paclitaxel+nivolumab+APX005M

Interventions: intervention 1: APX005M intervention 2: Nivolumab intervention 3: Nab-Paclitaxel intervention 4: Gemcitabine
Intervention descriptions: intervention 1: Administer intravenously once every 28-day Cycle intervention 2: Administer intravenously twice every 28-day cycle intervention 3: Administer intravenously on 3 times every 28-day cycle intervention 4: Administer intravenously 3 times every 28-day cycle

Protocol document:
Prot_000.pdf: 
1 
 
 
 
FINAL CLINICAL STUDY PROTOCOL 
Protocol Number: PICI0002 
Protocol Title: Open-label, Multicenter, Phase 1b/2 Clinical Study to 
Evaluate the Safety and Efficacy of CD40 Agonistic Monoclonal Antibody 
(APX005M) Administered Together with Gemcitabine and nab-Paclitaxel 
with or without PD-1 Blocking Antibody (Nivolumab) in Patients with 
Previously Untreated Metastatic Pancreatic Adenocarcinoma 
 
IND Number: 
132683 
Name of Products: 
APX005M (experimental) 
Nivolumab (experimental) 
Gemcitabine (standard of care) 
nab-Paclitaxel (standard of care) 
Phase of Development: 
1b/2 
Indication: 
Previously untreated metastatic pancreatic cancer 
Sponsor: 
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 
415-610-5466 
Fax: 415-872-5305 
Collaborator 
Cancer Research Institute 
One Exchange Plaza 
55 Broadway, Suite1802 
New York, NY 10006 
Protocol Date: 
Final Protocol: March 13, 2017 
Amendment 1: April 14, 2017 
Amendment 2: May 15, 2017 
Amendment 3: September 29, 2017 
Amendment 4: November 30, 2017 
Amendment 5: March 22, 2018 
Amendment 6: September 26, 2018 
Amendment 7: October 11, 2019 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Parker Institute for 
Cancer Immunotherapy. Any unauthorized copying or use of this document is prohibited. 




Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
3 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and 
with any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) except 
where necessary to eliminate an immediate hazard to patients. 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as 
described in this protocol and any other information provided by Parker Institute for 
Cancer Immunotherapy including, but not limited to, the current Investigator’s 
Brochure (IB).  
• 
That I am aware of, and will comply with, Good Clinical Practices (GCP) and all 
applicable regulatory requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the study drugs, the Parker Institute for Cancer Immunotherapy study protocol, and of 
their study-related duties and functions as described in the protocol. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
4 
 
1 
SYNOPSIS 
Title of Study: 
Open-label, Multicenter, Phase 1b/2 Clinical Study to Evaluate the Safety and 
Efficacy of CD40 Agonistic Monoclonal Antibody (APX005M) Administered 
Together with Gemcitabine and nab-Paclitaxel with or without PD-1 Blocking 
Antibody (Nivolumab) in Patients with Previously Untreated Metastatic 
Pancreatic Adenocarcinoma 
Protocol Number: 
PICI0002 
Phase of Development: 
1b/2 
Objectives: 
Phase 1b: 
Primary: 
1. To determine the feasibility, safety and dose-limiting toxicities (DLT) 
of each treatment cohort.  
2. To determine the recommended Phase 2 dose (RP2D) of APX005M 
when combined with nab-paclitaxel (NP)/gemcitabine (Gem). 
3. To determine the RP2D of APX005M when combined with 
nivolumab/NP/Gem. 
Secondary: 
1. To determine objective response (OR) and duration of response (DOR) 
of each treatment cohort. 
Exploratory: 
1. To assess the pharmacokinetics (PK) of APX005M in Cycles 1 to 4. 
2. To assess immune pharmacodynamic effects of each treatment cohort, 
in both blood and tumor tissue. 
Phase 2: 
Primary: 
1. 
To estimate overall survival (OS) of each treatment arm. 
2. 
To compare 1-year OS rate of each treatment arm to the historical rate 
for NP/Gem. 
Secondary: 
1. To determine the objective response rate (ORR), disease control rate 
(DCR), DOR, and progression-free survival (PFS) of each treatment 
arm. 
2. To further characterize the feasibility and safety of each treatment arm. 
Exploratory: 
1. To assess the PK of APX005M in Cycles 1 to 4 (Arms B and C). 
2. To assess immune pharmacodynamic effects of each treatment arm, in 
both blood and tumor tissue. 
3. To assess associations between immune biomarkers and clinical 
outcomes. 
4. To evaluate baseline and on-treatment microbiome profiles. 
5. To construct multivariable linear models to dissect the 
pharmacodynamic effects of APX005M and nivolumab on immune 
biomarkers. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
5 
 
Study Design: 
This is a multicenter, open-label, Phase 1b/2 study to evaluate the 
immunotherapy agents APX005M and nivolumab, in combination with Gem and 
NP in patients with previously untreated metastatic pancreatic adenocarcinoma. 
 
Phase 1b 
In the Phase 1b portion of the study, the following 4 treatment cohorts will be 
evaluated for feasibility and safety: 
B1: NP/Gem/APX005M 0.1 mg/kg 
B2: NP/Gem/APX005M 0.3 mg/kg 
C1: Nivolumab/NP/Gem/APX005M 0.1 mg/kg 
C2: Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
Enrollment in Cohorts B2 and C1 may occur concurrently. Enrollment in 
Cohort C2 may begin once enrollment in Cohort C1 has been completed. 
Each cohort in the Phase 1b portion of the study will include approximately 
6 DLT-evaluable patients. A cohort corresponding to Arm A of Phase 2 
(nivolumab/NP/Gem) will not be tested, since an external study is being 
conducted to confirm the safety of nivolumab in combination with NP/Gem. 
DLT is defined as any Grade 3 or higher toxicity that is treatment-related but not 
related to the natural progression of the tumor and occurs during the DLT 
observation period. 
 
Phase 2 (Randomized) 
Patients will be randomized to one of three arms: Arm A1, Arm B2, or Arm C2 
(shown below). 
Treatment arms: 
A1: Nivolumab/NP/Gem  
B2: NP/Gem/APX005M 0.3 mg/kg 
C2: Nivolumab/NP/Gem/APX005M 0.3 mg/kg  
 
A total of approximately 93 patients will be randomized/enrolled in Phase 2 (35 
Arm A1, 29 Arm B2, 29 Arm C2). Twelve DLT-evaluable patients from the 
Phase 1b study, enrolled at the RP2D of APX005M in Arm C (i.e., 6 patients on 
B2 and 6 patients on C2) will be included in the Phase 2 analysis. Thus, each arm 
will enroll 35 patients, for a total of approximately105 patients. In the first step 
of randomization, 12 patients will be randomized in a 4:1:1 allocation to achieve 
balance in the total number of patients in each arm (since Arm A1 did not enroll 
patients in Phase 1b, more patients have to be allocated to Arm A1). Once the 12 
patients are randomized, step 2 will randomize the remaining 81 patients in a 
1:1:1 allocation. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
6 
 
Selection of Patients: 
Main Inclusion Criteria: 
1. Patient has histologically or cytologically documented diagnosis of 
pancreatic adenocarcinoma with metastatic disease. Locally advanced 
patients are not eligible. 
2. Patient must have measurable disease by Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1. 
3. Patients must be age 18 years or older. 
4. Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1. 
5. A baseline tumor tissue sample is mandatory for enrollment. If archival 
tumor tissue is not available, then a fresh tumor biopsy must be provided.  
6. Patients must have the following laboratory values at Screening, without 
transfusions or growth factors, within 2 weeks of the first dose of 
investigational agents: 
 Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (in absence of 
growth factor support) 
 Platelet count ≥ 150 x 109/L 
 Hemoglobin ≥ 9 g/dL(without transfusion support) 
 Serum creatinine ≤ 1.5 mg/dL, and creatinine clearance ≥ 50 
ml/min as measured by Cockcroft and Gault formula  
 Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) ≤ 2.5 x institution’s ULN for patients 
with no concurrent liver metastases, OR ≤ 5.0 x institution’s 
ULN for patients with concurrent liver metastases 
 Total bilirubin ≤ 1.5 x ULN, except in patients with 
documented Gilbert’s Syndrome who must have a total 
bilirubin ≤ 3 x ULN 
7. Women of childbearing potential (WOCBP) must have a negative 
pregnancy test (serum or urine) within the 7 days prior to study drug 
administration, and a negative urine pregnancy test within the 3 days 
before the first study drug administration, or a negative serum pregnancy 
test within 24 hours before the first study drug administration. 
8. WOCBP and male patients who are sexually active with WOCBP must 
agree before receiving the first dose of study drugs to use 2 highly effective 
methods of contraception (including a physical barrier) during the study 
and for 5 months for women and 7 months for men following the last dose 
of study drug, as described in the body of the protocol. 
9. Patients must have the ability to understand and willingness to sign a 
written informed consent document. 
Main Exclusion Criteria: 
1. Patient must not have received any prior treatment, including 
chemotherapy, for metastatic pancreatic adenocarcinoma, with the 
following exceptions and notes: 
a. 
Patients who have received prior adjuvant or neoadjuvant 
therapy for pancreatic adenocarcinoma are eligible if the last 
dose of adjuvant therapy was more than 4 months before the 
date of study entry. In this case, prior Gem and/or NP are 
allowable. 
b. Prior resection surgery is allowable. 
c. 
Patients initially diagnosed with locally advanced pancreatic 
cancer who have undergone chemotherapy then resection and 
were with no evidence of disease are eligible if metastatic 
relapse of disease has occurred and if the last dose of 
chemotherapy was more than 4 months before the date of study 
entry. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
7 
 
2. Patients must not have another active invasive malignancy, with the 
following exceptions and notes: 
a. 
History of a non-invasive malignancy, such as cervical cancer 
in situ, non-melanomatous carcinoma of the skin, in situ 
melanoma, or ductal carcinoma in situ of the breast, is allowed. 
b. History of malignancy that is in complete remission after 
treatment with curative intent is allowed. 
c. 
No current or history of a hematologic malignancy is allowed, 
including patients who have undergone a bone marrow 
transplant. 
3. History of clinically significant sensitivity or allergy to monoclonal 
antibodies, their excipients or intravenous gamma globulin 
4. Previous exposure to CD40, PD-1, PD-L1, CTLA-4 antibodies or any 
other immunomodulatory agent 
5. History of (non-infectious) pneumonitis that required corticosteroids or 
current pneumonitis, or history of interstitial lung disease 
6. Patients must not have a known or suspected history of an autoimmune 
disorder, including but not limited to inflammatory bowel disease, celiac 
disease, Wegner syndrome, Hashimoto syndrome, systemic lupus 
erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis, within 
3 years of the first dose of investigational agent, except for the following: 
a. 
Patients with Type 1 diabetes mellitus, hypothyroidism only 
requiring hormone replacement, skin disorders such as vitiligo, 
or alopecia not requiring systemic therapy, or conditions not 
expected to recur in the absence of an external trigger are 
eligible. 
b. Patients with a history of Hashimoto syndrome within 3 years 
of the first dose of investigational agent, which resolved to 
hypothyroidism alone. 
7. Patients must not have an uncontrolled intercurrent illness, including an 
ongoing or active infection, current pneumonitis, symptomatic congestive 
heart failure (New York Heart Association class III or IV), unstable 
angina, uncontrolled hypertension, cardiac arrhythmia, interstitial lung 
disease, active coagulopathy, or uncontrolled diabetes. 
8. Patients must not have a history of myocardial infarction within 6 months 
or a history of arterial thromboembolic event within 3 months of the first 
dose of investigational agent. 
9. Patients must not have a history of human immunodeficiency virus, 
hepatitis B (HB), or hepatitis C, except for the following: 
a. 
Patients with anti-HB core antibody but with undetectable HB 
virus deoxyribonucleic acid (DNA) and negative for HB 
surface antigen 
b. Patients with resolved or treated hepatitis C virus (HCV) (i.e. 
HCV antibody positive but undetectable HCV RNA) 
10. Patients must not have a history of primary immunodeficiency. 
11. Patients must not receive concurrent or prior use of an immunosuppressive 
agent within 14 days of the first dose of investigational agent, with the 
following exceptions and notes: 
a. 
Systemic steroids at physiologic doses (equivalent to dose of 
10 mg oral prednisone) are permitted. Steroids as anti-emetics 
for chemotherapy are not allowed. 
b. Intranasal, inhaled, topical, intra-articular, and ocular 
corticosteroids with minimal systemic absorption are 
permitted. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
8 
 
c. 
Patients with a condition with anticipated use of systemic 
steroids above the equivalent of 10 mg prednisone are 
excluded. 
d. Transient courses of steroids may be approved by the Medical 
Monitor on a case by case basis, dependent on dose and reason. 
12. Patients must not have a history of clinically manifested central nervous 
system (CNS) metastases. 
a. 
Patients with known or suspected leptomeningeal disease or 
cord compression are not eligible. 
13. Patients must not have had major surgery as determined by the PI within 
4 weeks before the first dose of study drug. 
14. Patients must not have received another investigational agent within the 
shorter of 4 weeks or 5 half-lives before the first dose of investigational 
agent. 
15. Patients must not have received a live attenuated vaccine within 28 days 
before the first dose of investigational agent, and patients, if enrolled, 
should not receive live vaccines during the study or for 180 days after the 
last dose of investigational agent. 
16. Females who are pregnant or lactating or who intend to become pregnant 
during participation in the study are not eligible to participate. 
17. Patients who have any clinically significant psychiatric, social, or medical 
condition that, in the opinion of the investigator, could increase the 
patient’s risk, interfere with protocol adherence, or affect the patient’s 
ability to give informed consent are ineligible to participate in the study. 
Planned Sample Size: 
Up to 24 DLT-evaluable patients will be enrolled in the Phase 1b portion of the 
study. A total of approximately 93 patients will be randomized/enrolled in 
Phase 2. Thus, the total sample size is expected to be approximately 117 
patients. 
Investigational Therapy: 
Phase 1b: 
APX005M (0.1 or 0.3 mg/kg) in combination with NP (125 mg/m2) and Gem 
(1000 mg/m2), all administrated intravenously (IV) 
OR 
APX005M (0.1 or 0.3 mg/kg) in combination with nivolumab (240 mg), NP 
(125 mg/m2) and Gem (1000 mg/m2), all administered IV 
 
Phase 2: 
Nivolumab (240 mg) in combination with NP (125 mg/m2) and Gem 
(1000 mg/m2), all administered IV 
OR 
APX005M (0.3 mg/kg) in combination with NP (125 mg/m2) and Gem 
(1000 mg/m2), all administrated IV 
OR 
APX005M (0.3 mg/kg) in combination with nivolumab (240 mg), NP 
(125 mg/m2) and Gem (1000 mg/m2), all administered IV 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
9 
 
Treatment Duration: 
Assuming all 4 cohorts are tested, upon completion of enrollment to Phase 1b, 1 
additional month of follow-up will occur before declaring the RP2D of 
APX005M. Then the Phase 2 portion of the study will have 12 additional 
months of follow-up. Target enrollment completion is within 24 months; 
however, enrollment will proceed until met or as determined by the study 
sponsor (Parker Institute for Cancer Immunotherapy [PICI]). Considering 
several months for data management and statistical analysis, the total duration 
of the study is likely to be 5 years. 
Patients will undergo screening and, if eligible, will undergo treatment in the 
assigned arm of the study until unacceptable toxicity, progression of disease, or 
withdrawal of consent. All patients will be followed for survival status until 
death or a maximum of 5 years. 
Study Endpoints: 
Phase 1b: 
Primary: 
• 
The frequency of DLT 
• 
The RP2D of APX005M when combined with NP/Gem or 
nivolumab/NP/Gem  
• 
The incidence of treatment-emergent AEs (TEAEs), serious adverse 
events (SAEs), and adverse events (AEs) causing discontinuation 
Secondary: 
• 
OR is determined by RECIST v1.1 
• 
DOR is defined as the time from first documentation of response 
(complete response [CR] or 
partial response [PR]) to first 
documentation of progressive disease (PD) 
Exploratory: 
• 
PK of APX005M will be determined in Cycles 1 to 4. 
• 
Immune pharmacodynamic endpoints may include, but are not limited 
to, the following: 
o Changes in the tumor microenvironment (including cellularity, 
stromal content, cellular infiltration, and tumor apoptosis) may be 
assessed by tumor multiplex immunohistochemistry or other 
appropriate technology. Pharmacodynamic and PK parameters, if 
available, may be used to influence the RP2D. 
o Gene expression may be determined by tumor RNA sequencing, 
peripheral blood RNA sequencing, or other appropriate technology. 
Other sequencing technologies, such as ATAC sequencing, may be 
performed. 
o Tumor genomics may be determined when possible by Clinical 
Laboratory Improvement Amendment-certified mutational panel 
assessments and/or by whole exome sequencing. 
o For variant calling and human leukocyte antigen (HLA) 
determination, normal tissue whole exome sequencing may be 
performed. In some cases, data regarding germ-line BRCA1/2 
mutations or microsatellite instability may be incorporated into 
analyses. 
o Cytokine and/or circulating factor analysis may be determined by a 
multiplex assay or other appropriate technology. 
o Flow cytometry or other related technologies, such as CyTof analysis 
of peripheral blood, may be used to assess phenotype, function, and 
other changes in immune cellular subsets. 
o Other markers to measure tumor burden, including circulating tumor 
DNA, tumor cells, and protein markers, may be measured in an 
exploratory fashion if material is available 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
10 
 
Phase 2: 
Primary: 
• 
OS is defined as the time from initiation of study therapy to date of death 
due to any cause or date of most recent patient contact. Patients who 
have not died are censored on their most recent contact date. 
• 
1-year OS rate in each treatment arm. 
Secondary: 
• 
Investigators’ assessment of OR is determined by RECIST v1.1 and the 
ORR is defined as the proportion of patients who achieve a CR or PR. 
• 
DCR is defined as the proportion of patients who achieve a CR or PR or 
SD. 
• 
DOR is defined as the time from first documentation of response (CR 
or PR) to first documentation of PD. 
• 
PFS is defined as the time from initiation of study therapy to date of first 
documented progression of disease, date of death due to any cause or 
date of most recent patient contact which documented progression-free 
status (i.e., clinic visit date or scan date). Patients who have not 
progressed or died are censored on their most recent progression-free 
date. 
• 
The incidence of AEs defined as unacceptable toxicities in Phase 2, 
TEAEs, SAEs, and AEs causing treatment discontinuation 
• 
Clinical laboratory data and vital signs (descriptive statistics) and 
numbers of patients with values outside limits of the normal range at 
each time point. 
Exploratory: 
• The exploratory endpoints for Phase 2 are the same as those described 
above for Phase 1b with the addition of evaluation of baseline and on-
treatment microbiome profiles with treatment outcomes. 
Statistical Methods and 
Planned Analyses: 
This is a multi-center, open-label Phase 1b/2 study of CD40 agonistic 
monoclonal antibody, APX005M, and/or PD-1 blocking antibody, nivolumab, 
in combination with NP and Gem and for patients with newly diagnosed 
metastatic pancreatic cancer. The primary objectives of the Phase 1b study are 
to determine the feasibility, safety and DLT of each treatment cohort and to 
determine the RP2D of APX005M in combination with NP/Gem and with 
nivolumab/NP/Gem. The primary objective of the randomized Phase 2 study is 
to evaluate OS in three treatment arms: nivolumab/NP/Gem, 
NP/Gem/APX005M and nivolumab/NP/Gem/APX005M by comparing the 
1-year OS rate with the historical value for NP/Gem. 
The safety population consists of all patients who received at least 1 dose of any 
study drug. This is the population for the primary analyses of safety. 
The DLT-evaluable population consists of patients who received 2 or 3 doses 
of NP/Gem and 1 dose of APX005M during Cycle 1, thus have completed the 
DLT observation period (ie, from the time of first administration of study drugs 
until prior to Cycle 2 Day 1) Patients who do not meet these criteria will be 
replaced in Phase 1b only, to assist with DLT and RP2D decision-making. 
The 
efficacy 
population 
consists 
of 
(1) 
all 
patients 
who 
were 
randomized/enrolled in Phase 2 and received at least 1 dose of any study drug 
and (2) the 12 DLT-evaluable patients (6 on Arm B and 6 on Arm C) who were 
enrolled in Phase 1b at the RP2D. The efficacy population is the population for 
the primary analyses of efficacy. 
Phase 1b Design: Four treatment cohorts will be evaluated for feasibility and 
safety. Cohorts B1 and B2 will escalate the dose of APX005M when combined 
with NP/Gem, and then Cohorts C1 and C2 will escalate the dose of APX005M 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
11 
 
when combined with nivolumab/NP/Gem. Enrollment in Cohorts B2 and C1 may 
occur concurrently. Enrollment in Cohort C2 may begin once enrollment in 
Cohort C1 has been completed. Approximately 6 DLT-evaluable patients will be 
enrolled in each cohort. A1 (nivolumab/NP/Gem) will not be tested in Phase 1b, 
since an external study is being conducted to confirm the safety of nivolumab in 
combination with NP/Gem. 
Statistical analyses will include the following: 
• 
The number of patients treated in each cohort will be reported, and 
reasons why any patient is not DLT evaluable will be summarized. 
• 
Approximately 6 DLT-evaluable patients will be fully analyzed in each 
treatment cohort. 
• 
Feasibility issues will be described for each treatment cohort. 
• 
Toxicities will be graded by NCI-CTCAE, causality attributed, and 
tabulated by treatment cohort. 
• 
RP2D of APX005M when combined with NP/Gem and with 
nivolumab/NP/Gem will be determined. 
• 
RECIST OR will be scored and tabulated along with DOR, by treatment 
cohort. 
• 
PK of APX005M. 
• 
Immune pharmacodynamic effects will be measured, including change 
from baseline, and reported by treatment cohort. 
 
Phase 2 Design: Once the RP2D of APX005M has been defined, the randomized 
Phase 2 portion of the study will commence. Patients will be randomized to one 
of 3 arms, defined by the addition of one or more immunotherapy agents to 
standard of care NP/Gem. The arms will be either A1 vs B2 vs C2 or A1 vs B1 
vs C1. Note that the APX005M dose must be the same in Arms B and C, 
regardless of whether a higher APX005M dose was determined to be safe in Arm 
B. For each regimen, efficacy will be evaluated by comparing the 1-year overall 
survival (OS) rate to the historical value for NP/Gem. 
Statistical analyses will include the following: 
• 
Thirty-five patients will be analyzed on each treatment arm. Twelve 
DLT-evaluable patients from Phase 1b (Arms B and C) and 93 patients 
from Phase 2 will comprise the population for the final analysis of 
efficacy. 
• 
OS will be estimated by the Kaplan-Meier method for each treatment 
arm. 
• 
The 1-year OS rate and 1-sided 95% confidence interval (CI) will be 
calculated for each treatment arm, to determine whether the lower bound 
of the CI excludes the historical value for NP/Gem. A 1-sided one-
sample Z test will also be conducted. The goal is to compare the survival 
probability at 1-year to the historical value of 0.35. 
• 
ORR and DCR and their 95% CIs will be calculated for each treatment 
arm. 
• 
PFS will be estimated by the Kaplan-Meier method for each treatment 
arm.  
• 
DOR will be calculated from dates of first documented response and 
progression of disease. 
• 
Toxicities will be graded by CTCAE v4.03 and tabulated by treatment 
arm.  
• 
PK of APX005M in Cycles 1 to 4 (Arms B and C). 
• 
Immune pharmacodynamic effects may be measured, including but not 
limited to change from baseline, and reported by treatment arm. 
• 
Test of associations between immune biomarkers and clinical outcomes  


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
12 
 
• 
Construct multivariable linear models to dissect the pharmacodynamic 
effects of APX005M and nivolumab on immune biomarkers. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
13 
 
2 
TABLE OF CONTENTS 
1 
SYNOPSIS....................................................................................................................... 4 
2 
TABLE OF CONTENTS............................................................................................... 13 
IN-TEXT TABLES .............................................................................................. 19 
IN-TEXT FIGURES ............................................................................................. 20 
3 
LIST OF ABBREVIATIONS ........................................................................................ 21 
4 
INTRODUCTION ......................................................................................................... 25 
4.1 
Background on Metastatic Pancreatic Cancer ....................................................25 
4.2 
Background on APX005M .................................................................................27 
4.2.1 
Pharmacology ......................................................................................27 
4.2.2 
Pharmacokinetics .................................................................................28 
4.2.3 
Clinical Experience ..............................................................................28 
4.2.4 
Summary of the Known and Potential Risks and Benefits ..................29 
4.2.5 
Dose Rationale .....................................................................................30 
4.3 
Background on Nivolumab .................................................................................30 
4.3.1 
Clinical Studies of Nivolumab .............................................................30 
4.4 
Background on Gemcitabine and nab-Paclitaxel ................................................32 
4.5 
Rationale .............................................................................................................33 
5 
STUDY OBJECTIVES AND ENDPOINTS ................................................................. 35 
5.1 
Study Objectives .................................................................................................35 
5.1.1 
Phase 1b ...............................................................................................35 
5.1.1.1 Primary Objectives: ...............................................................35 
5.1.1.2 Secondary Objectives: ...........................................................35 
5.1.1.3 Exploratory Objectives:.........................................................35 
5.1.2 
Phase 2 .................................................................................................35 
5.1.2.1 Primary Objectives: ...............................................................35 
5.1.2.2 Secondary Objectives: ...........................................................35 
5.1.2.3 Exploratory Objectives:.........................................................35 
5.2 
Study Endpoints ..................................................................................................36 
5.2.1 
Phase 1b ...............................................................................................36 
5.2.1.1 Primary Endpoints .................................................................36 
5.2.1.2 Secondary Endpoints .............................................................36 
5.2.1.3 Exploratory Endpoints...........................................................36 
5.2.2 
Phase 2 .................................................................................................37 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
14 
 
5.2.2.1 Primary Endpoints .................................................................37 
5.2.2.2 Secondary Endpoints .............................................................37 
5.2.2.3 Exploratory Endpoints...........................................................37 
6 
INVESTIGATIONAL PLAN ........................................................................................ 38 
6.1 
Description of Overall Study Design and Plan ...................................................38 
6.1.1 
Duration of Study Participation ...........................................................40 
6.1.2 
Total Number of Patients .....................................................................41 
6.1.3 
Early Termination Rules for Unacceptable Toxicity in Phase 2..........41 
6.1.4 
Treatment Beyond Unequivocal Disease Progression .........................41 
7 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................. 42 
7.1 
Inclusion Criteria ................................................................................................42 
7.1.1 
Childbearing Potential and Highly Effective Methods of Contraception
..............................................................................................................43 
7.2 
Exclusion Criteria ...............................................................................................44 
7.3 
Discontinuation, Withdrawal, and Replacement of Patients ..............................46 
7.3.1 
Discontinuation of Study Drug ............................................................46 
7.3.2 
Withdrawal/Discontinuation of Patients ..............................................47 
7.3.3 
Replacement of Patients .......................................................................47 
7.4 
Follow-Up for Drug Discontinuation/Patient Withdrawal from Study ..............47 
7.5 
Lost to Follow-Up ...............................................................................................48 
7.6 
Study Termination ..............................................................................................48 
8 
TREATMENTS ............................................................................................................. 49 
8.1 
Details of Study Treatments................................................................................50 
8.1.1 
APX005M ............................................................................................50 
8.1.2 
Nivolumab............................................................................................51 
8.1.3 
Nab-Paclitaxel ......................................................................................52 
8.1.4 
Gemcitabine .........................................................................................54 
8.2 
Preparation and Administration of Study Treatment ..........................................57 
8.2.1 
APX005M ............................................................................................57 
8.2.2 
Nivolumab............................................................................................57 
8.2.3 
Nab-paclitaxel ......................................................................................57 
8.2.4 
Gemcitabine .........................................................................................58 
8.3 
Monitoring Following APX005M Administration .............................................58 
8.4 
Dosage Schedule .................................................................................................58 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
15 
 
8.5 
Management of Study Drug-Related Toxicities .................................................59 
8.5.1 
Day 1 ....................................................................................................60 
8.5.2 
Day 3 ....................................................................................................62 
8.5.3 
Day 8 ....................................................................................................64 
8.5.4 
Day 15 ..................................................................................................66 
8.5.5 
Criteria for Treatment Continuation within a Cycle ............................69 
8.5.6 
APX005M, NP, and Gem Dose Modifications ....................................70 
8.6 
Study Treatment Assignment ..............................................................................70 
8.6.1 
Phase 1b ...............................................................................................70 
8.6.2 
Phase 2 .................................................................................................70 
8.7 
Blinding...............................................................................................................71 
8.8 
Treatment Accountability and Compliance ........................................................71 
8.9 
Prior and Concomitant Illnesses and Medications ..............................................71 
8.9.1 
Prior and Concomitant Illnesses ..........................................................71 
8.9.2 
Prior and Concomitant Medications ....................................................71 
8.9.3 
Prohibited Medications ........................................................................72 
9 
STUDY PROCEDURES ............................................................................................... 73 
10 
EFFICACY ASSESSMENTS ....................................................................................... 83 
10.1 
Response Criteria ................................................................................................84 
10.1.1 
Definitions of Measurable and Non-Measurable Disease ...................84 
10.1.2 
Guidelines for Evaluation of Measurable Disease ...............................84 
10.1.3 
Measurement of Effect .........................................................................85 
10.1.3.1 Target Lesions .....................................................................85 
10.1.3.2 Non-Target Lesions .............................................................85 
10.1.3.3 Response Criteria ................................................................85 
10.1.3.4 Evaluation of target lesions .................................................85 
10.1.3.5 Evaluation of non-target lesions ..........................................86 
10.1.3.6 Overall Objective Status......................................................86 
11 
PHARMACOKINETICS AND PHARMACODYNAMICS ........................................ 87 
11.1 
Pharmacokinetic Sampling .................................................................................87 
11.1.1 
Blood Samples .....................................................................................87 
11.1.2 
Analytical Methodology ......................................................................87 
11.2 
Immune Endpoints ..............................................................................................87 
11.2.1 
Immune Biomarkers.............................................................................88 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
16 
 
11.2.3 
Anti-drug antibodies ............................................................................89 
12 
SAFETY ASSESSMENTS............................................................................................ 90 
12.1 
Vital Signs ...........................................................................................................90 
12.2 
Physical Examination..........................................................................................90 
12.3 
Electrocardiogram ...............................................................................................90 
12.4 
Laboratory Assessments .....................................................................................90 
12.5 
Adverse Events, Adverse Events of Special Interest, and Serious Adverse 
Events ..................................................................................................................91 
12.5.1 
Time Period and Frequency for Collecting Adverse Events, Serious 
Adverse Events, and Other Reportable Safety Event Information ......91 
12.5.2 
Definition of Adverse Events...............................................................92 
12.5.2.1 Definition of Serious Adverse Events .................................92 
12.5.2.2 Definition of Adverse Events of Special Interest ................93 
12.5.3 
Recording Adverse Events ...................................................................93 
12.5.4 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events ..................95 
12.5.5 
Serious Adverse Event Reporting ........................................................95 
12.5.6 
Regulatory Reporting Requirements for Serious Adverse Events .......96 
12.5.6.1 Sponsor Reporting of Serious Adverse Events ...................96 
12.5.7 
Pregnancy .............................................................................................96 
12.5.8 
Overdose ..............................................................................................97 
13 
STATISTICAL ANALYSIS ......................................................................................... 98 
13.1 
Determination of Sample size ...........................................................................102 
13.1.1 
Phase 1b .............................................................................................102 
13.1.2 
Phase 2 ...............................................................................................102 
13.2 
Analysis Populations .........................................................................................103 
13.3 
Demographic and Baseline Characteristics ......................................................103 
13.4 
Efficacy Analysis ..............................................................................................103 
13.4.1 
Primary Efficacy Endpoint ................................................................103 
13.4.2 
Secondary Efficacy Endpoints ...........................................................104 
13.4.3 
Exploratory Endpoints .......................................................................104 
13.5 
Pharmacokinetic Analysis .................................................................................105 
13.6 
Safety Endpoints ...............................................................................................105 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
17 
 
13.6.1 
Phase 1b: Assessing Feasibility, Dose-Limiting Toxicity, and 
Recommended Dose for Phase 2 .......................................................105 
13.6.2 
Analysis of Adverse Events ...............................................................105 
13.7 
Interim Analysis ................................................................................................106 
13.8 
Data Monitoring ................................................................................................106 
13.8.1 
Data Review Team (DRT) .................................................................106 
14 
STUDY MANAGEMENT .......................................................................................... 107 
14.1 
Approval and Consent.......................................................................................107 
14.1.1 
Regulatory Guidelines .......................................................................107 
14.1.2 
Institutional Review Board/Independent Ethics Committee..............107 
14.1.3 
Informed Consent...............................................................................107 
14.2 
Data Handling ...................................................................................................107 
14.3 
Source Documents ............................................................................................108 
14.4 
Record Retention ..............................................................................................108 
14.5 
Monitoring ........................................................................................................108 
14.6 
Quality Control and Quality Assurance ............................................................108 
14.7 
Protocol Amendments and Protocol Deviations ...............................................109 
14.7.1 
Protocol Amendments ........................................................................109 
14.7.2 
Protocol Deviations ............................................................................109 
14.8 
Ethical Considerations ......................................................................................109 
14.9 
Financing and Insurance ...................................................................................109 
14.10 Publication Policy / Disclosure of Data ............................................................109 
15 
REFERENCES ............................................................................................................ 110 
16 
APPENDICES ............................................................................................................. 114 
16.1 
ECOG Performance Scale.................................................................................114 
16.2 
Nivolumab Toxicity Management Guide .........................................................115 
16.3 
Guidance for the Management of Infusion Reaction/Cytokine Release 
Syndrome ..........................................................................................................123 
16.4 
Document Revision History ..............................................................................124 
16.4.1 
Key Revisions in Amendment 1 ........................................................124 
16.4.2 
Key Revisions in Amendment 2 ........................................................124 
16.4.3 
Key Revisions in Amendment 3 ........................................................125 
16.4.4 
Key Revisions in Amendment 4 ........................................................127 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
18 
 
16.4.5 
Key Revisions in Amendment 5 ........................................................130 
16.4.6 
Key Revisions in Amendment 6 ........................................................132 
16.4.7 
Key Revisions in Amendment 7 ........................................................135 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
19 
 
IN-TEXT TABLES 
Table 1 
Highly Effective Methods of Contraception ...........................................................44 
Table 2 
Study Cohorts/Arms ................................................................................................49 
Table 3 
Treatment Regimens and Schedules .......................................................................58 
Table 4 
Management of Study Treatment-Related Toxicities on Day 1..............................60 
Table 5 
Management of Study Treatment-Related Toxicities on Day 3..............................63 
Table 6 
Management of Study Treatment-Related Toxicities on Day 8..............................64 
Table 7 
Management of Study Treatment-Related Toxicities on Day 15............................66 
Table 8 
APX005M, NP, and Gem Dose Modifications .......................................................70 
Table 9 
Phase 1b Treatment Assignment .............................................................................70 
Table 10 Phase 2 Design ........................................................................................................71 
Table 11 Schedule of Assessments (For Arms Including APX005M, Phase Ib)...................74 
Table 12 Schedule of Assessments (For Arms Including APX005M, Phase 2) ....................77 
Table 13  Schedule of Assessments (For Arms Not Including APX005M, Phase 2) ..............80 
Table 14 Laboratory Assessments .........................................................................................91 
Table 15 Classification of Adverse Events by Intensity ........................................................94 
Table 16 Classification of Adverse Events by Relationship to Study Drug ..........................94 
Table 17 Phase 1b Statistical Design .....................................................................................99 
Table 18 Phase 2 Statistical Design .....................................................................................100 
Table 19 Bayesian Termination Rules .................................................................................101 
Table 20 ECOG Performance Scale .....................................................................................114 
Table 21 Infusion-related Reaction/Cytokine Release Syndrome Management 
Recommendations .................................................................................................123 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
20 
 
IN-TEXT FIGURES 
Figure 1 Study Flow Chart ....................................................................................................38 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
21 
 
3 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody(ies) 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
AESI 
Adverse event(s) of special interest 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
Absolute neutrophil count 
APC 
Antigen-presenting cell 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
AUC 
Area under the plasma concentration-time curve 
BLOQ 
Below the limit of quantitation 
BUN 
Blood urea nitrogen 
CD 
Cluster of differentiation 
Cavgss 
Average concentration at steady state 
Cmin1 
Minimum concentration at 1 hour 
Cminss 
Minimum concentration at steady state 
Cmax 
Maximum serum concentration 
Cmaxss 
Maximum concentration at steady state 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CR 
Complete response 
CRF 
Case Report Form 
CT 
Computed tomography 
CTCAE 
Common Terminology for Cancer Adverse Events 
DC 
Dendritic cell 
dCTP 
Deoxycytidine triphosphate 
DILI 
Drug-induced liver injury 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
22 
 
DRT 
Data Review Team 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EOI 
End of infusion 
EOT 
End of treatment 
Fc 
Fragment crystallizable region 
FDA 
Food and Drug Administration 
FDG-PET/CT 
Positive emission tomography/computed tomography using 
fluorodeoxyglucose 
FT3 
Free Triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
Gem 
Gemcitabine 
GGT 
Gamma-glutamyl transpeptidase 
GLP 
Good Laboratory Practices 
HCG 
Human chorionic gonadotropin 
HB 
Hepatitis B 
HCV 
Hepatitis C virus 
HEENT 
Head, eye, ear, nose and throat examination 
HIPPA 
Health Insurance Portability Accountability Act 
HLA 
Human leukocyte antigen 
HSR 
Hypersensitivity reaction 
HUS 
Hemolytic uremic syndrome 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
i.p. 
Intraperitoneally 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
MCH 
Mean corpuscular hemoglobin 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
23 
 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
Natural killer 
NOAEL 
No observed adverse effect 
NP 
Nab-paclitaxel/Abraxane 
NSCLC 
Non-small-cell lung cancer 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PC 
Pancreatic cancer 
PD 
Progressive disease or pharmacodynamic 
PDA 
Pancreatic ductal adenocarcinoma 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PR 
Partial response 
RBC 
Red blood cell 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SAERF 
Serious Adverse Event Report Form 
SD 
Stable disease 
T3 
Triiodothyronine 
TEAE 
Treatment-emergent adverse event 
TME 
Tumor immune microenvironment 
TNFR 
Tumor necrosis factor receptor 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper limit of normal 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
24 
 
WBC 
White blood cell 
WES 
Whole exome sequencing 
WOCB 
Women of childbearing potential 
US 
United States 
USP 
United States Pharmacopeia 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
25 
 
4 
INTRODUCTION 
4.1 
Background on Metastatic Pancreatic Cancer 
Pancreatic cancer (PC) is one of the most lethal malignancies of the gastrointestinal tract, with 
a 5-year survival of about 8%. In the United States (US) an estimated total of 53,070 PCs will 
occur in 2016, with 41,780 estimated deaths among these patients. In 2016, PC surpassed 
breast cancer to become the third leading cause of cancer death in the US and is projected to 
become the second leading cause of cancer death by 2030.1 There are several potential reasons 
for the increased mortality associated with pancreatic adenocarcinoma. First, the majority of 
patients are diagnosed with pancreatic adenocarcinoma at an advanced stage, when the patient 
has unresectable disease and is therefore incurable. Even in the 15% to 20% of patients with 
resectable, and therefore potentially curable, disease at diagnosis, only about 10% to 15% of 
those patients are alive at 5 years with surgery alone. This only improves to 20% to 25% with 
gemcitabine (Gem) and/or concurrent chemoradiation adjuvant therapy.2-4 The low survival 
associated with resectable disease is thought to be due to microscopic metastases emerging 
early in the course of PC development. Furthermore, PC tends to be relatively resistant to 
chemotherapy, which accounts for the modest benefit of adjuvant therapy as noted above. Even 
with the development of more aggressive and effective regimens – namely FOLFIRINOX and 
Gem and nab-paclitaxel (NP) – the median overall survival (OS) is still less than a year for 
patients with metastatic pancreatic adenocarcinoma.5,6 Continued advancements in treatment 
of pancreatic adenocarcinoma are imperative. 
Immunotherapy 
Among the promising approaches to activating therapeutic antitumor immunity is the 
modulation of host immune system. Immune modulation includes inhibitory or stimulatory 
pathways in the immune system that are crucial for activating the immune response, 
maintaining self-tolerance, and modulating the duration and amplitude of physiological 
immune responses. Modulation of immune checkpoints by antibodies against immune 
inhibitory molecules has shown clinical benefits for patients with malignancies such as 
melanoma.7,8 Currently, antagonistic antibodies against immune inhibitory molecules such as 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1)/
programmed cell death ligand-1 (PD-L1) and agonistic antibodies against immune 
costimulatory molecules such as cluster of differentiation (CD)40 are under active 
development for different cancer indications. To date, the anti-CTLA4 antibody ipilimumab is 
US Food and Drug Administration (FDA) approved for use in metastatic melanoma both as a 
single agent or in combination with PD-1 inhibitors (nivolumab). The PD-1 inhibitors 
nivolumab and pembrolizumab are now approved in various diseases. 
Immunotherapy in Pancreatic Cancer 
While checkpoint inhibitors have been effective in melanoma and lung cancer, clinical benefit 
of CTLA-4 and PD-1 inhibitors as single agents in the management in PC patients has not been 
noted.9,10 Current immunotherapy studies utilize a combination of traditional anti-cancer 
therapy with checkpoint inhibitors, vaccines, or other immunotherapy agents as single or 
combination therapies, such as CD40 monoclonal antibodies (mAbs).11 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
26 
 
In this study, we are evaluating the combination of a CD40 agonist, APX005M, with a PD-1 
inhibitor, nivolumab, and standard chemotherapy for pancreatic adenocarcinoma, Gem and NP. 
CD40 Monoclonal Antibodies 
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 antigen presenting cells (APCs).12 
CD40 is expressed by dendritic cells (DCs), B cells, monocytes, and some non-lymphoid 
cells.13 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 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.14,15 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% to 70% of primary 
human solid tumor samples, including melanoma and carcinomas16 and 25% of PCs.17 
Activation of CD40 on tumor cells results in tumor cell apoptosis and inhibition of tumor 
growth.18 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.19-22 
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. 
A few CD40 agonistic antibodies have been evaluated in human clinical studies. Objective 
responses (ORs) have been observed with nearly every CD40 antibody formulation used as 
single agents across a variety of diseases, including PC. Toxicities have been transient and 
manageable. The majority of the clinical studies in cancer patients with solid tumors have been 
conducted with the fully human immunoglobulin G (IgG)2 CD40 antibody CP-870,893. In a 
Phase 1 clinical study, CP-870,893 was well tolerated; the maximum tolerated dose (MTD) 
was found to be 0.2 mg/kg. The main toxicity of CP-870,893 was cytokine release syndrome 
of mild to moderate severity. Antitumor activity was observed in several melanoma patients 
treated with CP-870,893.23,24 
One study indicated that CP-870,893 can also mediate an antitumor effect when combined with 
chemotherapy in patients with metastatic PC.25 Other CD40 agonistic antibodies that have 
been studied in human clinical studies are SGN-40 and ChiLob 7/4. SGN-40 is an IgG1 
humanized anti-CD40 antibody that is a weak CD40 agonist, which has been tested 
predominantly in hematological malignancies as monotherapy or in combination with 
rituximab and chemotherapy.26,27 The major adverse effects of SGN-40 were anemia, pleural 
effusion, and thrombocytopenia.26 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
27 
 
SEA-CD40 is an engineered version of SGN-40. SEA-CD40 and SGN-40 have the same amino 
acid sequences, but the fragment crystallizable (Fc) region of SEA-CD40 is defucosylated, 
leading to increased binding to and cross-linking by FcγRIIIa. 
ChiLob 7/4 is an IgG1 chimeric CD40 agonistic antibody that has been tested in a Phase 1 
clinical study in patients with solid tumors. The MTD of ChiLob 7/4 is 200mg/weekly × 4, and 
the major dose-limiting toxicity (DLT) was reversible liver enzyme elevation.28 Although 
CP-870,893 has potent CD40 agonistic activities, it is an IgG2 antibody, and thus lacks 
antibody effector functions that constitute an important mechanism of action for CD40 
antibody-mediated antitumor activities.24 Due to its chimeric structure, ChiLob 7/4 might be 
immunogenic, especially considering that the immune response is boosted by its CD40 
agonistic effects. 
ADC-1013 is a fully human IgG1 CD40-agonistic antibody in Phase 1 clinical trial for 
treatment of solid tumors.29 ADC-1013 is intended for intra-tumoral delivery. 
SGN-40 is an IgG1 antibody, but a weak CD40 agonist. Due to its chimeric structure, 
ChiLob 7/4 may potentially be more immunogenic considering that the immune response may 
be boosted by its CD40-agonistic effects. ADC-1013 has similar binding affinity as APX005M 
but is a weaker CD40-agonistic antibody likely due to its lack of binding to FcγRIIb. Although 
SEA-CD40 has increased potency compared with SGN-40, its high-affinity binding to 
FcγRIIIa may lead to enhanced antibody effector functions such as antibody-dependent cell-
mediated cytotoxicity (ADCC) on CD40-expressing cells such as DCs and B cells. 
An IgG1 humanized antibody that can utilize Fc receptors to cluster CD40 and enhance CD40-
agonistic effects, like APX005M, might be preferable both in terms of potential decreased 
immunogenicity and increased anti-tumor activity for use in cancer immunotherapy. 
4.2 
Background on APX005M 
4.2.1 
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.31 
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 interferon-gamma (IFN-γ) in response to viral antigens, and enhances T-cell 
response to tumor antigens. APX005M combined with a toll-like receptor 4 (TLR4) agonist or 
an antibody against 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 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
28 
 
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 [APX005M IB]. These data suggest that APX005M, as a 
single agent, can induce potent growth inhibition of CD40-expressing human tumors. 
Preliminary human data show that APX005M induces a dose-dependent activation of APCs 
(as demonstrated by increases in expression of activation markers such as CD54, CD70, CD80, 
CD86, human leukocyte antigen [HLA]-DR), T cell activation and increases in circulating 
levels of interleukin (IL)12, IFN-γ, TNF-α and IL6. 
4.2.2 
Pharmacokinetics 
Nonclinical pharmacokinetics (PK) of APX005M were determined in a Good Laboratory 
Practice (GLP) repeat-dose toxicology study using cynomolgus monkeys. Weekly intravenous 
(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) [IB]. 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. In the first in human study of 
APX005M, 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 led 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. 
4.2.3 
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 DLT-evaluable subjects experienced a DLT 
(Grade 4 cytokine release syndrome). Two additional subjects at the 1 mg/kg dose level 
experienced serious adverse events (SAE) in later cycles (Grade 3 cytokine release syndrome 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
29 
 
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 of APX005M 
and to help establish the single agent recommended Phase 2 dose (RP2D). 
As of 08 November 2016, 30 subjects have received APX005M with a median exposure of 
3 cycles and had 321 adverse events (AE): 
• 89% of AEs were ≤ Grade 2. 
• 9% AEs were Grade 3. 
• 1.5% of AEs were Grade 4. 
• The majority of AEs were considered unrelated to APX005M by the Investigator. 
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, IFN-γ, TNF-α and IL6. 
For further details on the APX005M-001 study, please refer to latest version of the APX005M 
Investigator’s Brochure (IB). 
4.2.4 
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 patients 
receiving APX005M. Guidance for monitoring and management of cytokine release syndrome 
are included in Section 16.3 of this protocol and in the APX005M IB.  
Transient transaminase elevations (≤ Grade 2) have been observed in several patients with liver 
metastases, which were not associated with a particular dose of APX005M. Six patients 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 pharmacodynamic effect. Transient decreases in platelet counts were 
observed for some of the patients 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 ongoing Phase 1 study APX005M-001, APX005M demonstrated a dose-dependent 
activation of APCs, T cell activation and increases in circulating levels of cytokines. 
The biological effects and the overall tolerability of APX005M up to 1 mg/kg suggest a best 
in class profile for APX005M and the possibility of a safe and tolerable combination with other 
immunomodulatory antibodies such as nivolumab. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
30 
 
4.2.5 
Dose Rationale 
APX005M has been administered in the APX005M-001 study to patients with solid tumors as 
a single agent at 7 dose levels starting at 0.1 mg/kg up to 1.0 mg/kg every 21 days. At 0.6 and 
1 mg/kg dose levels 1 out of 6 patients experienced a DLT. The RP2D for APX005M as a 
single agent every 21 days is 0.3 mg/kg. 
The proposed doses of APX005M are 0.1 mg/kg (10 times lower than the highest dose of 
APX005M administered to human patients) and 0.3 mg/kg (approximately 3.3 times lower 
than the highest dose of APX005M administered to human patients).  
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 0.1 and 0.3 mg/kg every 21 days is a safe and pharmacodynamically active dose 
of APX005M. 
4.3 
Background on Nivolumab 
Nivolumab is a fully human monoclonal immunoglobulin G4 that targets the PD-1 blocking 
antibody. PD-1, also known as CD279, is a cell surface membrane receptor predominantly 
expressed on activated T and B lymphocytes and memory T lymphocytes and, when bound to 
its ligands PD-L1 or programmed cell death ligand-2 (PD-L2), negatively regulates the 
immune system. While PDL-1 and PDL-2 are commonly expressed on DCs and other APCs, 
a variety of different tumor cells can also express these ligands.32 
4.3.1 
Clinical Studies of Nivolumab 
Nivolumab is a human IgG4 mAb has specific FDA-approved indications in multiple diseases: 
metastatic melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), 
squamous cell carcinoma of the head and neck, and Hodgkin’s disease. Single-agent 
nivolumab has been studied33 at doses of 0.1 to 10 mg/kg every 2 weeks (Q2W) in 296 subjects 
with melanoma (n = 104), NSCLC (n = 122), castration-resistant prostate cancer (n = 17), RCC 
(n = 34), or colorectal carcinoma (n = 19). Drug-related Grade 3 or 4 AEs occurred in 14% of 
subjects, and there were 3 deaths from pulmonary toxicity. No MTD was defined at the doses 
tested. A relative dose intensity of ≥ 90% was achieved in 86% of subjects. Fifteen of 
296 subjects (5%) discontinued due to treatment-related AEs. The most common AEs, 
irrespective of causality, were fatigue, anorexia, diarrhea, nausea, cough, dyspnea, constipation, 
vomiting, rash, pyrexia, and headache. Common treatment-related AEs included fatigue, rash, 
diarrhea, pruritus, anorexia and nausea. The most common (≥ 5%) Grade ≥ 3 AEs included 
fatigue (5%). Treatment-related SAEs occurred in 32 of 296 subjects (11%) and > 1% included 
pneumonitis (2%). Drug-related events of special interest included pneumonitis, vitiligo, 
colitis, hepatitis, hypophysitis, uveitis, and thyroiditis. The spectrum, frequency and severity 
of treatment-related AEs were similar across dose levels tested. 
Antitumor activity was observed at all doses tested. ORs were observed NSCLC, melanoma, 
and RCC and in sites of metastasis including liver, lung, lymph nodes and bone. In subjects 
with NSCLC, ORs were observed at doses of 1.0, 3.0, or 10.0 mg/kg with rates of 6%, 32%, 
and 18% respectively. Responses were observed in 6/18 subjects with squamous tumors (33%), 
in 7/56 (12%) of those with non-squamous histology, and in 1 of 2 (50%) of those with 
unknown histology. Stable disease (SD) lasting ≥ 24 weeks was observed in 7 subjects (7%) 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
31 
 
with lung cancer. In melanoma, 26 ORs were observed at doses ranging from 0.1 to 10.0 mg/kg. 
At a dose of 3.0 mg/kg ORs were observed in 7 of 17 subjects (41%). SD lasting ≥ 24 weeks 
was observed in 6 subjects (6%). In RCC, ORs were seen in 4 of 17 subjects (24%) treated 
with 1.0 mg/kg and in 5 of 16 subjects (31%) treated with 10.0 mg/kg. SD lasting ≥ 24 weeks 
was observed in 9 subjects (27%). No responses were observed in subjects with colorectal or 
prostate cancer. 
A Phase 1 study has investigated nivolumab in combination with platinum-based doublet 
chemotherapy in chemotherapy-naïve NSCLC.34 Subjects with stage IIIB/IV NSCLC were 
randomized by histology to nivolumab (10 mg/kg Day 1/21)/Gem (1250 mg/m2 Days 1, 
8/21)/cisplatin (75 mg/m2 Day 1/21), nivolumab (10 mg/kg Day 1/21)/pemetrexed (500 mg/m2 
Day 1/21)/cisplatin (75 mg/m2 Day 1/21) or nivolumab (10 mg/kg Day 1/21)/carboplatin 
(AUC 6 Day 1/21)/paclitaxel (200 mg/m2 Day 1/21). Nivolumab doses were started at 
10 mg/kg every 3 weeks until progressive disease (PD); platinum doublet chemotherapy was 
given for a maximum of 4 cycles. Across the treatment arms of the study, no DLTs were seen 
at the 10 mg/kg nivolumab dose in combination with the platinum doublets. Tumor responses 
ranged from 33% to 47%, with carboplatin/paclitaxel in combination with nivolumab 10 mg/kg, 
demonstrating a 47% objective response rate (ORR). An additional arm assessed 
carboplatin/paclitaxel with 5 mg/kg nivolumab, which showed similar ORR of 43%, 
suggesting a lack of a correlation of dose with response at these doses tested. Across the arms, 
responses were durable, with an estimated median duration of 24 to 85 weeks. Median 
progression-free survival (PFS) in the carboplatin/paclitaxel arm in combination with 5 and 
10 mg/kg nivolumab was 31 and 21 weeks, respectively; and 1-year overall survival (OS) rate 
was 86% and 60%. The most common treatment-related Grade 3 or 4 AEs were pneumonitis 
(4 subjects, 7%), fatigue (3 subjects, 5%) and acute renal failure (3 subjects, 5%).34 
A Phase 1 study is exploring nivolumab in combination with taxanes chemotherapy in PC, 
NSCLC, and metastatic breast cancer. The interim results from the PC and NSCLC cohorts 
were published recently.35-36 
The primary objective of Part 1 is to evaluate DLTs. Subjects treated with ≥ 2 cycles of 
nivolumab with chemotherapy and remained on study for 14 calendar days or who 
discontinued due to DLT prior to completing 2 cycles of nivolumab were considered DLT 
evaluable. If deemed safe, treatment arms will be expanded in Part 2 to further assess safety, 
tolerability, and antitumor activity. In Arm A Part 1, subjects with advanced PC and 1 prior 
chemotherapy regimen received NP 125 mg/m2 on Days 1, 8, and 15 and nivolumab 3 mg/kg 
on Days 1 and 15 of a 28-day cycle.35-36 
If Arm A is safe, a cohort of CT-naive subjects will be enrolled in Arm B and treated with NP 
and Gem 1000 mg/m once weekly for 3 weeks of every 4 weeks + nivolumab. In Arm C, 
treatment-naive subjects with stage IIIB/IV NSCLC received 4 cycles of NP 100 mg/m2 on 
Days 1, 8, and 15 and carboplatin AUC 6 on Day 1 and nivolumab 5 mg/kg on Day 15 of a 
21-day cycle. If Arm C is safe, subjects in Arm D will receive the Arm C regimen, except 
nivolumab will start at Cycle 3. In both NSCLC arms, nivolumab monotherapy begins at 
Cycle 5.35-36 
As of June 28, 2016, 11 and 6 subjects were treated in Arms A and B in Part 1, respectively. 
No DLTs were reported in Arm A, and 1 in Arm B (nonimmune hepatitis, suspected to be due 
to Gem; resolved and subject continued nivolumab + NP without Gem). The most common 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
32 
 
Grade 3 or 4 treatment-emergent AEs were pulmonary embolism, neutropenia, and anemia in 
2 of 11 subjects (18%) in Arm A and anemia in 2 of 6 subjects (33%) in Arm B. Nine subjects 
discontinued due to PD (8 in Arm A, 1 in Arm B). Of the 9 response-evaluable subjects in 
Arm A, 2 had a partial response (PR), 4 had a SD and 3 had PD. Of the 6 response-evaluable 
subjects in Arm B, 3 had a PR and 3 had a SD.36 
It was concluded that adding nivolumab to NP ± Gem is feasible for subjects with advanced 
PC, and antitumor activity of this regimen appears to be encouraging.36 
Dose Rationale for Nivolumab 
The safety and efficacy of a 240 mg Q2W flat dose of nivolumab is expected to be similar to 
the 3 mg/kg Q2W dosing regimen. Per the nivolumab IB, a flat dose of nivolumab 240 mg 
Q2W was selected since it is identical to a dose of 3 mg/kg for subjects weighing 80 kg, the 
observed median body weight in nivolumab treated cancer subjects. Using a population PK 
model, the overall distributions of nivolumab exposures (average concentration at steady state 
[Cavgss], minimum concentration at steady state [Cminss], Cmaxss, and minimum concentration at 
1 hour [Cmin1]) are comparable after treatment with either 3 mg/kg or 240 mg nivolumab. The 
predicted range of nivolumab exposures (median and 90% prediction intervals) resulting from 
a 240 mg flat dose across the 35 to 160 kg weight range is maintained well below the 
corresponding exposures observed with the well tolerated 10 mg/kg nivolumab Q2W dosage. 
In a clinical study, 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 mg/kg). All 
the events were Grade 1 to 2 and were manageable. An infusion duration of 30 minutes for 
3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) 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-minute infusion 
was assessed in CA209153 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-minute infusion compared with that reported for subjects 
with the 60-minute infusion. Thus, it was shown that nivolumab can be safely infused over 
30 minutes. 
4.4 
Background on Gemcitabine and nab-Paclitaxel 
In 1996, Gem was approved for the management of metastatic pancreatic adenocarcinoma due 
to an improvement in median OS over 5-fluorouracil (5-FU; 5.65 versus 4.41 months).37 Gem 
monotherapy was the mainstay of treatment for over 10 years, before FOLFIRINOX 
demonstrated an improved 11.1-month median OS compared with 6.8 months with Gem 
monotherapy.5 Though there was a marked improvement in OS, FOLFIRINOX was also 
associated with significant AEs, including Grade 3 or 4 neutropenia (45.7%), neutropenic fever 
(5.4%), fatigue (23.6%), vomiting (14.5%), diarrhea (12.7%), and neuropathy (9%). 
In 2013, Gem and NP was approved for use in subjects with metastatic pancreatic 
adenocarcinoma, with studies demonstrating an 8.5-month median OS compared with 
5.7 months with Gem monotherapy. The most common Grade 3 or greater AEs associated with 
Gem and NP included neutropenia (38%), fatigue (17%), neutropenic fever (3%), and 
neuropathy (17%).6 Though Gem plus NP has not been compared head-to-head with 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
33 
 
FOLFIRINOX, the side effects from Gem and NP tend to be less frequent, and this result may 
better allow for testing additional chemotherapy combinations. Results from a randomized 
Phase 3 clinical study comparing NP plus Gem versus Gem alone in 861 first-line PC subjects 
showed subjects on NP plus Gem had a median survival of 8.5 months compared with 
6.7 months for those who received Gem alone.6 At the end of 1 year and 2 year, 35% and 9%, 
respectively, of those receiving the combination were alive, compared with 22% and 4% of 
those being treated with Gem only. Toxicities were modest and centered on reversible 
myelosuppression and peripheral neuropathy. 
4.5 
Rationale 
Scientific Summary 
Preclinical studies show that in mouse models of pancreatic carcinoma, the combination of 
Gem and NP with agonist CD40 mAb triggers an effective T cell response, for which clinical 
benefit can be safely extended with anti-PD-1. NP/Gem is poorly effective in this model as is 
either single agent CD40 or PD-1 mAb. Combination therapy, however, induces a robust T-cell 
response, marked infiltration of T cells into the tumor (not otherwise observed) and tumor 
response and increased survival. 
Clinical Summary 
Tumor regressions in patients with metastatic PC have been observed with NP/Gem, 
nivolumab/NP, nivolumab/NP/Gem, and Gem/CP870,893 (anti-CD40). The protocol now 
incorporates all four of these approaches by combining NP/Gem with nivolumab and 
APX005M (anti-CD40). 
Currently, no clinical data are available for the combination of APX005M plus Gem and NP 
with or without nivolumab. This combination is going to be explored in this Phase 1b/2 study, 
which includes a Phase 1b dose-finding part and a Phase 2 efficacy evaluation part in patients 
with previously untreated metastatic pancreatic adenocarcinoma (see Section 6.1 for study 
design details). The Phase 1 data will define the RP2D of APX005M when combined with the 
standard dose of Gem and NP, with or without nivolumab. 
Two doses for APX005M are being explored, based on data from its manufacturer, Apexigen, 
from findings of the first-in-human Phase 1 dose-escalation study. The doses of APX005M 
chosen for this study are 0.1 mg/kg (10 times lower than the highest dose of APX005M 
administered to human patients) and 0.3 mg/kg (the recommended single-agent dose; 
approximately 3.3 times lower than the highest dose of APX005M administered to human 
patients). Doses for nivolumab are based on prior experience of using this antibody in 
combination with Gem and NP. The doses of nivolumab, Gem, and NP selected for this study 
are per the FDA-approved US labeling. 
The second part of the study is aimed to evaluate in an exploratory manner the activity of 
APX005M combined with Gem and NP, with or without nivolumab in metastatic pancreas 
cancer patients. A randomization process will be used to avoid the potential bias in patient 
selection and to balance risk factors between treatment arms. 
Following FDA approval in 2013, the combination of Gem and NP has become a gold standard 
in the first-line setting for patient with metastatic PC; however, the prognosis remains poor. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
34 
 
This persistent unmet medical need in PC is directing researchers to explore new treatments, 
including immunological approaches. 
Nivolumab, a PD-1-specific antibody, has been shown to produce long-term remissions with 
limited toxicity in patients with advanced melanoma, and also showed activity in NSCLC, 
RCC, and Hodgkin’s lymphoma. So far, PC appeared refractory to single-agent checkpoint 
blockade alone.10 
Preclinical data support the rationale of this clinical study. A recent study using a genetically 
engineered mouse model of pancreatic ductal adenocarcinoma (PDA), which like human PDA 
exhibits minimal spontaneous immunity, demonstrated that despite robust expression of PD-1 
and PD-L1 in the tumor microenvironment, treatment with αPD-1 with or without αCTLA-4 
failed to improve the survival of mice or slow the growth of PDA tumors. However, 
administration of αCD40, Gem, and NP, induces T-cell immunity in mice with PDA, controls 
tumor growth and significantly improves survival in a CD8+ T-cell-dependent manner. In 
particular, αCD40/NP/Gem plus αPD-1 nearly doubles the median OS in genetically 
engineered Pdx1-Cre (KPC) mice with pre-established spontaneous pancreatic tumors.38 
Moreover, the capability of treated mice to reject second and third subcutaneous tumor 
challenges in a CD8+ T-cell-dependent fashion, thereby rendering long-term survival, suggests 
the establishment of antitumor immune memory with curative potential. These findings 
indicate that poorly immunogenic tumors, epitomized by the KPC pancreatic tumor model, can 
nevertheless be controlled by the adaptive immune system provided a dual approach of 
therapeutic T cell induction and checkpoint blockade is utilized. 
Mechanistically, a preclinical study in the KPC mouse model in PDA showed the ability of a 
single dose of αCD40 to alter T cells in the tumor immune microenvironment (TME), expand 
clonal T-cell populations, and convert the TME in PC to a site replete with infiltrating T cells.39 
In combination with a novel chemotherapy doublet, αCD40 treatment bypasses innate immune 
sensors to generate functional APCs and T cells, culminating in durable responses with 
curative potential, even in a highly immunosuppressive TME. 
In this study, we are evaluating the safety and efficacy of the combination of αCD40 agonist, 
APX005M, with a PD-1 inhibitor, nivolumab, and standard chemotherapy for pancreatic 
adenocarcinoma, Gem and NP. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
35 
 
5 
STUDY OBJECTIVES AND ENDPOINTS 
This study will be conducted in 2 phases, each with its own objectives and endpoints. 
5.1 
Study Objectives 
5.1.1 
Phase 1b 
5.1.1.1 
Primary Objectives: 
1. To determine the feasibility, safety, and DLTs of each treatment cohort. 
2. To determine the RP2D of APX005M when combined with NP/Gem. 
3. To determine the RP2D of APX005M when combined with nivolumab/NP/Gem. 
5.1.1.2 
Secondary Objectives: 
1. To determine OR and duration of response (DOR) of each treatment cohort. 
5.1.1.3 
Exploratory Objectives: 
1. To assess the PK of APX005M in Cycles 1 to 4. 
2. To assess immune pharmacodynamic effects of each treatment cohort, in both blood 
and tumor tissue. 
5.1.2 
Phase 2 
5.1.2.1 
Primary Objectives: 
1. To estimate the OS of each treatment arm. 
2. To compare 1-year OS rate of each treatment arm with the historical rate for NP/Gem. 
5.1.2.2 
Secondary Objectives: 
1. To determine the ORR, disease control rate (DCR), DOR, and PFS of each treatment 
arm. 
2. To further characterize the feasibility and safety of each treatment arm. 
5.1.2.3 
Exploratory Objectives: 
1. To assess the PK of APX005M in Cycles 1 to 4 (Arms B and C). 
2. To assess immune pharmacodynamic effects of each treatment arm, in both blood and 
tumor tissue. 
3. To assess associations between immune biomarkers and clinical outcomes. 
4. To evaluate baseline and on-treatment microbiome profiles. 
5. To construct multivariable linear models to dissect the pharmacodynamic effects of 
APX005M and nivolumab on immune biomarkers. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
36 
 
5.2 
Study Endpoints 
5.2.1 
Phase 1b 
5.2.1.1 
Primary Endpoints 
• The frequency of DLT. 
• The RP2D of APX005M when combined with NP/Gem or nivolumab/NP/Gem. 
• The incidence of treatment-emergent AEs (TEAEs), SAEs, and AEs causing treatment 
discontinuation. 
5.2.1.2 
Secondary Endpoints 
• OR is determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
• DOR is defined as time from first documentation of response (complete response [CR] 
or PR) to first documentation of PD. 
5.2.1.3 
Exploratory Endpoints 
• PK of APX005M will be determined in Cycles 1 to 4 (as described in Section 13.5). 
• Immune pharmacodynamic endpoints may include, but are not limited to, the following: 
o Changes in the tumor microenvironment (including cellularity, stromal content, 
cellular infiltration, and tumor apoptosis) may be assessed by tumor multiplex 
immunohistochemistry or other appropriate technology. Pharmacodynamic and PK 
parameters, if available, may be used to influence the RP2D. 
o Gene expression may be determined by tumor ribonucleic acid (RNA) sequencing, 
peripheral blood RNA sequencing, or other appropriate technology. Other 
sequencing technologies, such as assay for transposase-accessible chromatin 
(ATAC) sequencing, may be performed. 
o Tumor genomics may be determined when possible by Clinical Laboratory 
Improvement Amendment-certified mutational panel assessments and/or by whole 
exome sequencing. 
o For variant calling and HLA determination, normal tissue whole exome sequencing 
may be performed. In some cases, data regarding germline BRCA1/2 mutations or 
microsatellite (MS) instability will be incorporated into analyses. 
o Cytokine and/or circulating factor analysis may be determined by a multiplex assay 
or other appropriate technology. 
o Flow cytometry or other related technologies, such as CyTof analysis of peripheral 
blood, may be used to assess phenotype, function, and other changes in immune 
cellular subsets. 
o Other markers to measure tumor burden, including circulating tumor 
deoxyribonucleic acid (DNA), tumor cells, and protein markers, may be measured 
in an exploratory fashion if material is available. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
37 
 
5.2.2 
Phase 2 
5.2.2.1 
Primary Endpoints 
• OS, defined as the time from initiation of study therapy to date of death due to any 
cause or date of most recent patient contact. Patients who have not died are censored 
on their most recent contact date. 
• 1-year OS rate in each treatment arm. 
5.2.2.2 
Secondary Endpoints 
• Investigators’ assessment of OR is determined by RECIST v1.1 and ORR is defined as 
the proportion of patients who achieve a CR or PR. 
• DCR is defined as the proportion of patients who achieve a CR or PR or SD. 
• DOR is defined as the time from first documentation of response (CR or PR) to first 
documentation of PD.  
• PFS is defined as the time from initiation of study therapy to date of first documented 
progression of disease, date of death due to any cause or date of most recent patient 
contact which documented progression-free status (i.e., clinic visit date or scan date). 
Patients who have not progressed or died are censored on their most recent progression-
free date. 
• The incidence of AEs defined as unacceptable toxicities (see Section 6.1), TEAEs, 
SAEs, and AEs causing treatment discontinuation. 
• Clinical laboratory data and vital signs (descriptive statistics) and numbers of patients 
with values outside limits of the normal range at each time point. 
5.2.2.3 
Exploratory Endpoints 
The exploratory endpoints for Phase 2 are the same as those described for Phase 1b (see 
Section 5.2.1.3) with the addition of evaluation of baseline and on-treatment microbiome 
profiles with treatment outcomes. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
38 
 
6 
INVESTIGATIONAL PLAN 
6.1 
Description of Overall Study Design and Plan 
This is a multi-center, open-label, Phase 1b/2 study to evaluate the immunotherapy agents 
APX005M and nivolumab in combination with Gem and NP in patients with previously 
untreated metastatic pancreatic adenocarcinoma. 
Phase 1b will involve 4 treatment cohorts, and Phase 2 will involve randomization to 1 of 3 
treatment arms, as shown in Figure 1. 
Figure 1 
Study Flow Chart 
Phase 1b 
Phase 2 
 
 
 
 
 
 
 
 
 
 
 
Cohort B1: 
NP 
Gem 
APX005M 
0.1 mg/kg 
 
6 patients 
 
Cohort B2a: 
NP 
Gem 
APX005M 
0.3 mg/kg 
 
6 patients 
 
Cohort C1a: 
Nivolumab 
NP 
Gem 
APX005M 
0.1 mg/kg 
6 patients 
 
Cohort C2b: 
Nivolumab 
NP 
Gem 
APX005M 
0.3 mg/kg 
6 patients 
 
 
 
Arm A1: 
Nivolumab 
NP 
Gem 
 
35 patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm B2: 
NP 
Gem 
APX005M 0.3 mg/kg 
 
29 patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm C2: 
Nivolumab 
NP 
Gem 
APX005M 0.3 mg/kg 
 
29 patients 
 
a Enrollment in Cohorts B2 and C1 may occur concurrently. 
b Enrollment in Cohort C2 may begin once enrollment in Cohort C1 has been completed. 
In both Phase 1b and Phase 2, participants will undergo the following tumor biopsy procedures 
to assess tumor and immune markers: 
1. Prior to beginning study treatment (i.e., baseline biopsy, mandatory. Archival tissue is 
acceptable)  
2. During treatment (i.e., on-treatment biopsy; mandatory, if medically feasible); Cycle 2 
after second dose of APX005M, or after third dose Nivolumab for arms not including 
APX005M. Otherwise, any on-treatment biopsy will be accepted unless there is no 
lesion that can be safely biopsied 
3. Additional biopsies may be performed for patients who have prolonged stable disease, 
defined as stable for more than two, consecutive disease assessments by RECIST v1.1, 
and/or if tumor shrinkage is demonstrated, followed by a new lesion and/or radiological 
disease progression 
4. Ad hoc collections may be performed with Medical Monitor approval 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
39 
 
In both Phase 1b and Phase 2, NP/Gem could be dosed according to one of the schedules below 
depending on whether or not the patient experiences toxicity: 
1. 2 weeks on, 1 week off 
2. 3 weeks on, 1 week off 
Please note: Day 15 assessments are still required on the 2 weeks on, 1 week off schedule. 
Phase 1b 
In the Phase 1b portion of the study, 4 treatment cohorts will be evaluated for feasibility and 
safety (see Section 8.6.1). Enrollment in Cohorts B2 and C1 may occur concurrently. 
Enrollment in Cohort C2 may begin once enrollment in Cohort C1 has been completed. Each 
cohort of the study will include approximately 6 DLT-evaluable patients, defined as patients 
who received 2 or 3 doses of NP/Gem and 1 dose of APX005M during Cycle 1, thus have 
completed the DLT observation period (ie, from the time of first administration of 
investigational agents until prior to Cycle 2 Day 1). Patients who do not remain on study up to 
this time for reasons other than DLT will be replaced. DLTs will be graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03.  
A DLT is defined as any Grade 3 or higher toxicity that is treatment-related but not related to 
the natural progression of the tumor and occurs during the DLT observation period. The 
following will be considered DLTs:  
1. Grade 4 hematologic toxicity lasting ≥ 7 days 
2. Grade 3 or 4 neutropenia with a single temperature of > 38.3ºC (101ºF) or a sustained 
temperature of ≥ 38ºC (100.4ºF) for more than one hour 
3. Grade 4 thrombocytopenia (platelet count < 25,000 cells/mm3) if associated with: 
a. A bleeding event which does not result in hemodynamic instability but requires 
an elective platelet transfusion, or 
b. A life-threatening bleeding event which results in urgent intervention and 
admission to an Intensive Care Unit 
4. Grade 4 non-hematologic toxicity (not laboratory) 
5. Grade 3 non-hematologic toxicity (not laboratory) lasting > 3 days despite optimal 
supportive care 
6. Any Grade ≥ 3 non-hematologic laboratory value if: 
a. Medical intervention is required to treat the patient, or 
b. The abnormality leads to hospitalization, or 
c. The abnormality persists for > 1 week 
7. Grade 3 AEs that compromise a major organ (e.g., congestive heart failure) regardless 
of duration 
8. Grade 5 toxicity. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
40 
 
Randomized Phase 2 
Once the RP2D of APX005M in combination with nivolumab in the Phase 1b portion of the 
study is determined, the randomized Phase 2 portion will commence. Patients will be 
randomized to Arm A1, Arm B2, or Arm C2, or to Arm A1, Arm B1, or Arm C1, if Cohort B2 
and/or C2 are deemed unsafe in Phase 1b (see Section 8.6.2). Note that the APX005M dose 
must be the same in Arms B and C, regardless of whether a higher APX005M dose was 
determined to be safe in Arm B. For each regimen, efficacy will be evaluated by comparing 
the 1-year OS rate to the historical value for NP/Gem. A total of approximately 93 patients 
will be randomized/enrolled in Phase 2 (35 Arm A1, 29 Arm B2, 29 Arm C2). 
Based on the safety and efficacy data from Phase 1b, Arm B2 and C2 were selected for Phase 
2. 
Randomization will be managed by the Parker Institute for Cancer Immunotherapy (PICI), 
using an interactive web response system (IWRS). Patients must receive the first dose of study 
drug (Cycle 1 Day 1) within 3 days of randomization. 
An unacceptable toxicity is defined as any ≥ Grade 3 toxicity that is treatment-related but not 
related to the natural progression of the tumor and occurs during the Phase 2 period. The 
following will be considered unacceptable toxicities:  
1. Grade 4 thrombocytopenia (platelet count < 25,000 cells/mm3) if associated with: 
a. A life-threatening bleeding event which results in urgent intervention and 
admission to an Intensive Care Unit 
2. Any ≥ Grade 3 non-hematologic laboratory value if: 
a. Medical intervention is required to treat the patient, and 
b. The abnormality leads to hospitalization, and 
c. The abnormality persists for > 1 week 
3. Grade 3 or 4 AEs that compromise a major organ (e.g., congestive heart failure) 
regardless of duration 
4. Grade 5 toxicity 
 
6.1.1 
Duration of Study Participation 
The Phase 1b study will enroll for at least 9 months, assuming all 4 cohorts are tested, and 
have 1 additional month of follow-up before declaring the RP2D of APX005M. The Phase 2 
portion of the study will enroll for approximately 18 months and have 12 additional months of 
follow-up. All patients will be followed for survival status until death or a maximum of 5 years.  
Considering several months for data management and statistical analysis, the total duration of 
the study is likely to be 5 years. In both Phase 1b and 2, enrollment will proceed until met or 
as determined by the study sponsor (Parker Institute for Cancer Immunotherapy). 
Patients will undergo screening and, if eligible, will undergo treatment in the assigned arm of 
the study until unacceptable toxicity, progression of disease, or withdraw of consent as noted 
above. Treatment schedules per cohort/arm and phase of study are detailed in Section 8. All 
patients will be followed for survival status until death or a maximum of 5 years. Once a patient 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
41 
 
is in follow-up, patients will be followed by a clinic visit or phone call approximately every 
3 months as specified in Table 11, Table 12 and Table 13. In addition, ad hoc collection of 
survival and new anti-cancer therapy for active patients may be requested by the Sponsor. 
6.1.2 
Total Number of Patients 
Up to 24 DLT-evaluable patients will be enrolled in Phase 1b. A total of approximately 
93 patients will be randomized/enrolled in Phase 2. Thus, the total sample size is expected to 
be approximately 117 patients. 
6.1.3 
Early Termination Rules for Unacceptable Toxicity in Phase 2 
A Bayesian rule will be employed to monitor toxicity during Phase 2 (as described in 
Section 13) to determine whether a study arm or the study needs to be terminated. A Medical 
and Statistical Supervision (MSS) process involving a Data Review Team (DRT) will be 
responsible for monitoring toxicity, as described in Section 13.8.1.  
6.1.4 
Treatment Beyond Unequivocal Disease Progression 
Treatment decisions, particularly continuation versus discontinuation, will be made by the 
investigator on the basis of available clinical and imaging data at the site 
For patients with radiological progression according to RECIST v1.1, in the absence of 
performance status decline and significant symptoms due to disease progression, the 
investigator may elect to keep the patient on treatment, and repeated assessment of disease 
status will be performed. 
Patients must be informed of treatment beyond progression and this must be documented. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
42 
 
7 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients will be identified by referrals from physicians at participating cancer centers within 
the PICI, by outside physicians or health care providers, or by self-referral. 
To enroll patients into Phase 1b cohorts, sites will have to contact PICI to request an 
assignment. During Phase 1b, dosing of the first 3 patients of each cohort will be staggered by 
at least one week. If at one week, and for each of the 3 patients, there are no ongoing symptoms 
of cytokine release syndrome related to the infusion, and if no DLT occurs, subsequent patients 
to the cohort may be dosed without restriction. A meeting of the DRT will be held prior to each 
dose escalation (i.e., between cohorts); ad hoc meetings may be held if a particular DLT 
requires immediate follow-up. 
7.1 
Inclusion Criteria 
Patients must meet all of the following criteria at Screening and baseline to participate in the 
study: 
1. Patient has histologically or cytologically documented diagnosis of pancreatic 
adenocarcinoma with metastatic disease. Locally advanced patients are not eligible. 
2. Patient must have measurable disease by RECIST v1.1. 
3. Patients must be age 18 years or older. 
4. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 (see Appendix 16.1). 
5. A baseline tumor tissue sample is mandatory for enrollment. If archival tumor tissue is 
not available, then a fresh tumor biopsy must be provided.  
6. Patients must have the following laboratory values at Screening, without transfusions 
or growth factors, within 2 weeks of the first dose of investigational agents: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (in absence of growth factor 
support) 
• Platelet count ≥ 150 x 109/L 
• Hemoglobin ≥ 9 g/dL(without transfusion support) 
• Serum creatinine ≤ 1.5 mg/dL, and creatinine clearance ≥ 50 mL/min as 
measured by Cockcroft and Gault formula 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x 
institution’s upper limit of normal (ULN) for patients with no concurrent liver 
metastases, OR ≤ 5.0 x institution’s ULN for patients with concurrent liver 
metastases 
• Total bilirubin ≤ 1.5 x ULN, except in patients with documented Gilbert’s 
syndrome, who must have a total bilirubin ≤ 3 x ULN 
7. Women of childbearing potential (WOCBP; defined in Section 7.1.1) must have a 
negative pregnancy test (serum or urine) within the 7 days prior to study drug 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
43 
 
administration, and within the 3 days before the first study drug administration, or a 
negative pregnancy test within the 24 hours before the first study drug administration. 
8. WOCBP and male patients who are sexually active with WOCBP must agree to use 
2 highly effective methods of contraception (including a physical barrier; see 
Section 7.1.1) before the first dose of study drugs, during the study, and for 5 months 
for women and 7 months for men following the last dose of study drug. 
9. Patients must have the ability to understand and willingness to sign a written informed 
consent document. 
7.1.1 
Childbearing Potential and Highly Effective Methods of Contraception 
A WOCBP is defined as any female who has experienced menarche and who has not 
undergone surgical sterilization (hysterectomy and/or bilateral oophorectomy) and is not 
postmenopausal. Menopause is defined as 12 months of amenorrhea in women over the age 45 
years in the absence of other biological or physiological causes. In addition, females under the 
age of 55 years must have a serum follicle stimulating hormone level > 40 mIU/mL to confirm 
menopause. 
WOCBP must have a negative pregnancy test before starting study treatment. Blood or urine 
pregnancy tests must have a minimum test sensitivity of at least 25 IU/L. Kits measuring either 
total human chorionic gonadotropin (hCG) or the beta (β) fraction are acceptable. Monthly 
pregnancy testing, either serum or urine (with a minimum sensitivity 5 IU/L or equivalent units 
of HCG), is required. 
Females of childbearing potential who are sexually active with a nonsterilized male partner 
must use a highly effective method of contraception for 28 days prior to the first dose of 
investigational product, and must agree to continue using such precautions for 5 months after 
the final dose of investigational product; cessation of contraception after this point should be 
discussed with a responsible physician. Periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception. They must also refrain from 
egg cell donation for 6 months after the final dose of investigational product. 
A highly effective method of contraception is defined as one that results in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly. The acceptable methods of 
contraception are described in Table 1. 
Nonsterile males who are sexually active with a female partner of childbearing potential must 
use a highly effective method of contraception (see Table 1) from Day 1 through 7 months post 
last dose. For males adequate birth control methods is defined as double barrier contraception, 
i.e., condom + diaphragm, condom or diaphragm + spermicidal gel or foam. In addition, they 
must refrain from sperm donation for 7 months after the final dose of investigational product. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
44 
 
Table 1 
Highly Effective Methods of Contraception 
Barrier Methods 
Hormonal Methods 
Male condom with spermicidea 
Implants 
Male condom with diaphragm ± spermicide 
Hormone shot or injection 
Diaphragm with spermicide 
Combined pill 
Copper T intrauterine device 
Minipill 
Levonorgestrel-releasing intrauterine system (e.g., 
Mirena®)b 
Patch 
a If male condom without spermicide is used, another form of contraception is required to meet the definition of 
a highly effective method of contraception with a failure rate of less than 1%. 
b This is also considered a hormonal method. 
7.2 
Exclusion Criteria 
Patients meeting any of the following criteria are ineligible to participate in this study: 
1. Patient must not have received any prior treatment, including chemotherapy, biological 
therapy, or targeted therapy for metastatic pancreatic adenocarcinoma, with the 
following exceptions and notes: 
a. Patients who have received prior adjuvant therapy for pancreatic 
adenocarcinoma are eligible if neoadjuvant and adjuvant therapy (including 
chemotherapy and/or radiotherapy) was fully completed more than 4 months 
before the start of study treatment. In this case, prior Gem and/or NP is 
allowable. 
b. Prior resection surgery is allowable. 
c. Patients initially diagnosed with locally advanced PC who have undergone 
chemotherapy then resection and were with no evidence of disease are eligible 
if metastatic relapse of disease has occurred and if the last dose of chemotherapy 
was more than 4 months before the date of study entry. 
2. Patients must not have another active invasive malignancy, with the following 
exceptions and notes: 
a. History of a non-invasive malignancy, such as cervical cancer in situ, non-
melanomatous carcinoma of the skin, in situ melanoma, or ductal carcinoma in 
situ of the breast, is allowed. 
b. History of malignancy that is in complete remission after treatment with 
curative intent is allowed. 
c. No current or history of a hematologic malignancy is allowed, including 
patients who have undergone a bone marrow transplant. 
3. History of clinically significant sensitivity or allergy to mAbs, their excipients, or 
intravenous gamma globulin. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
45 
 
4. Previous exposure to CD40, PD-1, PD-L1, CTLA-4 antibodies or any other 
immunomodulatory agent. 
5. History of (non-infectious) pneumonitis that required corticosteroids or current 
pneumonitis, or history of interstitial lung disease. 
6. Patients must not have a known or suspected history of an autoimmune disorder, 
including but not limited to inflammatory bowel disease, celiac disease, Wegner 
syndrome, Hashimoto syndrome, systemic lupus erythematosus, scleroderma, 
sarcoidosis, or autoimmune hepatitis, within 3 years of the first dose of investigational 
agent, except for the following. 
a. Patients with Type 1 diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders such as vitiligo, or alopecia not requiring systemic 
therapy, or conditions not expected to recur in the absence of an external trigger 
are eligible. 
b. Patients with a history of Hashimoto syndrome within 3 years of the first dose 
of investigational agent, which resolved to hypothyroidism alone. 
7. Patients must not have an uncontrolled intercurrent illness, including an ongoing or 
active infection, current pneumonitis, symptomatic congestive heart failure (New York 
Heart Association class III or IV), unstable angina, uncontrolled hypertension, cardiac 
arrhythmia, interstitial lung disease, active coagulopathy, or uncontrolled diabetes. 
8. Patients must not have a history of myocardial infarction within 6 months or a history 
of arterial thromboembolic event within 3 months of the first dose of investigational 
agent. 
9. Patients must not have a history of human immunodeficiency virus, hepatitis B virus 
(HBV), or hepatitis C virus (HCV), except for the following: 
a. Patients with anti-hepatitis B core antibody but with undetectable HBV DNA 
and negative for hepatitis B surface antigen (HBsAg) 
b. Patients with resolved or treated HCV (i.e., HCV antibody positive but 
undetectable HCV RNA) 
10. Patients must not have a history of primary immunodeficiency. 
11. Patients must not receive concurrent or prior use of an immunosuppressive agent within 
14 days of the first dose of investigational agent, with the following exceptions and 
notes: 
a. Systemic steroids at physiologic doses (equivalent to dose of oral prednisone 
10 mg) are permitted. Steroids as anti-emetics for chemotherapy are not allowed. 
b. Intranasal, inhaled, topical, intra-articular, and ocular corticosteroids with 
minimal systemic absorption are permitted. 
c. Patients with a condition with anticipated use of systemic steroids above the 
equivalent of 10 mg prednisone are excluded. 
d. Transient courses of steroids may be approved by the Medical Monitor on a 
case by case basis, dependent on dose and reason. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
46 
 
12. Patients must not have a history of clinically manifested central nervous system (CNS) 
metastases. 
a. Patients with known or suspected leptomeningeal disease or cord compression 
are not eligible. 
13. Patients must not have had major surgery as determined by the PI within 4 weeks before 
the first dose of investigational agent. 
14. Patients must not have received another investigational agent within the shorter of 
4 weeks or 5 half-lives before the first dose of investigational agent. 
15. Patients must not have received a live attenuated vaccine within 28 days before the first 
dose of investigational agent, and patients, if enrolled, should not receive live vaccines 
during the study or for 180 days after the last dose of investigational agent. 
16. Females who are pregnant or lactating or who intend to become pregnant during 
participation in the study are not eligible to participate. 
17. Patients who have any clinically significant psychiatric, social, or medical condition 
that, in the opinion of the investigator, could increase the patient’s risk, interfere with 
protocol adherence, or affect the patient’s ability to give informed consent are ineligible 
to participate in the study. 
7.3 
Discontinuation, Withdrawal, and Replacement of Patients 
7.3.1 
Discontinuation of Study Drug 
An individual patient will not receive any further study drug (discontinue study drug) if any of 
the following occur in the patient in question: 
• Radiological progression, according to RECIST v1.1 (see Section 10.1), with a decline 
in performance status and significant symptoms due to PD. For criteria for treatment 
beyond disease progression please see Section 6.1.4. 
• Complete withdrawal of consent from the study (no further data collection permitted) 
• Withdrawal of consent from further treatment with study drug (data collection as per 
study schedule permitted) 
• Lost to follow-up 
• An AE that, in the opinion of the Investigator or the Sponsor, contraindicates further 
dosing 
• DLT during Phase 1b 
• Unacceptable Toxicity during Phase 2 
• Pregnancy or intent to become pregnant 
• Patient noncompliance that, in the opinion of the Investigator or Sponsor, warrants 
withdrawal (e.g., refusal to adhere to the scheduled visits) 
• Initiation of alternative anticancer therapy (excluding surgery or palliative radiotherapy, 
as permitted per Section 8.9.3), including another investigational agent 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
47 
 
• Intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis 
that became apparent during treatment and necessitated the patient's termination from 
the study 
• General or specific changes in the patient’s condition that renders him/her ineligible 
for further treatment according to the inclusion/exclusion criteria 
The primary reason for study drug discontinuation should be documented on the appropriate 
Electronic Case Report Form (eCRF) page. 
7.3.2 
Withdrawal/Discontinuation of Patients 
When study drug is discontinued, patients should have an end of treatment 
(EOT)/discontinuation assessment and continue follow-up assessments as outlined in the 
SOAs. Information on survival follow-up and new anticancer therapy will be collected for all 
patients via telephone calls, patient medical records, and/or clinic visits, for a maximum of 5 
years or until any of the following occurs: 
• Death 
• Lost to follow-up 
• Study termination by the Sponsor 
• Patient requests to be withdrawn from follow-up 
• Investigator requests that the patient is withdrawn from follow-up 
If a patient requests to be withdrawn from the study, the request must be documented in the 
source documents and signed by the Investigator. The primary reason for withdrawal from 
study should be documented on the appropriate eCRF page. If the patient withdraws from study, 
the Sponsor may retain and continue to use any data collected before such withdrawal of 
consent. In addition, the study staff may use a public information source (eg, county records) 
to obtain information about survival status only. However, patients who withdraw consent will 
not be followed for any reason after consent has been withdrawn. Patients who withdraw from 
the study will not be replaced. 
7.3.3 
Replacement of Patients 
In Phase 1b only, patients who do not complete the DLT observation period (as defined in 
Section 6.1) will be replaced, but these patients will continue on study for safety evaluation 
until PD or administration of different anti-cancer therapy.  
7.4 
Follow-Up for Drug Discontinuation/Patient Withdrawal from Study 
If a patient discontinues study treatment or is withdrawn from the study and/or treatment for 
any reason, the study site must immediately notify PICI. The date and the reason for study 
and/or treatment discontinuation must be recorded on the appropriate eCRF. Patients who 
discontinue study treatment are to attend the EOT, Day 30 and Day 100 Follow-up Visits to 
complete all assessments. 
In the event that a patient discontinues treatment prematurely due to a TEAE or serious TEAE, 
the TEAE or serious TEAE will be followed until it resolves (returns to normal or baseline 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
48 
 
values) or stabilizes, is judged by the Investigator to be no longer clinically significant or is 
deemed irreversible. 
Once a patient is withdrawn from the study, the patient may not re-enter the study. 
7.5 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in 
the study. 
• Before a patient is deemed lost to follow-up, the Investigator or designee will make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should documented in the patient’s 
medical record or study file. 
Should the patient continue to be unreachable, he/she will be considered lost to follow-up and 
will have completed the study.  This should be reflected in the End of Study eCRF. 
7.6 
Study Termination 
This study may be terminated at the discretion of the Sponsor or any regulatory agency. An 
Investigator may elect to discontinue or stop the study at his or her site for any reason including 
safety or low enrollment. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
49 
 
8 
TREATMENTS 
In Phase 1b, patients will be enrolled into 1 of 4 cohorts (Cohort B1, Cohort B2, Cohort C1, 
and Cohort C2), as outlined in Table 2. A cohort corresponding to Arm A1 of Phase 2 
(nivolumab/NP/Gem) will not be tested, since an external study is being conducted to confirm 
the safety of nivolumab in combination with NP/Gem. 
Once the RP2D of APX005M in combination with nivolumab/NP/Gem is determined, patients 
in Phase 2 will be randomized between Arm A1, Arm B2, or Arm C2. If Arm B2 and/or C2 
are determined to be toxic in the Phase 1b study, patients will be randomized between Arm A1, 
Arm B1, and Arm C1. Arms B1, B2, C1, and C2 will be the same as the corresponding cohorts 
in the Phase 1b study and Table 2. In Arm A1, patients will receive infusions of nivolumab 
240 mg, NP 125 mg/m2, and Gem 1000 mg/m2. Twelve DLT-evaluable patients from the 
Phase 1b study, enrolled at the RP2D of APX005M (i.e., 6 patients on B2 and 6 patients on 
C2), will be included in the efficacy analysis in Phase 2. The remaining 93 patients will be 
randomized as per Section 8.6. 
Table 2 
Study Cohorts/Arms 
Cohort/Arm 
Dosing Days Per Cyclea 
1 
3 
8 
15 
A1 
 
 
 
 
Nivolumab 240 mg IV 
X 
 
 
X 
NP 125 mg/m2 IV 
X 
 
X 
X 
Gem 1000 mg/m2 IV 
X 
 
X 
X 
B1 
 
 
 
 
NP 125 mg/m2 IV 
X 
 
X 
X 
Gem 1000 mg/m2 IV 
X 
 
X 
X 
APX005M 0.1 mg/kg IV 
 
X 
 
 
B2 
 
 
 
 
NP 125 mg/m2 IV 
X 
 
X 
X 
Gem 1000 mg/m2 IV 
X 
 
X 
X 
APX005M 0.3 mg IV 
 
X 
 
 
C1 
 
 
 
 
Nivolumab 240 mg IV 
X 
 
 
X 
NP 125 mg/m2 IV 
X 
 
X 
X 
Gem 1000 mg/m2 IV 
X 
 
X 
X 
APX005M 0.1 mg/kg IV 
 
X 
 
 
C2 
 
 
 
 
Nivolumab 240 mg IV 
X 
 
 
X 
NP 125 mg/m2 IV 
X 
 
X 
X 
Gem 1000 mg/m2 IV 
X 
 
X 
X 
APX005M 0.3 mg/kg IV 
 
X 
 
 
Gem = gemcitabine; IV = intravenous; NP = nab-paclitaxel 
a Depending on whether or not the patient experiences toxicity, NP/Gem could be administered according to one of the 
following dosing schedules: (1) 3 weeks on, 1 week off; and (2) 2 weeks on, 1 week off. Nivolumab should not be 
administered on Day 15 if NP/Gem is held on Day 15. Nivolumab doses should not be administered < 2 weeks apart. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
50 
 
8.1 
Details of Study Treatments 
Details of APX005M, nivolumab, NP, and Gem are provided below. Delay of treatment 
schedule, as allowed by the protocol, is permitted at the discretion of the treating Investigator 
(e.g. toxicity, weather). 
8.1.1 
APX005M 
Classification: Humanized IgG1 CD40 agonistic antibody 
Mechanism of Action: APX005M is a humanized IgG1 CD40 agonistic antibody that binds 
to CD40, activating the CD40 pathway, leading to activation of APCs, including B cells, 
monocytes, and DCs, and stimulates cytokine release. 
Storage and Stability: APX005M must be stored in a secure location with limited access 
under controlled temperature conditions of 2°C to 8°C (36°F to 46°F) and in accordance with 
local regulations. Vials should be stored in their original folding carton to protect from light. 
During preparation and administration of diluted APX005M product, protection from light is 
not required. 
Dose Specifics: 0.1 or 0.3 mg/kg IV on Day 3 of every Cycle (or Day 10 if delayed). Patients 
may only receive the delayed dose on Day 10 if they have received NP/Gem on Day 8. 
APX005M doses should not be administered < 2 weeks apart.  
Preparation: APX005M is prepared in normal saline per the Pharmacy Manual. 
Administration: Premedication is given as noted in Table 3. After dilution in normal saline, 
APX005M is administered by IV infusion over 60 minutes. It is recommended that the 
APX005M infusion does not exceed 120 minutes. APX005M must be administered to study 
patients by qualified personnel. 
Safety Precautions: When handling APX005M, study personnel should wear laboratory coats 
and disposable protective gloves and avoid contact with eyes, skin, and clothing. APX005M 
should be protected from light and contamination.  
Availability: APX005M will be provided by Apexigen. APX005M must be dispensed only 
from official study sites by authorized personnel according to local regulations. It is the 
responsibility of the Investigator to ensure that APX005M is only dispensed to study patients.  
Packaging and Labeling: APX005M is supplied in 20 mL Type 1 clear glass vials for IV 
injection. Each depyrogenated vial contains 10 mg/mL APX005M in a sterile, clear to slight 
opalescent, colorless to slightly yellow, preservative-free solution (pH 5.5) containing 25 mM 
sodium acetate, 248 mM trehalose, and 0.02% polysorbate 20 in water for injection with a 
target fill volume of 16.9 mL per vial. Glass vials are plugged with Teflon-coated rubber 
stoppers and sealed with aluminum seals. The 20 mL vials (16.9 mL/vial) are intended for 
single use. Additional APX005M details are provided in the Pharmacy Manual. 
Return and Destruction of APX005M: Upon completion or termination of the study, all 
unused and/or partially used APX005M must be returned to Apexigen or designee if not 
authorized by Apexigen or designee to be destroyed at the site. All returned APX005M must 
be accompanied by the appropriate documentation and clearly identified by protocol number 
and study site number on the outermost shipping container. Return supplies should be in the 
original containers (e.g., kits that have clinical labels attached). Empty containers should not 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
51 
 
be returned. It is the Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to the applicable 
federal, state, local, and institutional guidelines and procedures and appropriate records of 
disposal are kept. The return of unused APX005M should be arranged by the responsible Study 
Monitor. 
Side Effects: 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 patients receiving APX005M. Guidance for monitoring and management of cytokine 
release syndrome is included (in Section 13.6 of this protocol and in the APX005M IB). 
Transient transaminase elevations (≤ Grade 2) have been observed in several patients with liver 
metastases, which were not associated with a particular dose of APX005M. Six patients 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 PD effect. Transient decreases in platelet counts were observed for some 
of the patients 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 ongoing Phase 1 study APX005M-001, APX005M demonstrated a dose-dependent 
activation of APCs, T cell activation and increases in circulating levels of cytokines. 
8.1.2 
Nivolumab 
Other Names: Opdivo, BMS-936558, MDX-1106 
Classification: Human PD-1 antibody 
Mechanism of Action: Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor 
found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 
ligands occurs in some tumors and signaling through this pathway can contribute to inhibition 
of active T-cell immune surveillance of tumors. Nivolumab is a human IgG4 mAb that binds 
to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 
pathway-mediated inhibition of the immune response, including the anti-tumor immune 
response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased 
tumor growth. 
Storage and Stability: Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 
46°F) and protected from light and freezing. The unopened vials can be stored at room 
temperature (up to 25°C, 77°F) and room light for up to 48 hours. The administration of 
infusion must be completed within 24 hours of preparation. If not used immediately, the 
infusion solution may be stored under refrigeration conditions (2°C to 8°C, 36°F to 46°F) for 
up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at room temperature 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
52 
 
(20°C to 25°C, 68°F to 77°F) and room light. The maximum 8-hour period under room 
temperature and room light conditions includes the product administration period. 
Dose Specifics: 240 mg IV Day 1 and 15 of every 28-day cycle. Nivolumab doses should not 
be administered < 2 weeks apart. Nivolumab should not be administered on Day 15 if NP/Gem 
is held on Day 15. 
Preparation: Withdraw the required volume of nivolumab and transfer to an IV container. 
Dilute nivolumab with 0.9% sodium chloride injection, United States Pharmacopeia (USP) or 
5% dextrose injection, USP, to prepare an infusion with a final concentration ranging from 
1 mg/mL to 10 mg/mL. Mixed diluted solution by gentle inversion; do not shake. Discard 
partially used vials of nivolumab. 
Administration: Administer the infusion over 30 minutes through an IV line containing a 
sterile, nonpyrogenic, low protein binding in-line filter (pore size of 0.2 µm to 1.2 µm). Do not 
co-administer other drugs through the same IV line. Flush IV line at the end of the infusion. 
Safety Precautions: When handling nivolumab, wear laboratory coats and disposable 
protective gloves. Avoid contact with eyes, skin, and clothing. Protect from light and 
contamination. 
Availability: Nivolumab will be provided by Bristol-Myers Squibb in 100 mg vials 
(10 mg/mL) and labeled appropriately as investigational material for this study. 
Side Effects: 
• General disorders: Fatigue, anorexia, pyrexia, headache 
• Respiratory, thoracic, and mediastinal disorders: Cough, upper respiratory tract 
infection, pneumonitis 
• Hepatic: Increased AST, ALT, alkaline phosphatase, hepatitis 
• Gastrointestinal: Diarrhea, constipation, nausea, vomiting, colitis 
• Skin: Rash, pruritus, vitiligo 
• Endocrine: Hypophysitis, thyroiditis 
• Ophthalmologic: Uveitis 
For management of toxicities, see Section 8.5. 
8.1.3 
Nab-Paclitaxel 
Other Names: Abraxane 
Classification: Mitotic inhibitor (cytoskeletal target) 
Mechanism of Action: NP is a Cremophor EL-free, albumin-bound paclitaxel particle with a 
mean size of approximately 130 nm. NP is a unique protein formulation of a non-crystalline, 
amorphous form of paclitaxel in an insoluble particle state. 
Paclitaxel is a cytoskeletal drug that targets tubulin. Unlike tubulin-targeting drugs (such as 
colchicine) that inhibit microtubule assembly, paclitaxel stabilizes the microtubule polymer 
and protects it from disassembly. Therefore, chromosomes are unable to form a metaphase 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
53 
 
spindle formation. This blocks progression of mitosis. Prolonged activation of the mitotic 
checkpoint will then lead to apoptosis or lead the cell to return to G-phase without cell division. 
Storage and Stability: NP should be stored as vials in original cartons at 20ºC to 25ºC (68ºF 
to 77ºF) and protected from bright light. 
Dose Specifics: In the absence of toxicity, NP will be administered at 125 mg/m2 IV Day 1, 8 
and 15 of every 28-day cycle (ie, 3 weeks on, 1 week off cycle). If toxicity occurs, NP could 
be administered on a 2 weeks on, 1 week off cycle (see Section 8.5 for dose modification 
guidelines). For example, patients whose Day 8 dose of NP is delayed due to toxicity may 
receive the dose on Day 22. However, to receive the Day 22 dose, they must have received 
APX005M on Day 3. 
Preparation: Reconstitute each vial containing 100 mg of NP by injecting 20 mL of 0.9% 
Sodium Chloride Injection. Each mL of the reconstituted formulation will contain 5 mg/mL 
paclitaxel. 
Administration: This drug may be administered IV as prepared above over 30 minutes. Given 
the possibility of extravasation, it is advisable to closely monitor the infusion site for possible 
infiltration during drug administration. 
Availability: NP is commercially available as 100 mg of paclitaxel in a single-use vial. 
Side Effects: 
• Hematologic Disorders: Neutropenia was dose dependent and reversible. Pancytopenia 
has been observed in clinical studies. 
• Infections: Infectious episodes were reported in 24% of the patients treated with 
paclitaxel. Oral candidiasis, respiratory tract infections and pneumonia were the most 
frequently reported infectious complications. 
• Hypersensitivity Reactions (HSRs): Grade 1 or 2 HSRs occurred on the day of 
paclitaxel administration and consisted of dyspnea (1%) and flushing, hypotension, 
chest pain, and arrhythmia (all < 1%). 
• Cardiovascular: Hypotension, during the 30-minute infusion, occurred in 5% of 
patients. Bradycardia, during the 30-minute infusion, occurred in < 1% of patients. 
These vital sign changes most often caused no symptoms and required neither specific 
therapy nor treatment discontinuation. Severe cardiovascular events possibly related to 
single-agent paclitaxel occurred in approximately 3% of patients. These events 
included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular 
tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and 
hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks 
have been reported. Electrocardiogram (ECG) abnormalities were common among 
patients at baseline. ECG abnormalities on study did not usually result in symptoms, 
were not dose-limiting, and required no intervention. ECG abnormalities were noted in 
60% of patients. Among patients with a normal ECG prior to study entry, 35% of all 
patients developed an abnormal tracing while on study. The most frequently reported 
ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, 
and sinus tachycardia. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
54 
 
• Respiratory: Dyspnea (12%), cough (7%), and pneumothorax (< 1%) were reported 
after treatment with paclitaxel. 
• Neurologic: The frequency and severity of sensory neuropathy increased with 
cumulative dose. Sensory neuropathy was the cause of paclitaxel discontinuation in 
7/229 (3%) patients. Twenty-four patients (10%) treated with paclitaxel developed 
Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement 
after a median of 22 days; 10 patients resumed treatment at a reduced dose of paclitaxel 
and 2 discontinued due to peripheral neuropathy. Of the 10 patients without 
documented improvement, 4 discontinued the study due to peripheral neuropathy. No 
Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy 
(Grade 2) was observed in either arm of the controlled study. 
• Vision Disorders: Ocular/visual disturbances occurred in 13% of all patients (n = 366) 
treated with paclitaxel and 1% were severe. The severe cases (keratitis and blurred 
vision) were reported in patients who received higher doses than those recommended 
(300 or 375 mg/m2). These effects generally have been reversible. Other possible side 
effects include conjunctivitis and increased lacrimation.  
• Arthralgia/Myalgia: The symptoms were usually transient, occurred two or three days 
after paclitaxel administration, and resolved within a few days.  
• Hepatic: Grade 3 or 4 elevations in gamma-glutamyl transpeptidase were reported 
for 14% of patients treated with paclitaxel. 
• Renal: Overall 11% of patients experienced creatinine elevation, 1% severe. No 
discontinuations, dose reductions, or dose delays were caused by renal toxicities. 
Other Clinical Events: Nail changes (changes in pigmentation or discoloration of nail bed) 
have been reported. Edema occurred in 10% of patients; no patients had severe edema. 
Dehydration and pyrexia were also reported. Skin reactions including generalized or 
maculopapular rash, erythema, and pruritus have been observed with paclitaxel. There have 
been case reports of photosensitivity reactions, radiation recall phenomenon, and in some 
patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. 
Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have 
been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 
8.1.4 
Gemcitabine 
Other Names: 2'-Deoxy-2', 2’-difluorocytidine monohydrochloride, Gemzar 
Classification: Antimetabolite (nucleoside analog) 
Mechanism of Action: Gem exhibits cell phase specificity, primarily killing cells undergoing 
DNA synthesis (S phase) and also blocking the progression of cells through the G1/S phase 
boundary. Gem is metabolized intracellularly by nucleoside kinases to the active diphosphate 
and triphosphate nucleosides. The cytotoxic effect of Gem is attributed to a combination of 
two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of 
DNA synthesis. First, Gem diphosphate inhibits ribonucleotide reductase, which is responsible 
for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. 
Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in the 
concentrations of deoxynucleotides, including deoxycytidine triphosphate (dCTP). Second, 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
55 
 
Gem triphosphate competes with dCTP for incorporation into DNA. The reduction in the 
intracellular concentration of dCTP (by the action of the diphosphate) enhances the 
incorporation of Gem triphosphate into DNA (self-potentiation). After the Gem nucleotide is 
incorporated into DNA, only one additional nucleotide is added to the growing DNA strands. 
After this addition, there is inhibition of further DNA synthesis. DNA polymerase epsilon is 
unable to remove the Gem nucleotide and repair the growing DNA strands (masked chain 
termination). In T lymphoblastoid cells of the CEM cell line, Gem induces internucleosomal 
DNA fragmentation, one of the characteristics of programmed cell death. 
Storage and Stability: Un-reconstituted drug vials are stored at controlled room temperature. 
Reconstituted solution should be stored at controlled room temperature and used within 
24 hours. Solutions of Gem should not be refrigerated; crystallization may occur. The unused 
portion should be discarded. 
Dose Specifics: Gem is indicated as a single agent for the treatment of PC. In this indication, 
a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks followed by a week of 
rest, then once weekly for 3 weeks of every 4 weeks is used. In this protocol, in the absence of 
toxicity, we use a common modification of Gem dosing of 3 weeks on, 1 week off. Therefore, 
1000 mg/m2 IV is used on Days 1, 8 and 15 of every 28-day cycle. If toxicity occurs, Gem 
could be administered on a 2 weeks on, 1 week off cycle (see Section 8.5 for dose modification 
guidelines). For example, patients whose Day 8 dose of Gem is delayed due to toxicity may 
receive the dose on Day 22. However, to receive the Day 22 dose, they must have received 
APX005M on Day 3. 
Preparation: Reconstitute the 200-mg vial with 5 mL and the 1-g vial with 25 mL 
preservative-free normal saline to make a solution containing 38 mg/mL. Shake to dissolve. 
Administration: The drug may be administered IV as prepared above or further diluted with 
normal saline to a minimum concentration of 0.1 mg/mL. Gem is commonly diluted in 100 or 
250 mL of saline. Gem administration will be over 30 minutes. 
Availability: Gemcitabine is commercially available in 200-mg and 1-g vials. 
Side Effects: 
• Hematologic: Myelosuppression manifested by neutropenia, thrombocytopenia, and 
anemia occurs with Gem as a single agent and the risks are increased when 
Gemcitabine is combined with other cytotoxic drugs. In clinical studies, Grade 3-4 
neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, 
respectively of patients receiving single-agent. The frequencies of Grade 3-4 
neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8% to 28%, and 
5% to 55%, respectively, in patients receiving Gem in combination with another drug. 
• Dermatologic: A rash is seen in about 25% of patients and is associated with pruritus 
in about 10% of patients. The rash is usually mild, not dose-limiting, and responds to 
local therapy. Desquamation, vesiculation, and ulceration have been reported rarely. 
Alopecia is reported in < 1% of patients. 
• Gastrointestinal: Nausea and vomiting are reported in about two-thirds of patients and 
requires therapy in about 20% of patients. It is rarely (< 1%) dose-limiting, and is easily 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
56 
 
manageable with standard antiemetics. Diarrhea is reported in 8% of patients, 
constipation in 6%, and oral toxicity in 7%. 
• Hepatic: Abnormalities of hepatic transaminase enzymes occur in two-thirds of patients, 
but they are usually mild, nonprogressive, and rarely necessitate stopping treatment. 
Drug-induced liver injury, including liver failure and death, has been reported in 
patients receiving Gem alone or in combination with other potentially hepatotoxic 
drugs. Administration of Gem in patients with concurrent liver metastases or a pre-
existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to 
exacerbation of the underlying hepatic insufficiency. 
• Pulmonary: Bronchospasm after injection has been reported in less than 1% of patients 
and is usually mild and transient, but parenteral therapy may be required. Dyspnea 
within a few hours of injection is reported in 10% of patients. It is usually mild, short-
lived, rarely dose-limiting, and usually abates without any specific therapy. Cough and 
rhinitis are also commonly reported. Pulmonary toxicity, including interstitial 
pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress 
syndrome, has been reported. In some cases, these pulmonary events can lead to fatal 
respiratory failure despite discontinuation of therapy. The onset of pulmonary 
symptoms may occur up to 2 weeks after the last dose of Gem. 
• Neurologic: Somnolence has been reported in 10% of patients, and insomnia is 
common. 
• Cardiovascular: A few cases of hypotension were reported. Some cases of myocardial 
infarction, congestive heart failure, and arrhythmia have been reported, but there is no 
clear evidence that Gem causes cardiac toxicity. Peripheral edema is reported in about 
30% of patients. Some cases of facial edema have also been reported. Edema is usually 
mild to moderate, rarely dose-limiting, sometimes painful, and reversible after stopping 
Gem treatment. 
• Hemolytic Uremic Syndrome (HUS): HUS to include fatalities from renal failure or 
the requirement for dialysis can occur in patients treated with Gem. In clinical studies, 
HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were 
due to HUS. Renal failure may not be reversible even with discontinuation of therapy. 
• Embryofetal Toxicity: Gem can cause fetal harm when administered to a pregnant 
woman, based on its mechanism of action. Gem was teratogenic, embryotoxic, and 
fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a woman 
becomes pregnant while taking Gem, the patient should be apprised of the potential 
hazard to a fetus. 
• Exacerbation of Radiation Therapy Toxicity: Gem is not indicated for use in 
combination with radiation therapy. Concurrent (given together or ≤ 7 days apart) — 
Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a study 
in which Gem was administered at a dose of 1000 mg/m2 to patients with non-small 
cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
57 
 
• Capillary Leak Syndrome: Capillary leak syndrome with severe consequences has been 
reported in patients receiving Gem as a single agent or in combination with other 
chemotherapeutic agents. 
• Other: Flu-like symptoms are reported for about 20% of patients. This includes fever, 
headache, back pain, chills, myalgia, asthenia, and anorexia. Malaise and sweating are 
also commonly reported. 
8.2 
Preparation and Administration of Study Treatment 
For all study drugs, either a peripheral IV or a central port or line is acceptable for infusion. 
Patient weight will be assessed at Screening and Day 1 of each cycle. Dose adjustments are 
not required unless the subject has a ≥ 5% change in comparison to their initial weight on 
Cycle 1, Day 1. 
8.2.1 
APX005M 
APX005M will be prepared as per the Pharmacy Manual. Briefly, APX005M will be diluted 
in normal saline. After dilution in normal saline, APX005M will be administered by IV 
infusion over 60 minutes on Day 3 of each 28-day cycle. The APX005M infusion can be 
interrupted in the case of infusion reaction. Once symptoms resolve, infusion should be 
restarted at 50% of the initial infusion rate (e.g., from 50 mL/h to 25 mL/h). 
For each treatment cycle, APX005M should only be administered if patients received 
NP/Gem on Day 1. For APX005M dose delays (from Day 3 to Day 10), patients may only 
receive the Day 10 dose if they have received NP/Gem on Day 8.  
8.2.2 
Nivolumab 
Nivolumab will be prepared according to the package insert. Briefly, the required volume of 
nivolumab will be withdrawn and transferred to an IV container. Nivolumab will be diluted 
with 0.9% sodium chloride injection, USP or 5% dextrose injection, USP, to prepare an 
infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. This diluted solution 
will be mixed by gentle inversion. 
The dose will be administered over 30 minutes through an IV line containing a sterile, 
nonpyrogenic, low protein binding in-line filter (pore size of 0.2 µm to 1.2 µm) on Days 1 and 
15 of each 28-day cycle. Nivolumab doses should not be administered < 2 weeks apart. 
Nivolumab should not be administered on Day 15 if NP/Gem is held on Day 15. On each day 
nivolumab is given, it should be administered before Gem and NP. Do not co-administer 
other drugs through the same IV line. The IV line should be flushed at the end of the infusion. 
8.2.3 
Nab-paclitaxel 
NP will be prepared according to the package insert. Briefly, each vial of NP containing 
100 mg of drug will be reconstituted by injecting 20 mL of 0.9% sodium chloride injection. 
Each milliliter of the reconstituted formulation will contain 5 mg/mL paclitaxel. This dose will 
be administered IV as prepared above and over 30 minutes. In the absence of toxicity, NP 
could be administered on Days 1, 8, and 15 of each 28-day cycle (ie, 3 weeks on, 1 week off 
cycle). If toxicity occurs, NP may be administered on a 2 weeks on, 1 week off cycle. NP 
should be given after nivolumab and before Gem when given on the same days as either 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
58 
 
of these drugs. Given the possibility of extravasation, it is advisable to closely monitor the 
infusion site for possible infiltration during drug administration.  
For NP dose delays (from Day 8 to Day 22), patients may only receive the Day 22 dose if 
they have received APX005M on Day 3. 
8.2.4 
Gemcitabine 
Gem will be prepared according to the package insert. Briefly, the 200-mg vial of Gem will be 
reconstituted with 5 mL and the 1-g vial with 25 mL preservative-free- normal saline to make 
a solution containing 38 mg/ml. This will be shaken and dissolved. The dose will be 
administered IV as prepared above or further diluted with normal saline to a minimum 
concentration of 0.1 mg/mL. Gem is commonly diluted in 100 mL or 250 mL of saline, and 
administered IV over 30 minutes. In the absence of toxicity, Gem could be administered on 
Days 1, 8, and 15 of each 28-day cycle (ie, every 3 weeks on, 1 week off cycle). If toxicity 
occurs, Gem may be administered on a 2 weeks on, 1 week off cycle. Gem should be 
administered after nivolumab and NP when given on the same days. 
For Gem dose delays (from Day 8 to Day 22), patients may only receive the Day 22 dose 
if they have received APX005M on Day 3. 
8.3 
Monitoring Following APX005M Administration 
Patients will be monitored during and after the infusion of APX005 for at least 5 hours after 
the first 2 infusions of APX005M and as clinically indicated thereafter. All patients will be 
discharged from the clinic after clinical evaluation. Patients should have stable vital signs, 
including lack of orthostatic hypotension (systolic blood pressure > 100 mmHg, or a reduction 
to no lower than 10 mmHg from baseline) without IV hydration (no hydration for at least 2 
hours before discharge), lack of hypoxia (oxygen saturation > 90% without oxygen), 
temperature < 38ºC, and heart rate < 110 beats/min. After discharge, all patients 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. 
8.4 
Dosage Schedule 
Study treatments will be administered as described in Table 3. 
Table 3 
Treatment Regimens and Schedule 
Arm A1 
Drug 
Premedication 
Dose 
Route 
Cyclea 
Nivolumab 
None 
240 mg 
IV over 30 min 
Days 1, 15 
NP 
Per institutional 
standardsb 
125 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 
Gem 
1000 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 
Arm B1 
NP 
Per institutional 
standardsb 
125 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 
Gem 
1000 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 
APX005M 
Yesd 
0.1 mg/kg 
IV over 60 min 
Day 3 
Arm B2 
NP 
125 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
59 
 
Gem 
Per institutional 
standardsb 
1000 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 
APX005M 
Yesd 
0.3 mg/kg 
IV over 60 min 
Day 3 
Arm C1 
Nivolumab 
None 
240 mg 
IV over 30 min 
Days 1, 15 
NP 
Per institutional 
standardsb 
125 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 
Gem 
1000 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 
APX005M 
Yesd 
0.1 mg/kg 
IV over 60 min 
Day 3 
Arm C2 
Nivolumab 
None 
240 mg 
IV over 30 min 
Days 1, 15 
NP 
Per institutional 
standardsb 
125 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 
Gem 
1000 mg/m2 c 
IV over 30 min 
Days 1, 8, 15 
APX005M 
Yesd 
0.3 mg/kg 
IV over 60 min 
Day 3 
Gem = gemcitabine; IV = intravenous(ly); NP = nab-paclitaxel 
a Each cycle is 28 days. However, depending on whether or not the patient experiences toxicity, NP/Gem could be 
administered according to one of the following dosing schedules: (1) 3 weeks on, 1 week off; and (2) 2 weeks on, 1 week 
off. Nivolumab should not be administered on Day 15 if NP/Gem is held on Day 15. Nivolumab and APX005M doses 
should not be administered <2 weeks apart. Delay of treatment schedule, as allowed by the protocol, is permitted at the 
discretion of the treating Investigator (e.g. toxicity, weather). 
b Institutional standards may include a 5-HT3 antagonist (ondansetron, granisetron), but steroids such as dexamethasone 
should not be given as an anti-emetic unless treatment with a 5-HT3 antagonist or other nausea medications is ineffective 
in treating nausea and the overall PI has been notified. 
c Per commercial package insert. 
d Premedication is given 30 minutes before each administration of APX005M and includes a regimen containing an oral 
H1 antagonist (e.g., loratadine 10 mg), oral non-steroidal antiinflammatory- (e.g., ibuprofen 400 mg), acetaminophen 
650 mg, and optionally an oral H2 antagonist (e.g., ranitidine 150-300 mg, famotidine 10-40 mg), or also optionally, 
ondansetron doses (route of administration, and frequency per institutional standards). A window of -10 minutes is permitted 
(e.g. premedications may be administered up to 40 minutes, but no later than 30 minutes, prior to APX005M). 
 
8.5 
Management of Study Drug-Related Toxicities 
Management of suspected adverse drug reactions may require temporary treatment hold, 
reducing the dose of APX005M, NP or Gem, or discontinuation of some or all investigational 
products as presented in the following sections. If a patient experiences several toxicities, the 
recommended dose modification should be based on the highest grade toxicity. 
Up to 2 dose reductions are permitted for APX005M and Gem, and up to 3 dose reductions are 
permitted for NP. No dose reductions will be permitted for nivolumab per Table 4 and Table 
7. 
These dose adjustments are for AEs deemed related to the study medications. If, in the opinion 
of the treating Investigator, a toxicity is thought to be unrelated to study medications and 
resolves to a “Continue” or below lowest grade in Table 4, no dose adjustments for the study 
medications are necessary. 
For NP and/or Gem-related toxicity leading to discontinuation of the chemotherapy, treatment 
with APX005M and nivolumab, or either agent alone, may be continued with approval of the 
Medical Monitor.  
For any toxicity (regardless of grade) that, despite optimal supportive care, is felt by the 
treating Investigator to present a risk to the patient safety, additional dose reduction, treatment 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
60 
 
delay, or treatment discontinuation is permitted at the discretion of the treating Investigator. 
Dose re-escalation will be permitted with approval of the Medical Monitor.  
In the event APX005M is discontinued, due to drug-related toxicities, the participant may 
continue other study treatments with the approval of the Medical Monitor. In this case, Day 3 
assessments listed in Section 9 will no longer be required. 
8.5.1 
Day 1 
Guidelines for management of study treatment-related toxicity on Day 1 are summarized in 
Table 4. 
Table 4 
Management of Study Treatment-Related Toxicities on Day 1 
Toxicity 
Grade 
 
Nivolumab 
NP 
Gem 
Diarrhea/ 
colitis 
2 
1st occurrence: hold 
2nd occurrence or if not 
improving in 1 week with 
steroids: discontinue 
Continue 
Continue 
3 
Discontinue 
Dose reduction 
Dose reduction 
4 
Discontinue 
Hold. Dose reduction 
Hold. Dose reduction 
Mucositis 
3-4 
Hold 
Hold. Dose reduction 
Hold. Dose reduction 
Vomiting 
2-3 
Hold 
Continue. Add 
antiemetics 
Continue. Add 
antiemetics 
4 
Hold. Add antiemetics 
Hold. Dose reduction. 
Add antiemetics 
Hold. Dose 
reduction. Add 
antiemetics 
Increased 
total bilirubin 
2 
If patient has a normal 
baseline AST, ALT, hold. 
 
If patient’s baseline AST, 
ALT is within Grade 1 
toxicity range, continue 
Hold. 
Discontinue if not 
resolved in 4 weeks. 
Hold. 
Discontinue if not 
resolved in 4 weeks. 
3 
Hold 
 
 
4 
Discontinue 
Hold. Dose reduction. 
Discontinue if not 
resolved in 4 weeks. 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks. 
Increased 
AST, ALT  
2 
If patient has a normal 
baseline AST, ALT, hold. 
 
If patient’s baseline AST, 
ALT is within Grade 1 
toxicity range, continue 
Continue 
Continue 
3 
Hold 
Hold 
Hold 
4 
Discontinue 
Discontinue 
Discontinue 
Hypophysitis/ 
Endocrino-
pathies 
 
2 
Hold 
Continue 
Continue 
3-4 
1st occurrence: hold. 
Institute endocrine 
replacement therapy 
Continue 
Continue 
Hyperthyroid
-ism 
3 
1st occurrence: hold 
2nd occurrence: discontinue 
Continue 
Continue 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
61 
 
Toxicity 
Grade 
 
Nivolumab 
NP 
Gem 
4 
Discontinue 
Hold 
Hold 
Rash or other 
skin toxicity 
2 
Continue 
Dose reduction 
Dose reduction 
3 
Hold 
Dose reduction 
Dose reduction 
4 
Discontinue 
Discontinue 
Discontinue 
Neurological 
Toxicity 
2 
Hold 
Dose reduction 
Continue 
3-4 
Discontinue 
Hold. Dose reduction 
Discontinue if not 
resolved in 4 weeks 
Continue 
Infusion 
reaction 
2 
1st occurrence: continue 
2nd occurrence: discontinue 
Continue 
Continue 
3 
Discontinue 
Hold 
Hold 
4 
Discontinue 
Holda 
Hold 
Pneumonitis 
2 
1st occurrence: hold 
2nd occurrence or if not 
improving in 2 weeks: 
discontinue 
Hold 
Hold 
3-4 
Discontinue 
Discontinue 
Discontinue 
Creatinine 
Elevation 
2 
Hold 
If not improving in 1 
week: 
discontinue 
Continue 
Continue 
3 
Hold 
If not improving in 1 
week: 
discontinue 
Hold. Dose reduction. 
Discontinue if not 
resolved in 4 weeks. 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks 
4 
Discontinue 
Discontinue 
Discontinue 
Hypotension, 
dehydration 
or suspected 
adrenal crisis 
3 
Hold 
Hold 
Hold 
4 
Discontinue 
Discontinue 
Discontinue 
Fatigue 
2 (for >6 
weeks) 
3 
Grade 2: continue 
Grade 3: hold 
Grade 2: continue 
Grade 3: hold 
Grade 2: continue 
Grade 3: hold 
Uveitis, eye 
pain, or 
blurred vision 
2-4 
Hold 
 
Discontinue if not 
improved to grade 1 with 
topical treatment within 2 
weeks or if requires 
systemic therapy 
Hold 
Hold 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
62 
 
Toxicity 
Grade 
 
Nivolumab 
NP 
Gem 
Neutropenia 
3 
4 ≤ 7 days 
Hold 
Dose reduction.b 
Discontinue if not 
resolved in 4 weeks 
Dose reduction.b 
Discontinue if not 
resolved in 4 weeks 
4 > 7 days 
Discontinue 
Hold. Dose reduction. 
Discontinue if not 
resolved in 4 weeks. 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks. 
Febrile 
Neutropenia 
3-4 
Hold 
Hold. Dose reduction. 
Discontinue if not 
resolved in 4 weeks. 
1st occurrence: hold. 
Dose reduction. 
2nd occurrence: hold. 
2 dose reductions. 
Discontinue if not 
resolved in 4 weeks 
Thrombocyto
penia 
2 
Continue 
Dose reduction.b 
Discontinue if not 
resolved in 4 weeks 
Dose reduction.b 
Discontinue if not 
resolved in 4 weeks 
3 
Hold 
Hold. Dose reduction. 
Discontinue if not 
resolved in 4 weeks 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks 
3 with 
significant 
bleeding or 
transfusion 
4 
Discontinue 
Hold. Dose reduction. 
Discontinue if not 
resolved in 4 weeks 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks 
All Other 
Drug-Related 
Toxicity 
3 or Severe 
Hold 
Hold c Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks. 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks. 
4 
Discontinue 
Discontinued 
Discontinued 
Gem = gemcitabine; NP = nab-paclitaxel 
Hold = Hold dosing of investigational product until toxicity resolves to “Continue” or below lowest Grade stated in this table. 
Dose reduction = reduce dose by one dose level on following dose. The dose reduction applies to all subsequent doses. 
Discontinue = permanently discontinue that investigational product 
Note: The modifications in this table do not apply to Cycle 1. 
a If grade 4 infusion reaction is thought to be related to NP hypersensitivity, nab-paclitaxel should be permanently 
discontinued. 
b Reduce current dose. NP and Gem dose can be re-escalated to previous dose level for Grade 3 neutropenia and Grade 2 
thrombocytopenia < 1 week 
c Any other grade 3 nivolumab-related adverse event lasting > 7 days, except endocrinopathies controlled with physiologic 
hormone replacement or laboratory abnormalities, except as noted above, requires discontinuation of nivolumab. 
d Patients may only continue treatment for transient Grade 4 toxicity with approval of the Medical Monitor. 
 
8.5.2 
Day 3 
Guidelines for management of study treatment-related toxicities on Day 3 are summarized in 
Table 5. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
63 
 
Table 5 
Management of Study Treatment-Related Toxicities on Day 3 
Toxicity 
Grade 
APX005M 
Non-Hematologic Toxicities 
Diarrhea/colitis 
2 
1st occurrence: hold 
2nd occurrence: dose reduction 
3 
1st occurrence: dose reduction 
2nd occurrence: discontinue 
4 
Discontinue 
Mucositis 
3-4 
Continue 
Vomiting 
2-3 
Hold. Add antiemetics 
4 
Hold. Add antiemetics 
Increased bilirubin 
2 
Hold 
3-4 
Discontinue 
Increased AST, ALT  
2 
Hold 
3 
Hold. Dose reduction 
For patients with liver metastasis reduce dose only if 
Grade 3 > 72 hours 
4 
Discontinue 
Hypophysitis/ 
Endocrinopathies 
 
2 
Continue 
3-4 
1st occurrence: hold. Institute endocrine replacement 
therapy 
2nd occurrence: discontinue 
Hyperthyroidism 
3 
Hold. Dose reduction 
4 
Discontinue 
Rash or other skin toxicity 
2-3 
Hold 
4 
Discontinue 
Neurological Toxicity 
2 
Continue 
3-4 
Hold 
Infusion reaction 
2 
Continue 
3 
Hold. Dose reduction. 
4 
Discontinue 
APX005M cytokine 
release syndrome 
3 
Dose reduction 
4 
Discontinue 
Pneumonitis 
2 
1st occurrence: hold 
2nd occurrence: discontinue 
3-4 
Discontinue 
Creatinine Elevation 
2 
Hold and reassess on Day 10 
3 
Hold 
4 
Discontinue 
Hypotension, dehydration 
or suspected adrenal crisis 
3 
Hold. Dose reduction 
4 
Discontinue 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
64 
 
Toxicity 
Grade 
APX005M 
Fatigue 
2 (for > 6 weeks) or 
3 
Dose reduction 
All Other Drug-Related 
Toxicity 
3 or Severe 
1 occurrence: hold 
2nd occurrence: dose reduction 
4 
Discontinue 
Hematologic Toxicities 
Neutropenia 
3 
Continue 
4 
Hold 
Febrile Neutropenia 
3-4 
Hold 
Thrombocytopenia 
2 
Hold 
3 
Hold 
3 with significant 
bleeding or 
transfusion 
4 
Hold. Dose reduction 
Gem = gemcitabine; NP = nab-paclitaxel 
Hold = Hold dosing of investigational product until toxicity resolves to “Continue” or below lowest Grade stated in this table. 
Dose of APX005M held on Day 3 can be administered on Day 10 if criteria for treatment continuation within a cycle are met 
and the subject received Day 8 NP/Gem. New cycles should be delayed until criteria for initiation of a new cycle are 
met (Section 8.5.5). 
Dose reduction = reduce dose by one dose level on following dose 
Discontinue = permanently discontinue that investigational product 
 
8.5.3 
Day 8 
Guidelines for management of study treatment-related toxicities on Day 8 are summarized in 
Table 6. 
Table 6 
Management of Study Treatment-Related Toxicities on Day 8 
Toxicity 
Grade 
NP 
Gem 
Non-Hematologic Toxicities 
Diarrhea/colitis 
2 
Continue 
Continue 
3 
Dose reduction 
Dose reduction 
4 
Hold. Dose 
reduction 
Hold. Dose reduction 
Mucositis 
3-4 
Hold. Dose 
reduction 
Hold. Dose reduction 
Vomiting 
2-3 
Continue. Add 
antiemetics 
Continue. Add antiemetics 
4 
Hold. Dose 
reduction. Add 
antiemetics 
Hold. Dose reduction. Add antiemetics 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
65 
 
Toxicity 
Grade 
NP 
Gem 
Increased bilirubin 
2 
Hold. 
Discontinue if 
not resolved in 
4 weeks. 
Hold. 
Discontinue if not resolved in 4 weeks. 
3-4 
Hold. Dose 
reduction. 
Discontinue if 
not resolved in 
4 weeks. 
Hold. Dose reduction. 
Discontinue if not resolved in 4 weeks. 
Increased AST, 
ALT  
2 
Continue 
Continue 
3 
Hold 
Hold 
4 
Discontinue 
Discontinue 
Hypophysitis/ 
Endocrinopathies 
2 
Continue 
Continue 
3-4 
Continue 
Continue 
Hyperthyroidism 
3 
Continue 
Continue 
4 
Hold 
Hold 
Rash or other skin 
toxicity 
2-3 
Dose reduction 
Dose reduction 
4 
Discontinue 
Discontinue 
Neurological 
Toxicity 
2 
Dose reduction 
Continue 
3-4 
Hold. Dose 
reduction 
Discontinue if 
not resolved in 
4 weeks 
Continue 
Infusion reaction 
2 
Continue 
Continue 
3 
Hold 
Hold 
4 
Discontinue 
Hold 
Pneumonitis 
2 
Hold 
Hold 
3-4 
Discontinue 
Discontinue 
Creatinine 
Elevation 
2 
Continue 
Continue 
3 
Hold. Dose 
reduction. 
Discontinue if 
not resolved in 
4 weeks. 
Hold. Dose reduction. 
Discontinue if not resolved in 4 weeks 
4 
Discontinue 
Discontinue 
Hypotension, 
dehydration or 
suspected adrenal 
crisis 
3 
Hold 
Hold 
4 
Discontinue 
Discontinue 
Fatigue 
2 (for >6 
weeks) or 
3 
Grade 2: 
continue 
Grade 3: hold 
Grade 2: continue 
Grade 3: hold 
All Other Drug-
Related Toxicity 
3 or 
Severe 
Hold. Dose 
reduction. 
Discontinue if 
not resolved in 
4 weeks 
Hold. Dose reduction. Discontinue if not resolved in 
4 weeks 
4 
Discontinuea 
Discontinuea 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
66 
 
Toxicity 
Grade 
NP 
Gem 
Hematologic Toxicity 
Absolute neutrophil count 500 
- 999 cells/mm3 
Dose reductionb 
Dose reductionb 
Absolute neutrophil count 
< 500 cells/mm3 
Hold 
Hold 
Platelets 50,000 – 74,999 
cells/mm3 
Dose reductionb 
Dose reductionb 
Platelets < 50,000 cells/mm3 
Hold  
Hold 
Febrile 
Neutropenia 
3-4 
Hold. Dose 
reduction.b 
Discontinue if 
not resolved in 4 
weeks. 
1st occurrence: hold. Dose reduction.b 
2nd occurrence: hold. 2 dose reductions.b 
Discontinue if not resolved in 4 weeks 
Gem = gemcitabine; NP = nab-paclitaxel 
Hold = Hold dosing of investigational product until toxicity resolves to “Continue” or below lowest Grade stated in this table. 
Dose reduction = reduce dose by one dose level on following dose 
Discontinue = permanently discontinue that investigational product 
a Patients may only continue treatment for transient Grade 4 toxicity with approval of the Medical Monitor. 
b Reduce current dose. NP and Gem dose can be re-escalated to previous dose level for Grade 3 neutropenia and Grade 2 
thrombocytopenia < 1 week 
 
8.5.4 
Day 15 
Guidelines for management of study treatment-related toxicities on Day 15 are summarized in 
Table 7. 
Table 7 
Management of Study Treatment-Related Toxicities on Day 15 
Toxicity 
Grade 
Nivolumab 
NP 
Gem 
Non-Hematologic Toxicities 
Diarrhea/colitis 
2 
1st occurrence: hold 
2nd occurrence or if 
not improving in 1 
week with oral 
steroids: discontinue 
Continue 
Continue 
3 
Discontinue 
Dose reduction 
Dose reduction 
4 
Discontinue 
Hold. Dose 
reduction 
Hold. Dose reduction 
Mucositis 
3-4 
Hold 
Hold. Dose 
reduction 
Hold. Dose reduction 
Vomiting 
2-3 
Hold 
Continue. Add 
antiemetics 
Continue. Add 
antiemetics 
4 
Hold. Add antiemetics 
Hold. Dose 
reduction. Add 
antiemetics 
Hold. Dose reduction. 
Add antiemetics 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
67 
 
Toxicity 
Grade 
Nivolumab 
NP 
Gem 
Increased bilirubin 
2 
If patient has a normal 
baseline AST, ALT, 
hold. 
If patient’s baseline 
AST, ALT is within 
Grade 1 toxicity 
range, continue. 
Hold. 
Discontinue if not 
resolved in 4 weeks. 
Hold. 
Discontinue if not 
resolved in 4 weeks. 
3 
Hold 
 
 
4 
Discontinue 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks. 
Hold. Dose reduction. 
Discontinue if not 
resolved in 4 weeks. 
Increased AST, 
ALT  
2 
If patient has a normal 
baseline AST, ALT, 
hold. 
If patient’s baseline 
AST, ALT is within 
Grade 1 toxicity 
range, continue. 
Continue 
Continue 
3 
Hold 
Hold 
Hold 
4 
Discontinue 
Discontinue 
Discontinue 
Hypophysitis/ 
Endocrinopathies 
2 
Hold 
Continue 
Continue 
3 
 
1st occurrence: hold. 
Institute endocrine 
replacement therapy 
2nd occurrence: 
discontinue 
Continue 
Continue 
4 
Discontinue 
Continue 
Continue 
Hyperthyroidism 
3 
1st occurrence: hold 
2nd occurrence: 
discontinue 
Continue 
Continue 
4 
Discontinue 
Hold 
Hold 
Rash or other skin 
toxicity 
2 
Continue 
Dose reduction 
Dose reduction 
3 
Hold 
Dose reduction 
Dose reduction 
4 
Discontinue 
Discontinue 
Discontinue 
Neurological 
Toxicity 
2 
Hold 
Dose reduction 
Continue 
3-4 
Discontinue 
Hold. Dose 
reduction 
Discontinue if not 
resolved in 4 weeks 
Continue 
Nivolumab 
infusion reaction 
2 
1st occurrence: 
continue 
2nd occurrence: 
discontinue 
Continue 
Continue 
3 
Discontinue 
Hold 
Hold 
4 
Discontinue 
Hold 
Hold 
Pneumonitis 
2 
1st occurrence: hold 
2nd occurrence or if 
not improving in 2 
weeks: discontinue 
Hold 
Hold 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
68 
 
Toxicity 
Grade 
Nivolumab 
NP 
Gem 
3-4 
Discontinue 
Discontinue 
Discontinue 
Creatinine 
Elevation 
2 
Hold 
If not improving in 
1 week: 
discontinue 
Continue 
Continue 
3 
Hold 
If not improving in 1 
week: 
discontinue 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks. 
Hold. Dose reduction. 
Discontinue if not 
resolved in 4 weeks 
4 
Discontinue 
Discontinue 
Discontinue 
Hypotension, 
dehydration or 
suspected adrenal 
crisis 
3 
Hold 
Hold 
Hold 
4 
Discontinue 
Discontinue 
Discontinue 
Fatigue 
2 (for > 6 
weeks) or 
3 
Grade 2: continue 
Grade 3: hold 
Grade 2: continue 
Grade 3: hold 
Grade 2: continue 
Grade 3: hold 
Uveitis, eye pain, 
or blurred vision 
2-4 
Hold 
 
Discontinue if not 
improved to grade 1 
with topical treatment 
within 2 weeks or if 
requires systemic 
therapy 
Hold 
Hold 
All Other Drug-
Related Toxicityd 
3 or Severe 
Hold 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks 
Hold. Dose reduction. 
Discontinue if not 
resolved in 4 weeks 
4 
Discontinue 
Discontinuec 
Discontinuec 
Hematologic Toxicities 
If Day 8 doses were reduced or given without modification 
Absolute neutrophil count 500 – 
999 cells/mm3 
Continue 
Dose reduction 
Dose reduction 
Absolute neutrophil count < 500 
cells/mm3 
Hold 
Hold 
Hold 
Platelets 50,000 – 74,999 
cells/mm3 
Continue 
Dose reduction 
Dose reduction 
Platelets < 50,000 cells/mm3 
Hold 
Hold 
Hold 
If Day 8 doses were held 
Absolute neutrophil count ≥ 1000 
cells/mm3 
Continue 
Dose reduction 
from Day 1 dose 
Dose reduction from 
Day 1 dose 
Absolute neutrophil count 500 - 
999 cells/mm3 
Continue 
Dose reduction 2 
dose levels from 
Day 1 dose 
Dose reduction 2 dose 
levels from Day 1 dose 
Absolute neutrophil count < 500 
cells/mm3 
Hold 
Hold 
Hold 
Platelets ≥ 75,000 cells/mm3 
Continue 
Dose reduction 
from Day 1 dose 
Dose reduction from 
Day 1 dose 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
69 
 
Toxicity 
Grade 
Nivolumab 
NP 
Gem 
Platelets 50,000 – 74,999 
cells/mm3 
Continue 
Dose reduction 2 
dose levels from 
Day 1 dose 
Dose reduction 2 dose 
levels from Day 1 dose 
Platelets < 50,000 cells/mm3 
Hold 
Hold 
Hold 
Febrile 
Neutropenia 
3-4 
Hold 
Hold. Dose 
reduction. 
Discontinue if not 
resolved in 4 weeks. 
1st occurrence: hold. 
Dose reduction. 
2nd occurrence: hold. 2 
dose reductions. 
Discontinue if not 
resolved in 4 weeks 
Gem = gemcitabine; NP = nab-paclitaxel 
Hold = Hold dosing of investigational product until toxicity resolves to “Continue” or below lowest Grade stated in this table. 
Discontinue = permanently discontinue that investigational product 
a If Grade 4 infusion reaction is thought to be related to NP hypersensitivity, nab-paclitaxel- should be permanently 
discontinued. 
b Reduce current dose. NP and gemcitabine dose can be re-escalated to previous dose level for Grade 3 neutropenia and 
Grade 2 thrombocytopenia < 1 week 
c Patients may only continue treatment for transient Grade 4 toxicity with approval of the Medical Monitor. 
d Any other Grade 3 nivolumab-related adverse event lasting > 7 days, except endocrinopathies controlled with physiologic 
hormone replacement or laboratory abnormalities, except as noted above, requires discontinuation of nivolumab. 
 
8.5.5 
Criteria for Treatment Continuation within a Cycle 
During any cycle, administration of investigational products should be held for toxicities and 
grades specified in Section 8.5.1 through Section 8.5.4. 
Dose of APX005M held on Day 3 can be administered on Day 10 if NP/Gem is given on Day 8 
and all APX005M-related toxicities are ≤ Grade 1 excluding: 
• Grade 2 neuropathy 
• Grade 2 alopecia 
• Grade 2 fatigue 
• Grade 2 endocrinopathies 
• Grade 2 or 3 neutropenia without fever 
A dose of NP and/or gemcitabine held on Day 8 can be administered on Day 22 if all 
chemotherapy-related toxicities are ≤ Grade 1, except that the following are permitted: 
• Grade 2 neuropathy 
• Grade 2 alopecia 
• Grade 2 fatigue 
• Grade 2 AST or ALT increase 
• Grade 2 endocrinopathies 
• Grade 2 neutropenia 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
70 
 
8.5.6 
APX005M, NP, and Gem Dose Modifications 
If, in the opinion of the Investigator, dose reductions are required, they should be instituted as 
shown in Table 8. 
Table 8 
APX005M, NP, and Gem Dose Modifications 
APX005M 
Current Dose 
Modified Dose 
0.3 mg/kg 
0.2 mg/kg 
0.2 mg/kg 
0.1 mg/kg 
0.1 mg/kg 
0.06 mg/kg 
0.06 mg/kg 
0.03 mg/kg 
NP 
Current Dose 
Modified Dose 
125 mg/m2 
100 mg/m2 
100 mg/m2 
80 mg/m2 
80 mg/m2 
65 mg/m2 
Gem 
Current Dose 
Modified Dose 
1000 mg/m2 
800 mg/m2 
800 mg/m2 
640 mg/m2 
Gem = gemcitabine; NP = nab-paclitaxel 
 
8.6 
Study Treatment Assignment 
Treatment assignments and randomization will be managed by PICI. 
8.6.1 
Phase 1b 
In Phase 1b, patients will be enrolled into 1 of 4 cohorts (B1, B2, C1, and C2) as summarized 
in Table 9. 
Table 9 
Phase 1b Treatment Assignment 
Arm 
Regimen 
Number of DLT-Evaluable Patients 
B1 
NP/Gem/APX005M 0.1 mg/kg 
6 
B2 
NP/Gem/APX005M 0.3 mg/kg 
6 
C1 
Nivolumab/NP/Gem/APX005M 0.1 mg/kg 
6 
C2 
Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
6 
DLT = dose-limiting toxicity; Gem = gemcitabine; NP = nab-paclitaxel 
 
8.6.2 
Phase 2 
A total of approximately 105 patients will be randomized/enrolled in the Phase 2 portion of 
the study, including 12 patients from Phase 1b (i.e., 6 patients on B2 and 6 patients on C2).  
Approximately 93 patients will be randomized/enrolled and treated only in Phase 2.  
Recruitment is competitive and regulated in the current version of the Cohort Management 
Plan (a separate document). In step 1 of randomization, 12 of the 93 new patients will be 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
71 
 
randomized to the 3 arms in a 4:1:1 ratio in Arms A1, B2, and C2, to achieve balance in the 
total number of patients enrolled on the arms (since Arm A1 does not accrue in Phase 1b, more 
patients need to be enrolled in Arm A1). In step 2 of randomization, 81 patients will be 
randomized to Arms A1, B2, and C2 in a 1:1:1 allocation. The randomization cohorts are 
outlined in Table 10. 
Table 10 
Phase 2 Design 
Arm 
Regimen 
Phase 1b 
Phase 2 
Total 
Step 1 
Step 2 
 
 
Number of 
Patients 
Number 
of Patients 
Number of 
Patients 
Number of 
Patients 
A1 
Nivolumab/NP/Gem 
0 
8 
27 
35 
B2 
NP/Gem/APX005M 0.3 mg/kg 
6 
2 
27 
35 
C2 
Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
6 
2 
27 
35 
Gem = gemcitabine; NP = nab-paclitaxel 
a If Arm B2 and/or C2 is too toxic in Phase 1b, Arms B1 and C1 (APX005M 0.1 mg/kg) will be used in the Phase 2 portion. 
The dose of APX005M will remain the same in each arm in Phase 2, so even if B2 is safe and C2 is toxic, B1 and C1 will 
still be used in the randomization 
8.7 
Blinding 
This is an open-label study with no blinding. 
8.8 
Treatment Accountability and Compliance 
Administration of study drugs will be supervised by study personnel or assigned infusion room 
nursing staff, who will monitor compliance. 
8.9 
Prior and Concomitant Illnesses and Medications 
8.9.1 
Prior and Concomitant Illnesses 
Investigators should document all prior significant illnesses. Additional illnesses present at the 
time when informed consent is given and up to the time of first dosing (Cycle 1 Day 1) are to 
be regarded as concomitant illnesses. Illnesses first occurring or detected during the study 
and/or worsening of a concomitant illness during the study are to be documented as AEs on 
the appropriate eCRF. 
8.9.2 
Prior and Concomitant Medications 
All medications and other treatments taken by the patient during the study, including those 
treatments initiated prior to the start of the study, must be recorded on the appropriate eCRF. 
The entry must include the dose, regimen, route, indication, and dates of use. 
Medications taken by or administered to the patient for the time period before screening will 
be recorded on the eCRF. 
Patients who are taking the following medications prior to screening must have the minimum 
washout periods specified below and must not take the medications for the duration of the 
study. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
72 
 
• Systemic corticosteroids at physiologic dose (equivalent to dose of 10 mg oral 
prednisone): 14 days before first dose 
• Any investigational agent 28 days before first dose 
8.9.3 
Prohibited Medications 
After the baseline visit, medication to treat minor treatment-emergent illness(es) is generally 
permitted; however, the following therapies are expressly prohibited throughout the study: 
• Any other investigational drug, chemotherapy, extensive radiotherapy (involving ≥ 30% 
of bone marrow) or any other anti-cancer therapy (biologics or other targeted therapy) 
and anti-neoplastic steroid therapy. 
• Immunosuppressive agents (except for patients treated for immune-mediated AE) 
• Chronic systemic corticosteroids at physiologic dose (equivalent to dose of 10 mg oral 
prednisone) 14 days before first dose (except for patients who during the study 
developed endocrinopathies requiring stable doses of hormone replacement therapy 
such as hydrocortisone). A temporary course of steroids may be permitted, once 
discussed and approved by the medical monitor. 
o Transient use of steroids to control contrast agent allergies for radiographic 
studies are permitted. 
• Any live attenuated vaccine therapies used for the prevention of infectious diseases (for 
up to 30 days prior or after to any dose of study drug). 
• Antibodies or immunotherapy directed against interleukins or other cytokines or 
chemokines. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
73 
 
9 
STUDY PROCEDURES 
The timing of procedures and assessments to be performed throughout the study is presented 
in Table 11 and Table 12 (for treatment arms including APX005M) and Table 13 (for 
treatment arms not including APX005M).  
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
74 
 
Table 11 
Schedule of Assessments (For Arms Including APX005M, Phase Ib) 
Study Day 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 and Subsequent 
Cycles 
EOT 
 
Follow-Uph, s, t 
D1 
D3b 
D4b 
D8 
D15 
D1 
D3b 
D4b 
D8 
D15 
D1u 
D3b 
D8 
D15 
D30 
D100 
Survival 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
12-Lead Electrocardiogramd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination/Performance 
Status 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Serum Chemistry and Hematologye 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications Review 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Vital Signs (temperature, blood 
pressure, respiratory rate, pulse)f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body Weight 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Administration of Study Drugsg 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse Events Evaluationh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Sampling for PKi and ADAj 
Assessment 
 
 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
Blood Sampling for Immune 
Biomarkersk 
Xk 
X 
Xl 
Xl 
Xl 
X 
X 
 
 
 
 
X 
 
 
 
Xk 
 
 
 
Tumor Markerm 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessmentn, o 
X 
 
 
 
 
 
 
 
 
 
 
X 
Q8W 
 
 
 
Xp 
 
 
 
Tumor Biopsyq 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Testingr 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Follow-up for overall survival and 
new anti-cancer therapyt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
ADA = anti-drug antibody; AE = adverse event; C = Cycle; CA19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; D = Day; EOI = end of infusion; EOT = end of 
treatment; PK = pharmacokinetics; Q8W = every 8 weeks; RECIST = Response Evaluation Criteria in Solid Tumors. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
75 
 
a Screening evaluations are to be conducted within 28 days before the start of protocol therapy. Some screening procedures may occur on Cycle 1 Day 1 as appropriate. 
b Patients receiving APX005M on Day 3 must return to the study site within 24 hours after dose administration (ie, on Day 4) for assessment of AEs, vital signs, and collection of 
samples for clinical laboratory tests, PK/ADA and translational assessments. If APX005M dosing is delayed from Day 3 to Day 10 due to toxicity, as noted in Section 8.5.5, then 
the Day 4 assessments must be performed on Day 11.  
c Pregnancy test (women of childbearing potential), at Screening and within 24 h before first dose protocol therapy unless screening happens with 24 h of first dose, in which cases 
testing is not to be done twice. Either serum or urine testing may be used. During the study, monthly pregnancy testing (on Day 1 of each cycle) is required. 
d Performed in triplicate. May be repeated if necessary. 
e See Table 14 for specific chemistry and hematology laboratory assessments. All laboratory assessments should be reviewed prior to Day 8 of each cycle. 
f For Cycles 1-2, on days when APX005M is given, vital signs should be measured pre-infusion, at the end of infusion (EOI), as well as 2 and 5 hours post-EOI. During all other 
visits, vital signs should be measured pre-infusion. A window of ±10 minutes is permitted. 
g Premedication is given 30 minutes before each administration of APX005M and includes a regimen containing an oral H1 antagonist (e.g., loratadine 10 mg), oral non-steroidal 
anti-inflammatory- (e.g., ibuprofen 400 mg), acetaminophen 650 mg, and optionally an oral H2 antagonist (e.g., ranitidine 150-300 mg, famotidine 10-40 mg), or also optionally, 
ondansetron doses (route of administration, and frequency per institutional standards). A window of -10 minutes is permitted (e.g. premedications may be administered up to 
40 minutes, but no later than 30 minutes, prior to APX005M).  
h See Section 12 for detailed SAE and AE reporting requirements. The observation period for collection of AEs and AESIs extends from the start of study drug through 100 days 
after the last dose of study drug or the initiation of new anti-cancer therapy (whichever occurs first). The observation period for collection of SAEs extends from the time the 
patient signs consent through 100 days after the last dose of study drug or initiated of new anti-cancer therapy (whichever occurs first).  After treatment discontinuation, AEs 
related to study drug are to be followed until resolution or deemed irreversible by Investigator.  SAEs related to study drug must be reported at all times, regardless of whether 
new anti-cancer therapy has been initiated, and followed until resolution or deemed irreversible by the Investigator.   
i Blood samples for PK analysis are to be collected in Cycle 1 at pre-dose, EOI, 4 h (after starting infusion), Day 4 (24 h), Day 8, and Day 15. In Cycles 2-4, samples are to be 
collected at pre-dose and EOI, as described in the Laboratory Manual. 
j Blood samples for detection of ADA are to be collected, before APX005M administration, at Day 3 of Cycles 1-4 and at EOT. PK and ADA sampling will occur as a single blood 
draw, as described in the Laboratory Manual.  
k Only to be collected if the patient has given consent to keep tissue and blood biomarker samples for research at the time of screening assessment. If a patient discontinues treatment 
and begins any new anti-cancer therapy prior to the EOT visit, then EOT blood samples for immune biomarkers will not be collected.  For patients that remain on study for 1 year 
or more, immune biomarkers should be collected at 1 year and then Q6M thereafter, as specified in Section 11.   
l Circulating soluble analytes only. 
m CA19-9 and CEA will be collected if performed as part of standard of care. 
n Per standard of care to provide data for RECIST measurements as appropriate for each patient per the investigator physician. At a minimum at baseline this includes imaging of 
the chest, abdomen, and pelvis. 
o Restaging radiographic studies will be obtained at 8-week intervals after initiating study treatment for the first year, and at 3-month intervals thereafter. A window of -7 days is 
permitted (see Section 10). 
p See Section 10 for description of disease assessment collection after EOT. 
q A baseline tumor tissue sample is mandatory for enrollment. Archival tissue must be identified or a fresh tumor biopsy (3 to 4 core needle or excisional biopsies) obtained. Fine 
needle action is not acceptable. If medically feasible, a mandatory biopsy will also be obtained during Cycle 2 (after second dose APX005M). Otherwise, any on-treatment biopsy 
will be accepted unless there is no lesion that can be safely biopsied. Additional biopsies may be performed for patients who have prolonged stable disease, defined as more than 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
76 
 
two, consecutive disease assessments by RECIST v1.1 and/or if tumor shrinkage is initially demonstrated, followed by a new lesion and/or radiological disease progression.   Ad 
hoc biopsy collection is also permitted with the approval of the medical monitor. 
r Thyroid function testing is performed at Screening and on Day 1 of every other cycle starting from Cycle 3. 
s Patients should be seen at follow-up visits on Day 30 (± 7 days) and Day 100 (± 14 days) after last dose to be assessed for AEs, regardless of whether new anti-cancer therapy has 
been initiated.  
t   Patients are to be followed-up until death or for up to 5 years. After the Day 100 follow-up visit, patients will be contacted by telephone approximately every 3 months to collect 
survival status and new anti-cancer therapy. In addition, ad hoc collection of survival and new anti-cancer therapy may be requested by the Sponsor.  
u After Cycle 2, a window of ± 3 days is permitted at Day 1 for all subsequent cycles.  Should Day 1 be moved, all subsequent cycle visits need to be moved, as well (e.g., if Day 1 
is delayed 3 days, Days 3, 8 and 15 would be delayed 3 days, as well). 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
77 
 
ADA = anti-drug antibody; AE = adverse event; C = Cycle; CA19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; D = Day; EOI = end of infusion; EOT = end of 
treatment; PK = pharmacokinetics; Q8W = every 8 weeks; RECIST = Response Evaluation Criteria in Solid Tumors. 
 
Table 12 
Schedule of Assessments (For Arms Including APX005M, Phase 2) 
Study Day 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 and 
Subsequent Cycles 
EOT 
Follow-Upi,v,w 
D1 
D3b 
D4b 
D8 
D15 
D1 
D3b 
D4b 
D8 
D15 D1x 
D3b 
D8 
D15 
D30 
D100 
Survival 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
12-Lead Electrocardiogramd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination/ Performance 
Status 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Serum Chemistry and Hematologye 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications Review 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Vital Signs (temperature, blood 
pressure, respiratory rate, pulse)f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body Weight 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Administration of Study Drugsg, h 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse Events Evaluationi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Sampling for PKj and ADAk 
Assessment 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
Blood Sampling for Immune 
Biomarkersl 
Xm 
X 
Xn 
 
 
X 
X 
 
 
 
 
Xl 
 
 
 
Xl 
 
 
 
Stool Sample for Microbiome Profile o 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Markerp 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessmentq, r 
X 
 
 
 
 
 
 
 
 
 
 
X 
Q8W 
 
 
 
Xs 
 
 
 
Tumor Biopsyt 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
(optional) 
 
 
 
Thyroid Function Testingu 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Follow-up for overall survival and new 
anti-cancer therapyw 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
78 
 
a Screening evaluations are to be conducted within 28 days before the start of protocol therapy. Some screening procedures may occur on Cycle 1 Day 1 as appropriate. 
b For patients receiving APX005M, the Day 4 visit (or Day 11 visit if dosing is delayed) is optional after Cycle 2. 
c Pregnancy test (women of childbearing potential), at Screening and within 24 h before first dose protocol therapy unless screening happens with 24 h of first dose, in which cases 
testing is not to be done twice. Either serum or urine testing may be used. During the study, monthly pregnancy testing (on Day 1 of each cycle) is required. 
d Performed in triplicate. May be repeated if necessary. 
e See Table 14 for specific chemistry and hematology laboratory assessments. All laboratory assessments should be reviewed prior to Day 8 of each cycle. 
f For Cycles 1-2, on days when APX005M is given, vital signs should be measured pre-infusion, at the end of infusion (EOI), as well as 2 and 5 hours post-EOI. During all other 
visits, vital signs should be measured pre-infusion. A window of ±10 minutes is permitted. 
g Patients must receive the first dose of study drug within 3 days of randomization. 
h Premedication is given 30 minutes before each administration of APX005M and includes a regimen containing an oral H1 antagonist (e.g., loratadine 10 mg), oral non-steroidal 
anti-inflammatory- (e.g., ibuprofen 400 mg), acetaminophen 650 mg, and optionally an oral H2 antagonist (e.g., ranitidine 150-300 mg, famotidine 10-40 mg), or also optionally, 
ondansetron doses (route of administration, and frequency per institutional standards). A window of -10 minutes is permitted (e.g. premedications may be administered up to 40 
minutes, but no later than 30 minutes, prior to APX005M). 
i See Section 12 for detailed SAE and AE reporting requirements. The observation period for collection of AEs and AESIs extends from the start of study drug through 100 days 
after the last dose of study drug or the initiation of new anti-cancer therapy (whichever occurs first). The observation period for collection of SAEs extends from the time the 
patient signs consent through 100 days after the last dose of study drug or initiated of new anti-cancer therapy (whichever occurs first).  After treatment discontinuation, AEs 
related to study drug are to be followed until resolution or deemed irreversible by Investigator.  SAEs related to study drug must be reported at all times, regardless of whether 
new anti-cancer therapy has been initiated, and followed until resolution or deemed irreversible by the Investigator.   
j Blood samples for PK analysis are to be collected at pre-dose and EOI, in Cycles 1 to 4, as described in the Laboratory Manual. 
k Blood samples for detection of ADA are to be collected, before APX005M administration, at Day 3 of Cycles 1-4 and at EOT. PK and ADA sampling will occur as a single blood 
draw, as described in the Laboratory Manual. 
l Immune biomarker collections through Cycle 4 and at EOT. If a patient discontinues treatment and begins any new anti-cancer therapy prior to the EOT visit, then EOT blood 
samples for immune biomarkers will not be collected.  For patients that remain on study for 1 year or more, immune biomarkers should be collected at 1 year and then Q6M 
thereafter, as specified in Section 11.   
m Only to be collected if the patient has given consent to keep tissue and blood biomarker samples for research at the time of screening assessment. 
n Circulating soluble analytes only. 
o Stool samples will be collected for microbiome profiling at screening (prior to C1D1) and, if possible, during Cycle 2. Otherwise, any on-treatment stool collection will be accepted. 
p CA19-9 and CEA are required at Cycle 1 Day 1 and will continue to be collected any time on study if performed as part of standard of care. 
q Per standard of care to provide data for RECIST measurements as appropriate for each patient per the investigator physician. At a minimum at baseline this includes imaging of 
the chest, abdomen, and pelvis. 
r Restaging radiographic studies will be obtained at 8-week intervals after initiating study treatment for the first year, and at 3-month intervals thereafter. A window of -7 days is 
permitted (see Section 10). 
s See Section 10 for description of disease assessment collection after EOT. 
t A baseline tumor tissue sample is mandatory for enrollment. Archival tissue must be identified or a fresh tumor biopsy (3 to 4 core needle or excisional biopsies) obtained. Fine 
needle aspiration is not acceptable. If medically feasible, a mandatory biopsy will also be obtained during Cycle 2 (after second dose APX005M). Otherwise, any on-treatment 
biopsy will be accepted unless there is no lesion that can be safely biopsied. Additional biopsies may be performed for patients who have prolonged stable disease, defined as more 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
79 
 
than two, consecutive disease assessments by RECIST v1.1 and/or if tumor shrinkage is initially demonstrated, followed by a new lesion and/or radiological disease progression.    
Ad hoc biopsy collection is also permitted with the approval of the medical monitor. 
u Thyroid function testing is performed at Screening and on Day 1 of every other cycle starting from Cycle 3. 
v Patients should be seen at follow-up visits on Day 30 (± 7 days) and Day 100 (± 14 days) after last dose to be assessed for AEs, regardless of whether new anti-cancer therapy has 
been initiated.  
w Patients are to be followed-up until death or for up to 5 years. After the Day 100 follow-up visit, patients will be contacted by telephone approximately every 3 months to collect  
    survival status and new anti-cancer therapy. In addition, ad hoc collection of survival and new anti-cancer therapy may be requested by the Sponsor. 
x After Cycle 2, a window of ± 3 days is permitted at Day 1 for all subsequent cycles.  Should Day 1 be moved, all subsequent cycle visits need to be moved, as well (e.g., if Day 1 
is delayed 3 days, Days 3, 8 and 15 would be delayed 3 days, as well). 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
80 
 
Table 13  Schedule of Assessments (For Arms Not Including APX005M, Phase 2) 
 
 
Cycle 1 
Cycle 2 
Cycle 3 and Subsequent 
Cycles 
EOT 
 
Follow-Uph, r, s 
Study Day 
Screeninga 
D1 
D8 
D15 
D1 
D8 
D15 
D1t 
D8 
D15 
D30 
D100 
Survival 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testb 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
12-Lead Electrocardiogramc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination/Performance 
Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Serum Chemistry and Hematologyd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications Review 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Vital Signs (temperature, blood 
pressure, respiratory rate, pulse)e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body Weight 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Administration of Study Drugsf, g 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse Events Evaluationh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Sampling for Immune 
Biomarkersi 
Xj 
X 
 
X 
X 
 
 
Xi 
 
 
Xi 
 
 
 
Stool for Microbiome Profilingk 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Tumor Markerl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessmentm, n 
X 
 
 
 
 
 
 
X  
Q8W 
 
 
Xo 
 
 
 
Tumor Biopsyp 
X 
 
 
 
 
X 
 
 
 
 
X 
(optional) 
 
 
 
Thyroid Function Testingq 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
Follow-up for overall survival and 
new anticancer therapys 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
AE = adverse event; C = Cycle; CA19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; D = Day; EOT = end of treatment; Q8W = every 8 weeks; RECIST = 
Response Evaluation Criteria in Solid Tumors. 
a Screening evaluations are to be conducted within 28 days before the start of protocol therapy. Some screening procedures may occur on Cycle 1 Day 1 as appropriate. 
b Pregnancy test (women of childbearing potential), at Screening and within 24 h before first dose protocol therapy unless screening happens with 24 h of first dose, in which cases 
testing is not to be done twice. Either serum or urine testing may be used. During the study, monthly pregnancy testing (on Day 1 of each cycle) is required. 
c Performed in triplicate. May be repeated if necessary. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
81 
 
d See Table 14 for specific chemistry and hematology laboratory assessments. 
e Vital signs should be measured pre-infusion.  
f After Cycle 2, a window of ± 3 days after end of previous cycle is permitted for Day 1 of all subsequent cycles. 
g Patients must receive the first dose of study drug within 3 days of randomization. 
h See Section 12 for detailed SAE and AE reporting requirements. The observation period for collection of AEs and AESIs extends from the start of study drug through 100 days 
after the last dose of study drug or the initiation of new anti-cancer therapy (whichever occurs first). The observation period for collection of SAEs extends from the time the 
patient signs consent through 100 days after the last dose of study drug or initiated of new anti-cancer therapy (whichever occurs first).  After treatment discontinuation, AEs 
related to study drug are to be followed until resolution or deemed irreversible by Investigator.  SAEs related to study drug must be reported at all times, regardless of whether 
new anti-cancer therapy has been initiated, and followed until resolution or deemed irreversible by the Investigator.   
i Immune biomarker collections through Cycle 4 and at EOT. If a patient discontinues treatment and begins any new anti-cancer therapy prior to the EOT visit, then EOT blood 
samples for immune biomarkers will not be collected.  For patients that remain on study for 1 year or more, immune biomarkers should be collected at 1 year and then Q6M 
thereafter, as specified in Section 11.   
j Only to be collected if the patient has given consent to keep tissue and blood biomarker samples for research at the time of screening assessment. 
k In Phase 2, Stool samples will be collected for microbiome profiling at screening (prior to C1D1) and, if possible, during Cycle 2. Otherwise, any on treatment stool collection 
will be accepted. 
l CA19-9 and CEA are required at Cycle 1 Day 1 and will continue to be collected any time on study if performed as part of standard of care. 
m Per standard of care to provide data for RECIST measurements as appropriate for each patient per the investigator physician. At a minimum at baseline this includes imaging of 
the chest, abdomen, and pelvis. 
n Restaging radiographic studies will be obtained at 8-week intervals after initiating study treatment for the first year, and at 3-month intervals thereafter. A window of -7 days is 
permitted (see Section 10). 
o See Section 10 for description of disease assessment collection after EOT. 
p A baseline tumor tissue sample is mandatory for enrollment. Archival tissue must be identified or a fresh tumor biopsy (3 to 4 core needle or excisional biopsies) obtained. Fine 
needle aspiration is not acceptable. If medically feasible, a mandatory biopsy will also be obtained during Cycle 2 (after third dose nivolumab). Otherwise, any on-treatment biopsy 
will be accepted unless there is no lesion that can be safely biopsied. Additional biopsies may be performed for patients who have prolonged stable disease, defined as more than 
two, consecutive disease assessments by RECIST v1.1 and/or if tumor shrinkage is initially demonstrated, followed by a new lesion and/or radiological disease progression.  Ad 
hoc biopsy collection is also permitted with the approval of the medical monitor. 
q Thyroid function testing is performed at Screening and on Day 1 of every other cycle starting from Cycle 3. 
r Patients should be seen at follow-up visits on Day 30 (± 7 days) and Day 100 (± 14 days) after last dose to be assessed for AEs, regardless of whether new anti-cancer therapy has 
been initiated.  
s  Patients are to be followed-up until death or for up to 5 years. After the Day 100 follow-up visit, patients will be contacted by telephone approximately every 3 months to collect  
    survival status and new anti-cancer therapy. In addition, ad hoc collection of survival and new anti-cancer therapy may be requested by the Sponsor. 
t  After Cycle 2, a window of ± 3 days is permitted at Day 1 for all subsequent cycles.  Should Day 1 be moved, all subsequent cycle visits need to be moved, as well (e.g., if Day 1   
    is delayed 3 days, Days 3, 8 and 15 would be delayed 3 days, as well). 
 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
82 
 
Timing of Study Assessments for Treatment Delays 
Study assessments must be completed on the day the patient receives treatment. If treatment is 
delayed, the study assessments will be postponed. Only clinical laboratory assessments that 
were not completed, or were clinically relevant on the missed treatment day, are required be 
performed/repeated on the day treatment resumes. 
APX005M Dose Delays: Patients in Phase 1b receiving APX005M on Day 3 must return to 
the study site within 24 hours after dose administration (ie, on Day 4) for assessment of AEs, 
vital signs, and collection of samples for clinical laboratory tests, PK/ADA and translational 
assessments. If APX005M dosing is delayed from Day 3 to Day 10 due to toxicity, as noted in 
Section 8.5.5, then the Day 4 assessments must be performed on Day 11. For patients receiving 
APX005M in Phase 2, the Day 4 visit (or Day 11 visit if dosing is delayed) is optional after 
Cycle 2. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
83 
 
10 
EFFICACY ASSESSMENTS 
Participants will undergo tumor assessments as described in the Schedule of Assessments (see 
Section 9): 
• Disease assessments are performed to provide data for RECIST. At a minimum, at 
baseline, this should include imaging of the chest, abdomen, and pelvis. 
• Throughout the study, restaging radiographic studies will be obtained at 8-week 
intervals after initiating study treatment for the first year, and at 3-month intervals 
thereafter. A window of ±7 days is permitted. 
Disease assessments performed as part of standard of care will continue to be collected after 
treatment discontinuation.  The following criteria serve to provide additional guidelines around 
when disease assessments (i.e., RECIST measurements) should be collected after a patient has 
discontinued study treatment, and if treatment is continued beyond radiological progression: 
• 
If a patient discontinues treatment due to radiographic disease progression (PD), as 
defined by RECIST v1.1, then no additional disease assessments are collected. These 
patients should be followed for survival status until death, withdrawal of consent, or 
study termination. Safety follow-up should continue as described in the Schedule of 
Assessments (Section 9). 
• 
If a patient has elected to continue treatment after having demonstrated PD per 
RECIST v1.1 criteria, disease assessments should continue to be collected as described 
in the Schedule of Assessments (Q8W; Section 9). 
• 
If a patient discontinues treatment due to symptomatic deterioration, every attempt 
should be made to continue collecting standard of care disease assessments: 
o If not medically feasible, clinical progression needs to be documented as the 
reason for treatment discontinuation. 
o If medically feasible, standard of care disease assessments should continue to 
be collected until the patient has demonstrated PD per RECIST v1.1 criteria. 
o In either scenario, these patients should be followed for survival status until 
death, withdrawal of consent, or study termination. Safety follow up should 
continue as described in the Schedule of Assessments (Section 9). 
• 
If a patient discontinues treatment for any other reason (e.g. toxicity, protocol 
deviation), standard of care disease assessments should continue to be collected until 
the patient has demonstrated PD per RECIST v1.1 criteria. These patients should be 
followed for survival status until death, withdrawal of consent, or study termination. 
Safety follow up should continue as described in the Schedule of Assessments (Section 
9). 
• 
If a patient initiates new anti-cancer therapy, collection of disease assessments is no 
longer required. These patients should be followed for survival status until death, 
withdrawal of consent, or study termination. Safety follow up should continue as 
described in the Schedule of Assessments (Section 9). 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
84 
 
• 
If a patient discontinues treatment and withdraws consent, no additional assessments 
or follow-up should be performed. 
10.1 
Response Criteria 
Response and progression will be evaluated in this study using the international criteria 
proposed by the RECIST Version 1.1 Committee. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria. 
Note: Lesions are either measurable or non-measurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. The irradiated index lesion is not included in the RECIST 
determination; however, tumor response of this lesion will be assessed and tabulated separately 
using criteria from RECIST. 
10.1.1 
Definitions of Measurable and Non-Measurable Disease  
Measurable disease is defined as at least 1 lesion whose longest diameter can be accurately 
measured as ≥ 2.0 cm with conventional techniques or as ≥ 1.0 cm with spiral computed 
tomography (CT) scan. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules, palpable lymph nodes). Lesions on chest x-ray are acceptable 
as measurable lesions when they are clearly defined and surrounded by aerated lung. However, 
CT is preferable. 
Lymph nodes with a short axis of > 15 mm by CT are considered measurable and assessable 
as target lesions. Only the short axis measurement should be included in the sum of lesions in 
calculation of tumor response. Nodes that shrink to < 10 mm short axis are considered normal. 
All other lesions (or sites of disease), including small lesions (longest diameter < 2.0 cm with 
conventional techniques or as < 1.0 cm with spiral CT) are considered non-measurable disease. 
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, abdominal masses (not followed by CT or magnetic resonance imaging [MRI]), 
and cystic lesions are all non-measurable. 
10.1.2 
Guidelines for Evaluation of Measurable Disease 
Assessment of measurable disease will be performed locally at each study site. 
Measurement Methods: The same method of assessment and the same technique should be 
used to characterize each identified and reported lesion at baseline and during follow-up. For 
patients having only lesions measuring at least 1 cm to < 2 cm, spiral CT imaging must be used 
for both pre- and post-treatment tumor assessments. Imaging-based evaluation is preferred to 
evaluation by clinical examination when both methods have been used at the same evaluation 
to assess the antitumor effect of a treatment. 
New lesions on the basis of positron emission tomography (PET)/CT using 
fluorodeoxyglucose (FDG)-PET/CT imaging can be identified according to the following: 
• Negative FDG-PET/CT at baseline, with a positive FDG-PET/CT at follow-up is a sign 
of PD based on a new lesion. 
• No FDG-PET/CT at baseline and a positive FDG-PET/CT at follow up:  


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
85 
 
o If the positive FDG-PET/CT at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. 
If the positive FDG-PET/CT at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET/CT scan). 
If the positive FDG-PET/CT at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. A “positive” FDG-
PET/CT scan lesion means one that is visually FDG avid relative to the background tissue on 
the attenuation corrected image. 
10.1.3 
Measurement of Effect 
10.1.3.1 
Target Lesions 
All measurable lesions up to a maximum of 5 lesions representative of all involved organs 
should be identified as target lesions and recorded and measured at baseline. If the protocol 
specified studies are performed, and there are fewer than 5 lesions identified (as there often 
will be), there is no reason to perform additional studies beyond those specified in the protocol 
to discover new lesions. For any 1 organ, no more than 2 lesions need to be measured. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repetitive measurements (either by imaging techniques or clinically). 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
10.1.3.2 
Non-Target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required, and these lesions should be followed 
in accord with the following section. 
10.1.3.3 
Response Criteria 
All identified sites of disease must be followed on re-evaluation. Specifically, a change in 
objective status to either a PR or CR cannot be done without rechecking all identified sites (i.e., 
target and non-target lesions) of pre-existing disease. 
10.1.3.4 
Evaluation of target lesions 
• CR: Disappearance of all target lesions 
• PR: At least a 30% decrease in the sum of the LD of target lesions, taking as reference 
the baseline sum LD 
• PD: At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. 
(Note: the appearance of one or more new lesions at the end of cycle scan is also 
considered progression). 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
86 
 
• SD: 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started 
10.1.3.5 
Evaluation of non-target lesions 
• CR: Disappearance of all non-target lesions  
• Non-CR/Non-PR: Persistence of one or more non-target lesion without evidence of 
unequivocal progression of the non-target lesions or appearance of new lesions 
• PD: Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances 
the opinion of the treating physician should prevail, and the progression status should be 
confirmed at a later time by the PI. 
10.1.3.6 
Overall Objective Status 
The overall OR status for an evaluation is determined by combining the patient’s status on 
target lesions, non-target lesions, and new disease. 
Symptomatic deterioration: Patients with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, 
and not either related to study treatment or other medical conditions, should be reported as PD 
due to “symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment due to symptomatic deterioration that may 
include weight loss > 10% of body weight, worsening of tumor-related symptoms, and/or 
decline in performance status of > 1 level on ECOG scale. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
87 
 
11 
PHARMACOKINETICS AND PHARMACODYNAMICS 
11.1 
Pharmacokinetic Sampling 
PK analysis will involve determination of circulating concentrations of APX005M at times 
specified in Table 11 and Table 12. 
11.1.1 
Blood Samples 
Blood samples for PK analysis of APX005M levels will be collected as follows: 
Phase 1b: PK in Cycle 1 at pre-dose, end of infusion (EOI), 4 h (after starting infusion), 24 h, 
Day 8, and Day 15. Cycles 2-4: pre-dose, EOI and EOT. 
Phase 2: Pre-dose and EOI samples in Cycles 1-4 and EOT. 
For patients who begin a new anti-cancer therapy prior to their EOT visit, an EOT PK blood 
draw is not required.   
Samples will be collected at the time points indicated in the Schedule of Assessments (Table 
11 and Table 12). The actual date and time of each blood sample collection will be recorded. 
The timing of PK samples may be altered and/or PK samples may be obtained at additional 
time points to ensure thorough PK monitoring. 
Details of PK blood sample collection, processing, storage, and shipping procedures are 
provided in a separate Laboratory Manual.  
11.1.2 
Analytical Methodology 
The concentration of APX005M will be determined from the samples using a validated 
analytical method. See Section 13.5 for a list of PK parameters that will be calculated. 
11.2 
Immune Endpoints 
Specimen Collection: Tumor tissue (archival, fresh core or excisional tumor biopsies) must 
be available or collected prior to the start of treatment. If medically feasible, a mandatory 
biopsy will also be obtained during Cycle 2. For arms including APX005M, the biopsy will 
take place after the second dose of APX005M and, for arms not including APX005M, after the 
third dose of nivolumab. Otherwise, any on-treatment biopsy will be accepted unless there is 
no lesion that can be safely biopsied. Additional biopsies may be performed for patients who 
have prolonged stable disease, defined as stable for more than two, consecutive disease 
assessments by RECIST v1.1, and/or if tumor shrinkage is demonstrated, followed by a new 
lesion and/or radiological disease progression Ad hoc collections may also be performed with 
Medical Monitor approval.  
Blood for plasma, serum, circulating tumor DNA and PBMC will be collectedly at baseline 
and serially during therapy as noted above. Tumor samples and blood samples will be 
processed according to the study Laboratory Manual. 
Blood samples will be collected for immune biomarkers at Cycle 1 pre-dose on Day 3, Day 4 
(24 hours after start of APX005M infusion), and Day 8 during Phase 1b. For Phase 2, blood 
samples will be collected as outlined in the schedule of assessments at screening, through 
Cycle 4 and EOT. Ad hoc collections may also be performed with Medical Monitor approval. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
88 
 
For any patient who remains on study for 1 year, immune biomarkers may also be collected at 
1 year and then every 6 months (12, 18, 24, 30, etc. months). 
Blood samples for detection of ADA are to be collected before APX005M administration in 
Cycles 1-4, and at the EOT. 
Stool samples will be collected at screening (prior to Cycle 1, Day 1) and during Cycle 2, if 
possible. Otherwise, any on-treatment stool sample will be accepted. 
11.2.1 
Immune Biomarkers 
Detailed sample collection, processing, storage, and shipping procedures are provided in a 
separate Laboratory Manual. Depending on sample availability, a battery of immune assays is 
planned, that may include but will not necessarily limited to the following: 
Analysis of Myeloid and B Cell Activation: Using un-manipulated peripheral blood, monocytes, 
B cells, dendritic cells before and after treatment can be analyzed using flow cytometry to 
measure cell surface immune markers using a panel of immune parameters such as CD11b, 
CD19, CD123, CD11c (to define the subsets) and CD86, MHC class I and II, CD70, and CD54 
(to measure activation). For each parameter and each cell type, the percentage of cells positive 
for the marker and/or mean fluorescence intensity (MFI) at time points after treated can be 
compared to baseline and the change are calculated as %after/%baseline or MFIafter/MFIbaseline. 
Tissue Assessment: Tissue can be analyzed by hematoxylin and eosin staining and by 
immunohistochemistry for PD-L1 and for immune markers (such as CD45, CD68, CD3, CD8, 
CD4, Foxp3, CD20, myeloperoxidase), tumor markers (AFP, Ki-67, cleaved caspase 3), 
vascular (CD31) and stromal markers (collagen type I); and by Masson’s trichrome. The tumor 
may also be assessed by a mutational panel and if sufficient material is available, tumor whole 
exome sequencing (WES) and RNA sequencing may be performed. If RNA quality is 
insufficient, Nanostring technology or equivalent for immune activation gene expression may 
be performed instead of RNA-Seq or in addition. From germline WES from PBMC, HLA type 
can be determined. From tumor WES, tumor RNA-Seq, and germline WES, patient-specific 
neo epitopes arising from tumor somatic missense mutations can be predicted 
bioinformatically. 
Analysis of T-cell Activation: Together with complete blood count differentials, multiplex flow 
cytometry analysis of PBMC can 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, effector memory) or 
activation vs. exhaustion status can be assessed using additional markers such as Eomes, Tbet, 
Granzyme B, Ki-67, CD45RA, ICOS, CD45RO, CCR7, CD28, CD27, CD57, CD25, CD69, 
HLA-DR, CTLA4, and PD-1. When possible, trends may be tracked in T-cell subsets based 
on analysis of multiple post-treatment samples. NK cells subsets may also be assessed using 
CD16 and CD56, with CD69 as an activation marker. 
An analysis of PBMC may be additionally performed using CyTOF technology for deeper 
analysis of immune subsets and activation status in peripheral blood. 
Immune activation may be additionally assessed using RNA-Seq of PBMC. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
89 
 
Inflammatory Cytokines/Chemokines: Blood may be used to determine concentrations of 
cytokines and other circulating factors that may include but not limited to transforming growth 
factor (TGF)-β, IL-1, TNF-α, IL-6 and others using a multiplex platform or other standard 
analytical methods. 
T-cell Receptor (TCR) Deep Sequencing: DNA isolated from PBMC (as well as from paraffin-
embedded tissue) can be analyzed by deep sequencing to detect and track specific TCR clones. 
This technique permits assessment of specific adaptive immune response independent of 
having to know the particular relevant tumor antigen, which of course may vary patient to 
patient. Comparison of TCR beta sequence data in serial samples from blood and tumor can 
demonstrate de novo evolution of an anti-tumor T cell repertoire. 
Circulating tumor material: Blood samples may be tested for circulating biomarkers including 
cell-free DNA and tumor cells. 
Stool: Stool samples may be tested for microbiome profile using sequencing or metabolomic 
methods. 
Additional Research: Beyond the assays noted above, and provided that sample material is 
left over, and with approval of the overall PI and sponsor, investigators/sponsor may perform 
additional research assays on tumor or blood samples collected in this protocol. Future 
Biomedical Research may be conducted on specimens consented for future biomedical 
research during this clinical trial. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research. 
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of disease and/or their therapeutic treatments. The overarching goal is to use 
such information to understand disease, safety and potential treatments for future patients.  
11.2.3 
Anti-drug antibodies 
Pre-APX005M samples for PK/ADA are planned for ADA analysis, as well as at EOT. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
90 
 
12 
SAFETY ASSESSMENTS 
Safety assessments (vital signs, physical examinations, ECG recording, AEs, clinical 
laboratory results (routine hematology and biochemistry) are to be performed at protocol-
specified visits, as specified in the Schedule of Assessments (Table 11, Table 12, and Table 
13). 
12.1 
Vital Signs 
Vital signs (body temperature, heart rate, respiratory rate, systolic and diastolic blood pressure 
measurements) will be evaluated at the visits indicated in the Schedule of Assessments (Table 
11, Table 12, and Table 13). Blood pressure measurements are to be taken in the same arm for 
the duration of the study. Body weight (without shoes) will be recorded whenever vital signs 
are recorded, and height (without shoes) will be recorded at Screening only. 
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range blood pressure, respiratory rate or heart rate measurements will be 
repeated at the Investigator’s discretion. Any confirmed, clinically significant vital sign 
measurements must be recorded as AEs. 
12.2 
Physical Examination 
A complete physical examination will be performed at Screening Visit 1, according to 
institutional standards. Physical examinations will be performed by a physician or designated 
nurse practitioner or physician’s assistant. In addition, medical history will be recorded at 
Screening, including smoking history, if applicable. 
A limited physical examination to verify continued patient eligibility and to follow up any 
change in medical history will be performed at the visits indicated in the Schedule of 
Assessments (Table 11, Table 12, and Table 13). Symptom-driven limited physical 
examinations will be performed as clinically indicated at any study visit. All changes not 
present at baseline or described in the past medical history and identified as clinically 
noteworthy must be recorded as AEs. 
12.3 
Electrocardiogram 
A 12-lead resting ECG will be obtained at the visits indicated in the Schedule of Assessments 
(Table 11, Table 12, and Table 13). 
At Screening, the Investigator will examine the ECG traces for signs of cardiac disease that 
could exclude the patient from the study. An assessment of normal or abnormal will be 
recorded and if the ECG is considered abnormal, the abnormality will be documented on the 
CRF. ECGs will be repeated if clinically significant abnormalities are observed or artifacts are 
present. 
12.4 
Laboratory Assessments 
Samples for laboratory assessments (listed in Table 14) are to be obtained at designated visits 
as detailed in the Schedule of Assessments (Table 11 and Table 12 for arms including 
APX005M and Table 13 for arms not including APX005M). 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
91 
 
All laboratory reports must be reviewed, signed, and dated by the Investigator. A legible copy 
of all reports must be filed with both the patient's CRF and medical record (source document) 
for that visit. Any laboratory test result considered by the Investigator to be clinically 
significant should be considered an AE (clinically significant AEs include those that require 
an intervention). Clinically significant abnormal values occurring during the study will be 
followed until repeat test results return to normal/baseline, stabilize, or are no longer clinically 
significant.  
Table 14 
Laboratory Assessments 
12.5 
Adverse Events, Adverse Events of Special Interest, and Serious Adverse 
Events 
12.5.1 
Time Period and Frequency for Collecting Adverse Events, Serious Adverse 
Events, and Other Reportable Safety Event Information 
All AEs will be collected from the start of study drug through 100 days after the last dose of 
study drug, or until initiation of a new systemic anti-cancer therapy (whichever occurs first). 
All treatment-related AEs ongoing at the time of treatment discontinuation are to be followed 
until resolution, or deemed irreversible by the Investigator, regardless of whether new anti-
cancer therapy has been initiated. 
All SAEs, will be collected from the time the patient signs informed consent through 100 days 
after the last dose of study drug, or until initiation of a new systemic anti-cancer therapy 
(whichever occurs first).  SAEs related to study drug must be reported at all times, regardless 
of whether new anti-cancer therapy has been initiated.  All treatment-related SAEs must also 
to be followed until resolution, or deemed irreversible by the Investigator, regardless of 
whether new anti-cancer therapy has been initiated.   
Prior to initiation of study drug, only SAEs that are related to a protocol-mandated intervention, 
including those that occur prior to the assignment of study procedures (eg, screening invasive 
procedures, such as biopsies) should be reported. After obtaining informed consent, but prior 
to initiation of study drug, other medical occurrences will be recorded as medical history. 
Hematology 
Chemistry 
Urine 
Thyroid Function Tests 
Complete Blood Count 
(CBC) with differential, 
including: 
Hematocrit (Hct) 
Hemoglobin (Hb) 
Platelet Count 
 
White Blood Cell (WBC) 
Count with differential, 
including: 
Eosinophils 
Lymphocytes 
Neutrophils 
Albumin 
Alkaline Phosphate 
Alanine Aminotransferase 
(ALT) 
Alanine Aminotransferase 
(AST) 
Blood Urea Nitrogen (BUN) 
Carbon Dioxide (CO2) 
Creatinine 
Electrolytes (Na, K, Cl) 
Total Bilirubin 
Direct Bilirubin 
Standard analysis; 
can be dipstick 
Thyroid stimulating 
hormone (TSH) 
Triiodothyronine 
(T3)Free 
Triiodothyronine (FT3) 
Free thyroxine (FT4) 
 
Pregnancy test: A pregnancy test will be performed on all female subjects of child-bearing potential at 
Screening as noted above. Either serum or urine test is permitted. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
92 
 
If the Investigator learns of any SAE, including a death, at any time after the end of the AE 
reporting period, and he/she considers the event to be reasonably related to the study drug or 
study participation, the Investigator must promptly notify the Sponsor or its designee. The 
Investigator should report these events directly to the Sponsor or its designee, either by faxing 
or emailing the study-specific Serious Adverse Event Report Form (SAERF). 
12.5.2 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient, temporally associated with the use of 
study drug, whether or not considered related to the study drug. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a study drug. 
Investigators will seek information on AE at each patient contact. AEs reported by the patient 
(or, when appropriate, by a caregiver, surrogate, or the patient’s legally authorized 
representative) or noted by study personnel will be recorded in the patient’s medical record 
and on the Adverse Event eCRF page. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the patient to discontinue the study drug. 
12.5.2.1 
Definition of Serious Adverse Events 
An AE is considered “serious” if in the view of either the Investigator or Sponsor, it meets 1 or 
more of the following criteria: 
• Is fatal 
• Is life-threatening 
• Results in in-patient hospitalization or prolongation of existing hospitalization. If 
hospitalization occurs, then the SAERF must follow initial admission to the hospital, 
regardless of duration of hospitalization. 
• Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
Important medical events are those that may not be immediately life-threatening but are clearly 
of major clinical significance. They may jeopardize the patient, and may require intervention 
to prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, 
a seizure that did not result in inpatient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious. 
A planned medical or surgical procedure is considered an SAE for this study, even if it requires 
hospitalization.  


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
93 
 
12.5.2.2 
Definition of Adverse Events of Special Interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the study drug(s) and may require close monitoring and rapid communication 
by the investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting 
of AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this/these study drug(s). 
AESIs for this study population, listed below, must be reported by Investigators to the Sponsor 
but will not be expedited on an individual basis. Instead these AESIs will be reviewed in 
aggregate during data review.  
List of Adverse Events of Special Interest for this Study 
• Cytokine release syndrome 
• Infusional reactions 
• Low platelet count 
• Increased liver function test results 
Infusion of biological products is commonly associated with infusion-related reactions. 
Anaphylaxis and infusion-related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion-related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic monoclonal antibodies delivered 
through IV infusion. These reactions are less common following subsequent exposures. Unlike 
infusion-related reactions, anaphylaxis is a rare event, usually occurring after subsequent 
exposure to an antigen, and it is most commonly accompanied by severe systemic skin and or 
mucosal reactions. 
The Investigator is advised to carefully examine symptoms of adverse reactions observed 
during or shortly after exposure to APX005M, and consider the above-mentioned facts prior 
to making a final diagnosis. Reactions occurring at the time of or shortly after subsequent 
infusions of study drug(s) are to be judged by the Investigator at his/her own discretion. 
Should the Investigator determine an infusion-related reaction or cytokine release syndrome 
have occurred, the underlying symptoms must be reported as individual Adverse Events in 
addition to the reaction or syndrome. This applies to the Adverse Event reporting guidelines 
detailed in Section 12.5, as well as Adverse Event eCRF entry.  
AESIs that meet seriousness criteria as defined in Section 12.5.2.1, should be reported in the 
same way as SAEs, described in Section 12.5.5. 
12.5.3 
Recording Adverse Events 
Patients will be instructed to report AEs at each study visit.  
All AEs will be collected from the start of study drug through 100 days after the last dose of 
study drug, or until initiation of a new systemic anti-cancer therapy (whichever occurs first). 
All treatment-related AEs ongoing at the time of treatment discontinuation are to be followed 
until resolution, or deemed irreversible by the Investigator, regardless of whether new anti-
cancer therapy has been initiated. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
94 
 
Specific guidelines for classifying AEs by intensity and relationship to study drug are given in 
Table 15 and Table 16. 
The severity of AEs will be graded according to the NCI CTCAE version 4.03 (Grades 1 to 5). 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on the general guideline in Table 15. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
Table 15 
Classification of Adverse Events by Intensity 
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 ADL 
Grade 3: Severe or 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 
 
Table 16 
Classification of Adverse Events by Relationship to Study Drug 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc.). 
UNLIKELY: This category applies to those AEs that are judged to be unrelated to the test drug, but for which 
no extraneous cause may be found. An AE may be considered unlikely to be related to study drug if or when it 
meets 2 of the following criteria: (1) it does not follow a reasonable temporal sequence from administration of 
the test drug; (2) it could readily have been produced by the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; (3) it does not follow a known pattern of 
response to the test drug; or (4) it does not reappear or worsen when the drug is re-administered. 
POSSIBLY: This category applies to those AEs for which a connection with the test drug administration 
appears unlikely but cannot be ruled out with certainty. An AE may be considered possibly related if or when 
it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration of the 
drug; (2) it could not readily have been produced by the patient’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the patient; or (3) it follows a known pattern of response to the test 
drug. 
PROBABLY: This category applies to those AEs that the investigator feels with a high degree of certainty are 
related to the test drug. An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; (3) it disappears or decreases on cessation or 
reduction in dose (note that there are exceptions when an AE does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or (4) it follows a known pattern of response to the test drug. 
DEFINITELY:  This category applies to those AEs that the investigator feels are incontrovertibly related to 
test drug. An AE may be assigned an attribution of definitely related if or when it meets all of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with re-exposure to drug (if rechallenge occurs); and (4) it follows a known 
pattern of response to the test drug. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
95 
 
The relationship to study drug (either APX005M or nivolumab) will be recorded on the eCRF. 
At each contact with the patient, the Investigator will seek information on AEs by specific 
questioning and, as appropriate, by examination. Information on all AEs will be recorded 
immediately in the source document, and also in the appropriate AE module of the CRF. All 
clearly related signs, symptoms, and abnormal diagnostic procedures results should recorded 
in the source document, though should be grouped under one diagnosis. 
All AEs occurring during the study period will be recorded. The clinical course of each event 
will be followed until resolution or stabilization, or until it has been determined that the study 
treatment or participation is not the cause. SAEs that are still ongoing at the end of the study 
period will be followed up to determine the final outcome. Any SAE that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation will 
be recorded and reported immediately (see Section 12.5.5). 
12.5.4 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Progression of the cancer under study is not itself considered a reportable event. Any suspected 
endpoint which upon review from the Investigator is not considered progression of the cancer 
under study must be reported as an SAE. Within 24 hours of determination that the event is 
not progression of the cancer under study, an SAERF should be forwarded to PICI 
Pharmacovigilance Group as described in Section 12.5.5. 
All deaths will be recorded on the Death eCRF page. 
12.5.5 
Serious Adverse Event Reporting 
All SAEs, will be collected from the time the patient signs informed consent through 100 days 
after the last dose of study drug, or until initiation of a new systemic anti-cancer therapy 
(whichever occurs first).  SAEs related to study drug must be reported at all times, regardless 
of whether new anti-cancer therapy has been initiated.  All treatment-related SAEs must also 
to be followed until resolution, or deemed irreversible by the Investigator, regardless of 
whether new anti-cancer therapy has been initiated.   
Prior to the initiation of study drug, only SAEs that are related to a protocol-mandated 
intervention should be reported. 
All SAEs must be reported to the PICI Pharmacovigilance Group. Any SAE occurring after 
the initial study drug due to any cause, whether or not related to the study drug, must be 
reported within 24 hours of site awareness of the event.  Please fax or email the SAERF to the 
PICI Pharmacovigilance Group within 24 hours of event awareness. If technical issues arise, 
please contact the PICI Pharmacovigilance Group immediately. 
PICI Pharmacovigilance Group Contact Information: 
• Pharmacovigilance Fax Number: 415-610-5471 
• Pharmacovigilance email: safety@parkerici.org 
• Pharmacovigilance Telephone Number: 415-930-4414 
If the Investigator contacts the PICI Pharmacovigilance Group by telephone, then the SAERF 
must follow within one business day.  


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
96 
 
The event must also be recorded on the standard AE eCRF. Preliminary reports of SAEs must 
be followed by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, death certificates, autopsy reports, and other 
documents when requested and applicable. SAE reports must be made whether or not the 
Investigator considers the event to be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. Clinical, laboratory, and diagnostic measures should be employed as needed in order 
to determine the etiology of the problem. The Investigator must report all additional follow-up 
evaluations to the PICI Pharmacovigilance Group when requested. All SAEs will be followed 
until the Investigator and Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the patient’s 
active participation in the study is to be followed until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), is deemed irreversible, or is shown to not be 
attributable to the study drug or procedures. If a subject withdraws consent for data collection, 
the event will not be followed. 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. The Investigator is responsible for ensuring that all SAEs are followed 
until either resolved or stable. 
12.5.6 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
treatment under clinical investigation are met. Investigators must also comply with local 
requirements for reporting SAEs to the IRB/IEC or other local health authorities. 
12.5.6.1 
Sponsor Reporting of Serious Adverse Events 
SAEs will be reported by the PICI Pharmacovigilance Group to regulatory authorities, the 
overall PI, Bristol-Myers Squibb, Apexigen, the IRB, as appropriate. The process for such 
reporting, including contact information and specific instructions for reporting to each of these 
organizations, is described in the Safety Monitoring Plan (a separate document). 
12.5.7 
Pregnancy 
Female patients of child-bearing potential must have a negative pregnancy test at Screening. 
Following administration of study drug, any known cases of pregnancy in female patients or 
female partners of male patients will be reported until the patient completes or withdraws from 
the study. The pregnancy will be reported immediately by phone and by faxing a completed 
Pregnancy Report to the PICI Pharmacovigilance Group within 24 hours of knowledge of the 
confirmation of pregnancy. The pregnancy will be processed as an SAE, as a medically 
significant event, and the Investigator will follow the patient until completion of the pregnancy 
and must assess the outcome in the shortest possible time but not more than 30 days after 
completion of the pregnancy. The Investigator should notify the PICI Pharmacovigilance 
Group of the pregnancy outcome by submitting a follow-up Pregnancy Report. If the outcome 
of the pregnancy meets the following criteria:  


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
97 
 
• Spontaneous or therapeutic abortion (any congenital anomaly detected in an aborted 
fetus is to be documented) 
• Stillbirth 
• Neonatal death 
• Congenital anomaly 
The Investigator will report the event by phone and by faxing a completed SAERF to the PICI 
Pharmacovigilance Group within 24 hours of knowledge of the event.  
12.5.8 
Overdose 
The Investigator must immediately notify PICI Pharmacovigilance Group of any occurrence 
of overdose with study drug. Overdose is defined as any dose higher than the dose specified to 
be administered in accordance with the protocol. 
All overdoses should be reported as SAEs (see Section 12.5.5). Details of signs and symptoms, 
clinical management, and outcome should be reported, if available. Overdoses should also be 
captured as protocol deviations. 
The Monitoring plan contains a section related to classification of deviations, and overdoses 
will be classified in that document. Deviations are to be captured in the deviation log and 
reviewed on an ongoing basis by the PICI Medical Monitor and Project Manager. The PI is 
notified by PICI of respective deviations and has the obligation to report to the IRB. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
98 
 
13 
STATISTICAL ANALYSIS 
This is a multi-center open-label Phase 1b/2 trial of CD40 agonistic monoclonal antibody 
(APX005M) administered with nab-paclitaxel and Gem with or without nivolumab in 
previously untreated metastatic pancreatic adenocarcinoma. The primary objectives of the 
Phase 1b study are to determine the feasibility, safety and DLTs of each treatment cohort and 
to determine the RP2D of APX005M in combination with NP/Gem and with 
nivolumab/NP/Gem. The primary objective of the randomized Phase 2 study is to evaluate OS 
in 
three 
treatment 
arms: 
nivolumab/NP/Gem, 
NP/Gem/APX005M 
and 
nivolumab/NP/Gem/APX005M by comparing the 1-year OS rate with the historical value for 
NP/Gem. The study is not powered for statistical comparison among arms, and no interim 
analyses are planned in Phase 2.  
Phase 1b Design: 
Four treatment cohorts will be evaluated for feasibility and safety, as shown in Table 17. 
During Phase 1b, dosing of the first 3 patients of each cohort will be staggered by at least one 
week. If at one week, and for each of the 3 patients, there are no ongoing symptoms of cytokine 
release syndrome related to the infusion, and if no DLT occurs, subsequent patients to the 
cohort may be dosed without restriction. Cohorts B1 and B2 will escalate the dose of 
APX005M when combined with NP/Gem, and then Cohorts C1 and C2 will escalate the dose 
of APX005M when combined with nivolumab/NP/Gem. Approximately 6 DLT-evaluable 
patients will be enrolled in each cohort. A1 (nivolumab/NP/Gem) will not be tested, since an 
external study is being conducted to confirm the safety of nivolumab in combination with 
NP/Gem. For all cohorts, a treatment cycle is 4 weeks (3 weeks of treatment with 1 week of 
rest). 
In general, DLT is defined as any Grade 3 or higher toxicity that is treatment-related but not 
related to the natural progression of the tumor and occurs during the DLT observation period 
(see Section 6.1). The DLT observation period is defined as the time from first administration 
of investigational agents until prior to Cycle 2 Day 1. 
The DLT-evaluable population consists of patients who received 2 or 3 doses of NP/Gem and 
1 dose of APX005M during Cycle 1, thus have completed the DLT observation period. Patients 
who do not remain on study up to this time for reasons other than DLT will be replaced. 
Dose escalation will proceed if 1 or fewer DLT-evaluable patients experience DLT during this 
observation period. Dose escalation will cease if 2 or more DLT-evaluable patients experience 
DLT. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
99 
 
Table 17 
Phase 1b Statistical Design 
Cohort 
Regimen 
Number of 
DLT-Evaluable 
Patients 
Comments 
A1 
Nivolumab/NP/Gem 
0 
Nivolumab dose from external 
study 
B1 
NP/Gem/APX005M 0.1 mg/kg 
6 
 
B2 
NP/Gem/APX005M 0.3 mg/kg 
6 
 
C1 
Nivolumab/NP/Gem/APX005M 0.1 mg/kg 
6 
 
C2 
Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
6 
Tested only if B2 is safe 
DLT = dose-limiting toxicity; Gem = gemcitabine; NP = nab-paclitaxel 
On the basis of discussions among the site PIs, Sponsors, and other stakeholders, concerning 
feasibility, safety, clinical and immune PD effects (totality of available data), the RP2D is 
defined by the highest APX005M dose with < 2 DLT in 6 DLT-evaluable patients, unless the 
totality of available data suggests a lower APX005M dose.  
Phase 1b Objectives: 
The primary objectives are to 
1. Determine feasibility, safety, and DLT of each treatment cohort 
2. Determine the RP2D of APX005M when combined with NP/Gem 
3. Determine the RP2D of APX005M when combined with nivolumab/NP/Gem 
The secondary objectives are to 
1. Determine OR and DOR of each treatment cohort 
The exploratory objectives are: 
1. Assess the PK of APX005M 
2. Assess immune pharmacodynamic effects of each treatment arm, in both blood and 
tumor tissue 
Phase 1b Plans for Data Analysis: Statistical analyses will include the following: 
• The number of patients treated in each cohort will be reported, and reasons why any 
patient is not DLT evaluable will be summarized. 
• Approximately 6 DLT-evaluable patients will be fully analyzed in each treatment 
cohort. 
• Feasibility, defined by the number of patients who complete the DLT observation 
period and receive the intended therapy without delays or dose modification, will be 
described for each treatment arm. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
100 
 
• Toxicities will be graded by NCI CTCAE v4.03, causality attributed, and tabulated by 
treatment arm. 
• RP2D of APX005M when combined with NP/Gem and with nivolumab/NP/Gem will 
be determined. 
• RECIST OR will be scored and tabulated along with DOR, by treatment arm. 
• PK of APX005M 
• Immune PD effects will be measured and summarized, including change from baseline, 
and reported by treatment arm. 
Phase 2 Design 
Once the RP2D of APX005M for Arm C has been defined, the randomized Phase 2 portion of 
the study will commence (Table 18). Patients will be randomized to 1 of 3 arms, defined by 
the addition of one or more immunotherapy agents to standard of care NP/Gem. The arms will 
be either A1 vs B2 vs C2 or A1 vs B1 vs C1. Note the APX005M dose must be the same in 
Arms B and C, regardless of whether a higher APX005M dose was determined to be safe in 
Arm B. For each regimen, efficacy will be evaluated by comparing the 1-year OS rate to the 
historical value for NP/Gem. 
It is common for randomized Phase 2 studies that test the addition of an experimental agent to 
a standard of care regimen to include the standard of care arm. However, the setting for this 
study is unique. NP/Gem, the standard of care regimen, was reported recently in a very similar 
patient population, and the 1-year OS rate was estimated with extremely high precision (i.e., 
1-year OS rate was 35% with 95% CI 30%-39%) based on 431 treated patients.6 With hundreds 
of patients with PC treated with NP/Gem since that report, experts in this field agree that the 
1-year OS rate estimate appears to be very robust. Thus, this study will not include a standard 
of care arm. 
As shown in Table 18, 12 DLT-evaluable patients who were enrolled in Phase 1b at the RP2D 
(6 on Arm B and 6 on Arm C) will be included in the efficacy evaluation and approximately 
93 additional patients will be randomized in Phase 2, for a total sample size of approximately 
105 patients (35 per treatment arm). In step 1, 12 patients will be randomized in a 4:1:1 
allocation, to achieve balance in the total number of patients enrolled in the arms (i.e., Arm A1 
must be allocated more patients). Then, in step 2, 81 patients will be randomized in a 1:1:1 
allocation. 
Table 18 
Phase 2 Statistical Design 
Arm 
Regimen 
Phase 1b 
Phase 2 
Total 
Step 1 
Step 2 
Number of 
Patients 
Number of 
Patients 
Number of 
Patients 
Number of 
Patients 
A1 
Nivolumab/NP/Gem 
0 
8 
27 
35 
B2a 
NP/Gem/APX005M 0.3 mg/kg 
6 
2 
27 
35 
C2a 
Nivolumab/NP/Gem/APX005M 
0.3 mg/kg 
6 
2 
27 
35 
a Or B1 and C1, if either B2 or C2 is not tolerable. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
101 
 
 
Phase 2 Objectives: 
The primary objectives are to 
1. Estimate OS of each treatment arm 
2. Compare 1-year OS rate of each treatment arm to the historical rate for NP/Gem 
The secondary objectives are to 
1. Determine the ORR, DCR, DOR, and PFS of each treatment arm 
2. Further characterize the feasibility and safety of each treatment arm 
The exploratory objectives are to 
1. Assess PK of APX005M in Cycles 1 to 4 
2. Assess immune pharmacodynamic effects of each treatment arm, in both blood and 
tumor tissue 
3. Assess associations between immune biomarkers and clinical outcomes 
4. Evaluate baseline and on-treatment microbiome profiles and association with clinical 
outcomes 
5. Construct multivariable linear models to dissect the pharmacodynamic effects of 
APX005M and nivolumab on immune biomarkers 
Early Termination Rules for Unacceptable Toxicity in Phase 2 
A Bayesian rule will be employed to monitor toxicity during Phase 2 (Table 19). A minimally 
informative beta (0.5, 2.5) prior has been assumed, which is information that is equivalent to 
half the weight of 1 DLT in 6 patients treated, the definition of a safe dose in Phase 1b. For 
each treatment arm, if the number of patients with an unacceptable toxicity (defined in 
Section 6.1) is greater than or equal to the number in Table 19, then termination of that 
particular treatment arm will be considered, as it is likely that the toxicity rate is > 30%, as 
noted by the Bayesian posterior probabilities. This rule is intentionally conservative early in 
the enrollment phase. 
Table 19 
Bayesian Termination Rules 
Rules for Toxicity Rate >30% 
Patients treated on an arm 
10 
15 
20 
25 
30 
Patients with unacceptable toxicity 
4 
6 
9 
11 
13 
Posterior Probability [toxicity rate > 30%] 
0.61 
0.69 
0.87 
0.88 
0.90 
Action 
Consider termination of arm, re-evaluate study design. 
 
Phase 2 Plans for Data Analysis: 
Statistical analyses will include the following: 
• 35 patients will be analyzed on each treatment arm. 12 DLT-evaluable patients from 
Phase 1 (Arms B and C) and 93 patients from Phase 2 will compose the population for 
the final analysis of efficacy. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
102 
 
• OS will be estimated by the Kaplan-Meier method for each treatment arm. 
• The 1-year OS rate and 1-sided 95% confidence interval (CI) will be calculated for 
each treatment arm, to determine whether the lower bound of the CI excludes the 
historical value (or a recently updated value) for NP/Gem. 
• A 1-sided one-sample Z test will also be conducted. The goal is to compare the survival 
probability at 1-year to the historical value of 0.35. 
• ORR and DCR and their 95% CIs will be calculated for each treatment arm. 
• DOR will be calculated from dates of first documented response and progression of 
disease. 
• PFS will be estimated by the Kaplan-Meier method and the median PFS and 95% CI 
will be calculated for each treatment arm. Toxicities will be graded by NCI CTCAE 
v4.03 and summarized by treatment arm. 
• PK of APX005M 
• Immune pharmacodynamic endpoints (see Section 5.2.2.3) will be measured and 
summarized, including change from baseline, and reported by treatment arm. In 
addition to scatter and box plots, continuous variables will be summarized with the 
number of patients (N), mean, standard deviation, median, minimum, and maximum 
by treatment group. 
• Associations between baseline values and changes in immune pharmacodynamic 
variables or microbiome profiles and clinical outcomes will be assessed. Logistic and 
Cox regression models will be employed for binary (responder/non-responder) 
outcomes and OS or PFS outcomes, respectively. 
• Multivariable linear models will be constructed to dissect the effects of APX005M and 
nivolumab on immune biomarkers. To begin, a linear model is constructed with a post-
treatment value of a biomarker at a selected time point as the dependent variable and 
the pre-treatment value, two indicator variables for APX005M and nivolumab 
treatment and treatment interaction term, as the independent variables. To analyze 
serial measurement of immune biomarkers, a linear mixed effects model is constructed 
to assess the impact of the individual and combined therapies on longitudinal changes, 
taking into account within-patient correlation of the serial samples. 
13.1 
Determination of Sample size 
13.1.1 
Phase 1b 
Assuming 4 treatment cohorts will be evaluated for feasibility, safety, and DLTs, up to 
24 DLT-evaluable patients will be enrolled.  
13.1.2 
Phase 2 
Approximately ninety-three patients will be enrolled in Phase 2. This is a screening study, such 
that for each treatment arm, the 1-year OS rate will be estimated and compared with a historical 
value of 35% for NP/Gem.6 The study is not powered to detect a meaningful difference in OS 
among the 3 arms, since these are novel experimental arms and OS is unknown.  


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
103 
 
The null hypothesis is a 1-year OS rate of 35% and the alternative hypothesis is a 1-year OS 
rate of 58%. The 1-year OS rate is estimated by the Kaplan-Meier method. A sample size of 
35 patients on each arm provides 88% power to test this hypothesis, using a 1-sided one-sample 
Z test with 5% type I error rate, assuming a minimum of 1 year of follow-up for each patient. 
Moreover, the sample size of 35 patients on each arm provides 81% power to statistically test 
the null hypothesis versus a slightly more conservative alternative hypothesis that the 1-year 
OS rate is 55%, given the same design assumptions. 
These calculations assume that at least 105 patients (35 patients x 3 arms) will be enrolled. 
There is no assumption about the duration of patient enrollment, only that there will be a 
minimum of 1 year of follow-up for each patient. 
13.2 
Analysis Populations 
The safety population consists of all patients who received at least 1 dose of any study drug. 
This is the population for the primary analyses of safety. A subset of the safety population is 
the DLT-evaluable population, described in Section 6.1. 
The DLT-evaluable population consists of patients who received 2 or 3 doses of NP/Gem 
during Cycle 1, as well as one dose of APX005M, thus have completed the DLT observation 
period (ie, from the time of first administration of investigational agents until prior to Cycle 2 
Day 1). Patients who do not meet these criteria will be replaced in Phase 1b only, to assist with 
DLT and RP2D decision-making. 
The efficacy population consists of (1) all patients who were randomized/enrolled in Phase 2 
and received at least 1 dose of any study drug and (2) the 12 DLT-evaluable patients (6 on Arm 
B and 6 on Arm C) who were enrolled in Phase 1b at the RP2D. The efficacy population is the 
population for the primary analyses of efficacy. 
13.3 
Demographic and Baseline Characteristics 
All data will be listed, and summary tables will be provided. Summary statistics will be 
presented by treatment arm. For continuous variables, data will be summarized with the 
number of patients (N), mean, standard deviation, median, minimum, and maximum by 
treatment group. For categorical variables, data will be tabulated with the number and 
proportion of patients for each category by treatment arm. 
13.4 
Efficacy Analysis 
13.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be determined as follows: 
• OS is defined as the time from initiation of study therapy to date of death due to any 
cause or date of most recent patient contact. Patients who were alive are censored on 
their most recent contact date. 
• 1-year OS rate in each treatment arm 
• Subgroup analysis: For each treatment arm, OS will be analyzed in the subset of 
patients in the efficacy population who remain on study for at least 6 weeks. This subset 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
104 
 
is in contrast to the efficacy population in the primary analysis. The 1-year OS rate and 
1-sided 95% CI will again be calculated and compared with a historical value. 
 
13.4.2 
Secondary Efficacy Endpoints 
The following secondary endpoints will be determined in the Phase 2 portion of the study: 
• OR is determined by RECIST and the ORR is defined as the proportion of patients who 
achieve a CR or PR. A 95% CI for the rate will be constructed. The half-width of this 
confidence interval will be no greater than 16.5%, based on 35 patients in each 
treatment arm 
• DCR is defined as the proportion of patients who achieve a CR, PR, or SD. A 95% CI 
for the rate will be constructed. The half-width of this CI will be no greater than 16.5%, 
based on 35 patients in each treatment arm 
• DOR is defined as the time for first documentation of response (CR or PR) to first 
documentation of PD. PFS is defined as the time from initiation of study therapy to 
date of first documented PD, date of death due to any cause or date of most recent 
patient contact which documented progression-free status (i.e., clinic visit date or scan 
date). Patients who have not progressed or died are censored on their most recent 
progression-free date. 
 
13.4.3 
Exploratory Endpoints 
Tissue Assessment: From germline WES, HLA type can be determined. From tumor WES, 
tumor RNA-Seq, and germline WES, patient-specific neo epitopes arising from tumor somatic 
missense mutations can be predicted bioinformatically. 
Analysis of T-cell Activation: For each T-cell subset, differentiation status (e.g., naïve, central 
memory, effector memory) or activation vs. exhaustion status may be assessed using additional 
markers such as Eomes, Tbet, Granzyme B, Ki-67, CD45RA, ICOS, CD45RO, CCR7, CD28, 
CD27, CD57, CD25, CD69, HLA-DR, CTLA-4, and PD-1. When possible, trends will be 
tracked in T-cell subsets based on analysis of multiple post-treatment samples. NK cells 
subsets may also be assessed using CD16 and CD56, with CD69 as an activation marker. 
Analysis of Myeloid and B-cell Activation: For each parameter of B-cell activation and each 
cell type, the percentage of cells positive for the marker and/or MFI at time points after treated 
can be compared to baseline and the change calculated as %after/%baseline or MFIafter/MFIbaseline. 
Inflammatory Cytokines/Chemokines: Concentrations of cytokines and other circulating 
factors may include but are not limited to TGF-β, IL-1, TNF-α, IL-6 and others may be 
determined and summarized. 
TCR Deep Sequencing: Comparison of TCR beta sequence data in serial samples from blood 
and tumor may be used to demonstrate de novo evolution of an anti-tumor T-cell repertoire. 
Microbiome profile: Stool samples may be tested for microbiome profile using sequencing or 
metabolomic methods. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
105 
 
13.5 
Pharmacokinetic Analysis 
Circulating concentrations of APX005M will be determined from venous blood samples 
collected periodically during the study, as indicated in the Schedule of Assessments (Table 11 
and Table 12). 
The standard PK parameters of peak plasma concentration (Cmax), area under the curve 
(AUC0-x), elimination half-life (t1/2), elimination rate constant (λ), volume of distribution (Vz), 
and clearance (C) will be estimated by standard noncompartmental methods. This description 
could also include single- and multiple-dose parameters, use of WinNonlin program, and linear 
least squares. 
13.6 
Safety Endpoints 
13.6.1 
Phase 1b: Assessing Feasibility, Dose-Limiting Toxicity, and Recommended 
Dose for Phase 2 
The following will be determined for the Phase 1b portion of the study: 
• Feasibility is defined by the number of patients who complete the DLT observation 
period and receive the intended therapy without delays or dose modification. 
• A DLT is defined as any Grade 3 or higher toxicity that is treatment-related but not 
related to the natural progression of the tumor and occurs during the DLT observation 
period. See Section 6.1 for further details. 
• The RP2D of APX005M when combined with NP/Gem or nivolumab/NP/Gem is 
defined by the highest APX005M dose with < 2 DLTs in 6 DLT-evaluable patients, 
unless the totality of available data, including clinical and pharmacodynamic effects, 
suggests a lower APX005M dose. 
13.6.2 
Analysis of Adverse Events 
All reported AEs will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities. The incidence of TEAEs (events with onset dates on or after the start of 
the study drug) will be included in incidence tables. Events with missing onset dates will be 
included as treatment-emergent. If a patient experiences more than 1 occurrence of the same 
AE, the occurrence with the greatest severity and the closest association with the study drug 
will be used in the summary tables. SAEs and AEs causing treatment discontinuation will be 
tabulated. All AEs will be listed by patient, along with information regarding onset, duration, 
relationship and severity to study drug, action taken with study drug, treatment of event, and 
outcome. 
Clinical laboratory data and vital signs will be summarized using descriptive statistics 
including mean values and mean change from baseline values, as well as numbers of patients 
with values outside limits of the normal range at each time point. 
Summary tables will be provided for concomitant medications initiated during the study period. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
106 
 
13.7 
Interim Analysis 
Given the hypothesis generating nature of this study, the Sponsor may conduct up to 3 interim 
analyses of safety and efficacy during the Phase 1b and Phase 2 portions of the study. Should 
an interim analysis occur, it will be performed and interpreted by members of the Sponsor 
study team. If warranted, interim safety and efficacy results may be shared with study 
Investigators. The decision to conduct an interim analysis, its timing and scope, and who will 
have access to the results, will be documented in the sponsor’s trial master file and statistical 
analysis plan prior to the conduct of the interim analysis. The clinical study report will also 
document that such an interim analysis occurred. 
13.8 
Data Monitoring 
13.8.1 
Data Review Team (DRT) 
To ensure patients’ safety during Phase 1b and Phase 2, a DRT will review the safety data on 
a regular basis. The DRT consists of members from the Sponsor, the overall PI, the lead 
statistician, and all active PIs. The DRT will decide on DLTs relevant for the treatment and 
will decide by consensus on dose escalation, dose de-escalation, prolongation of the DLT 
observation period, suspension of enrollment based on safety, PK or possibly 
pharmacodynamic data, and will recommend the dose level for the Phase 2 part. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
107 
 
14 
STUDY MANAGEMENT 
14.1 
Approval and Consent 
14.1.1 
Regulatory Guidelines 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, Subpart D, of 
Title 21 of the Code of Federal Regulations (CFR), and in compliance with Good Clinical 
Practice (GCP) guidelines. 
14.1.2 
Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IRB/Independent 
Ethics Committee (IEC). Approval is required for the study protocol, investigational drug 
brochure, protocol amendments, informed consent forms (ICFs), and patient information 
sheets. 
14.1.3 
Informed Consent 
For each study patient, written informed consent will be obtained prior to any protocol-related 
activities. As part of this procedure, the PI or one of his/her associates must explain orally and 
in writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the patient is aware of the potential risks, inconveniences, or adverse effects that 
may occur. The patient should be informed that he/she may withdraw from the study at any 
time, and the patient will receive all information that is required by local regulations and 
International Council for Harmonization (ICH) guidelines. The PI will provide the Sponsor or 
its representative with a copy of the IRB/IEC-approved ICF prior to the start of the study. 
14.2 
Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRFs that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. 
Clinical data will be entered on eCRFs for transmission to the Sponsor. Data on eCRFs 
transmitted via the web-based, electronic data capture (EDC) system must correspond to and 
be supported by source documentation maintained at the study site, unless the study site makes 
direct data entry to the databases for which no other original or source documentation is 
maintained. In such cases, the study site should document which eCRFs are patient to direct 
data entry and should have in place procedures to obtain and retain copies of the information 
submitted by direct data entry. All study forms and records transmitted to the Sponsor must 
carry only coded identifiers such that personally identifying information is not transmitted. The 
primary method of data transmittal is via the secure, EDC system maintained by PICI. Access 
to the EDC system is available to authorized users via the study’s Internet website, where an 
assigned username and password are required for access.  
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
108 
 
14.3 
Source Documents 
Source documents are considered to be all information in original records and certified copies 
of original records of clinical findings, observations, data or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. 
14.4 
Record Retention 
Study records and source documents must be preserved for at least 15 years after the 
completion or discontinuation of/withdrawal from the study or 2 years after the last approval 
of a marketing application in an ICH region, whichever is the longer time period. 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation). The 
Investigator shall ensure that study patients authorize the use and disclosure of protected health 
information in accordance with HIPAA Privacy Regulation and in a form satisfactory to the 
Sponsor. 
14.5 
Monitoring 
The study will be monitored to ensure that it is conducted and documented properly according 
to the protocol, GCP, and all applicable regulatory requirements.  
On-site monitoring visits will be made at appropriate times during the study. Clinical monitors 
must have direct access to source documentation in order to check the completeness, clarity, 
and consistency of the data recorded on the eCRFs for each patient.  
The Investigator will make available to the clinical monitor source documents and medical 
records necessary to verify eCRFs. In addition, the Investigator will work closely with the 
clinical monitor and, as needed, provide them appropriate evidence that the conduct of the 
study is being done in accordance with applicable regulations and GCP guidelines.  
14.6 
Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, and reliability of the study 
data presented to the Sponsor lies with the Investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure 
that the study is being conducted in compliance with the protocol, Standard Operating 
Procedures, GCP, and all applicable regulatory requirements. Audits will be independent of 
and separate from the routine monitoring and quality control functions. Quality assurance 
procedures will be performed at study sites and during data management to assure that safety 
and efficacy data are adequate and well documented.  
 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
109 
 
14.7 
Protocol Amendments and Protocol Deviations  
14.7.1 
Protocol Amendments 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no impact 
on the safety of patients or the conduct of the study will be classed as administrative 
amendments and will be submitted to the IRB/IEC for information only. The Sponsor will 
ensure that acknowledgment is received and filed. Amendments that are classed as substantial 
amendments must be submitted to the appropriate Regulatory Authorities and the IRBs/IECs 
for approval. 
14.7.2 
Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed. Protocol deviations and/or 
violations and the reasons they occurred will be included in the clinical study report. Reporting 
of protocol deviations to the IRB/IEC and in accordance with applicable Regulatory Authority 
mandates is an Investigator responsibility. 
14.8 
Ethical Considerations 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, Subpart D, of 
Title 21 of the CFR, and in compliance with GCP guidelines. 
IRBs/IECs will review and approve this protocol and the ICF. All patients are required to give 
written informed consent prior to participation in the study.  
14.9 
Financing and Insurance 
Prior to the study commencing, the Sponsor (or its designee) and the Investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement 
will be documented in a financial agreement that will be signed by the Investigator (or the 
institution signatory) and the Sponsor (or its designee). 
The Investigator is required to have adequate current insurance to cover claims for its 
negligence and/or malpractice. The Sponsor, or the manufacturer of the study drug, will 
provide insurance coverage for the clinical study as required by national regulations. 
14.10 
Publication Policy / Disclosure of Data  
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be patient to the terms of a clinical study agreement that will 
be agreed between the Institution and the Sponsor or their designee. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
110 
 
15 
REFERENCES 
1. 
Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 
2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United 
States. Cancer Res 2014;74(11):2913-21. 
2. 
Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of 
chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J 
Med 2004;350(12):1200-10. 
3. 
Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs 
observation in patients undergoing curative-intent resection of pancreatic cancer: a 
randomized controlled trial. JAMA 2007;297(3):267-77. 
4. 
Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine 
and long-term outcomes among patients with resected pancreatic cancer: the 
CONKO-001 randomized trial. JAMA 2013;310(14):1473-81. 
5. 
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for 
metastatic pancreatic cancer. N Engl J Med 2011 May 12;364(19):1817-25. 
6. 
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with 
nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369(18):1691-703. 
7. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat 
Rev Cancer 2012;12(4):252-64. 
8. 
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369(2):122-33. 
9. 
Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (anti-
CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J 
Immunother 2010;33:828-33. 
10. 
Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 
antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65. 
11. 
Bauer C, Kühnemuth B, Deuwell P, et al. Prevailing over T cell exhaustion: New 
developments in the immunotherapy of pancreatic cancer. Cancer Lett 
2016;381(1):259-68. 
12. 
Aggarwal BB. Signalling pathways of the TNF superfamily: A double-edged sword. 
Nat Rev Immunol 2003;3(9):745-56. 
13. 
Banchereau J, Bazan F, Blanchard D, et al. The CD40 antigen and its ligand. Annu 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
111 
 
Rev Immunol 1994;12:881-922. 
14. 
Clark EA, Ledbetter JA. How B and T cells talk to each other. Nature 
1994;367(6462):425-8. 
15. 
Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev 
Immunol 1998;16:111-35. 
16. 
Eliopoulos AG, Young LS. The role of the CD40 pathway in the pathogenesis and 
treatment of cancer. Curr Opin Pharmacol 2004;4(4):360-7. 
17. 
Unek T, Unek IT, Agalar AA, et al. CD40 expression in pancreatic cancer. 
Hepatogastroenterology 2013;60(128):2085-93). 
18. 
Hess S, Engelmann H. A novel function of CD40: Induction of cell death in 
transformed cells. J Exp Med 1996;183(1):159-67. 
19. 
Tong AW, Stone MJ. Prospects for CD40-directed experimental therapy of human 
cancer. Cancer Gene Ther 2003;10(1):1-13. 
20. 
Law CL, Grewal IS. Therapeutic interventions targeting CD40L (CD154) and CD40: 
The opportunities and challenges. Adv Exp Med Biol 2009;647:8-36. 
21. 
Khong A, Nelson DJ, Nowak AK, et al. The use of agonistic anti-CD40 therapy in 
treatments for cancer. Int Rev Immunol 2012;31(4):246-66. 
22. 
Rakhmilevich AL, Alderson KL, Sondel PM. T-cell-independent antitumor effects of 
CD40 ligation. Int Rev Immunol 2012;31(4):267-78. 
23. 
Ruter J, Antonia SJ, Burris HA, et al. Immune modulation with weekly dosing of an 
agonist CD40 antibody in a phase I study of patients with advanced solid tumors. 
Cancer Biol Ther 2010;10(10):983-93. 
24. 
Vonderheide RH, Flaherty KT, Khalil M, et al. Clinical activity and immune 
modulation in cancer patients treated with CP-870,893, a novel CD40 agonist 
monoclonal antibody. J Clin Oncol 2007;25(7):876-83. 
25. 
Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and 
show efficacy against pancreatic carcinoma in mice and humans. Science 
2011;331(6024):1612-6. 
26. 
Forero-Torres A, Bartlett N, Beaven A, et al. Pilot study of dacetuzumab in 
combination with rituximab and gemcitabine for relapsed or refractory diffuse large 
B-cell lymphoma. Leuk Lymphoma 2013;54(2):277-83. 
27. 
Lewis TS, McCormick RS, Stone IJ, et al. Proapoptotic signaling activity of the 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
112 
 
anti-CD40 monoclonal antibody dacetuzumab circumvents multiple oncogenic 
transformation events and chemosensitizes NHL cells. Leukemia 
2011;25(6):1007-16. 
28. 
Johnson P, Challis R, Chowdhury F, et al. Clinical and biological effects of an agonist 
anti-CD40 antibody: A Cancer Research UK phase I study. Clin Cancer Res 
2015;21(6):1321-8. 
29. 
Mangsbo SM, Broos S, Fletcher E, et al. The human agonistic CD40 antibody ADC-
1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. Clin 
Cancer Res. 2015;21(5):1115-26. 
30. 
Li F, Ravetch JV. Inhibitory Fcgamma receptor engagement drives adjuvant and anti-
tumor activities of agonistic CD40 antibodies. Science 2011;333(6045):1030-4. 
31. 
Barr TA, Heath AW. Functional activity of CD40 antibodies correlates to the position 
of binding relative to CD154. Immunology 2001;102(1):39-43. 
32. 
Zou W, Chen. Inhibitory B7-family molecules in the tumour microenvironment. Nat 
Rev Immunol 2008;8:467-77. 
33. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
anti-PD-1 antibody in cancer. N Engl J Med 2012;366(26):2443-54. 
34. 
Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with 
platinum-based doublet chemotherapy for first-line treatment of advanced 
non-small-cell lung cancer. J Clin Oncol 2016;34(25):2969-79. 
35. 
George B, Kelly K, Ko A, et al. Phase I study of nivolumab + Nab-paclitaxel in solid 
tumors: preliminary analysis of small cell lung cancer cohort: track: advanced 
NSCLC. J Thorac Oncol 2016;11:S211-12. 
36. 
Wainberg, ZA, Hochster HS, George B, et al. Phase I Study of Nivolumab (Nivo) 
Nab-Paclitaxel (Nab-P) ± Gemcitabine (Gem) in Solid Tumors: Interim Results from 
the Pancreatic Cancer (PC) Cohorts. 2017 Gastrointestinal Cancers Symposium: 
abstract 412 
37. 
Burris, H.A., Moore MJ, Andersen J, et al. Improvements in survival and clinical 
benefit with gemcitabine as first-line therapy for subjects with advanced pancreas 
cancer: a randomized trial. J Clin Oncol, 1997. 15: p. 2403-13. 
38. 
Winograd R, Byrne KT, Evans RA, et al. 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(4):399-411. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
113 
 
39. 
Byrne KT, Vonderheide H. CD40 stimulation obviates innate sensors and drives T 
cell immunity in cancer. Cell Rep 2016;15(12):2719-32. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
114 
 
16 
APPENDICES 
16.1 
ECOG Performance Scale 
Table 20 
ECOG Performance Scale 
Grade 
ECOG Performance Status  
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light housework, office work  
2  
Ambulatory and capable of 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  
Dead  
ECOG = Eastern Cooperative Oncology Group. 
(Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J 
Clin Oncol. 1982;5(6):649-55). 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
115 
 
16.2 
Nivolumab Toxicity Management Guide 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
116 
 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
117 
 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
118 
 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
119 
 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
120 
 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
121 
 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
122 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
123 
 
16.3 
Guidance for the Management of 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. 
 
Patients 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. 
 
• Grade 2: stop infusion and treat symptoms following guidance in Table 21. 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). 
• Grade 3-4: stop infusion and treat symptoms following guidance in Table 21. 
 
Table 21 
Infusion-related Reaction/Cytokine Release Syndrome Management 
Recommendations  
Suspected Cytokine Release Syndrome-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, nonsteroidal anti-
inflammatory drugs, antihistaminics, anti-
emetics, analgesics as needed 
• In case of mild symptoms persisting for > 
24 hours assess for infections; empiric 
treatment of concurrent bacterial infections 
• Symptoms or clinical findings 
requiring and responding to 
moderate intervention, such as: 
o O2 requirement < 40% 
• Hypotension responsive to fluids ± 
low dose of 1 vasopressor (e.g., < 
50 mg/min of phenylephrine) 
o CTCAE Grade 2 organ toxicity 
No extensive 
comorbidities 
• All of the above 
• Monitor cardiac and other organ functions 
closely 
• Extensive 
comorbidities 
• Age ≥ 70 
years  
• All of the above 
• Corticosteroids 
• Consider tocilizumab 
• 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 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
124 
 
16.4 
Document Revision History 
16.4.1 
Key Revisions in Amendment 1 
• Section 6.1: added “Grade 3 adverse events that compromise a major organ (e.g. 
Congestive Heart Failure) regardless of duration” per FDA request. 
• Section 7.1: added “Glomerular Filtration Rate (GFR) ≥ 50 ml/min” per FDA request. 
• Section 8.1.6: added safety monitoring post APX005M “After discharge, all patients 
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” per FDA 
request. 
• Table 10: added Thyroid function testing per FDA request 
• Table 11: added Thyroid function testing per FDA request 
• Section 9.2.1: added Thyroid function testing per FDA request 
• Section 9.2.8: added Thyroid function testing per FDA request 
• Section 16.3: added a new section titled “Guidance for the Management of Infusion 
Reaction/Cytokine Release Syndrome” per FDA request 
16.4.2 
Key Revisions in Amendment 2 
• Synopsis: deleted “Reference therapy” to avoid confusion, and updated according to 
revisions in the protocol text 
• Section 4.3.1: updated with latest clinical results with nivolumab per request of 
Scientific Review of leading site 
• Section 4.5: updated rationale per request of Scientific Review of leading site 
• Figure 1: clarified Phase II dose per request of IRB of record 
• Section 7.1, inclusion criteria #5: replaced “CFR with “creatinine clearance ≥ 50 
ml/min as measured by Cockcroft and Gault formula” for better comply of FDA’s 
request 
• Section 7.2: updated to avoid duplication and to be consistent with the rest of the 
protocol 
• Section 7.3: deleted Protocol Deviation section as this is detailed in other documents 
• Table 10: deleted Day 4 events under Cycle 3 and Subsequent cycles, as Day 4 visit is 
optional  
• Section 11.2: Revised collection of blood samples for detection of anti-drug antibodies 
to be at before APX005M administration in Cycles 1-4, and then every other cycle and 
at the end of treatment. 
• Table 12: deleted Table 12 as these are standard tests not specifically for safety analysis 
• Section 16.4: added a new section “Document Revision History” for better track of 
document revisions. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
125 
 
16.4.3 
Key Revisions in Amendment 3 
• Inclusion/Exclusion Changes: 
o Synopsis and Section 7.1:  
▪ Language added to clarify requirement of baseline tumor tissue for trial 
participation, “A baseline tumor tissue sample is mandatory for 
enrollment.” 
o Synopsis and Section 7.2:  
▪ Language added to exclusion 11 to allow the transient use of steroids, 
“Transient courses of steroids may be approved by the medical monitor 
on a case by case basis, dependent on dose and reason.” 
▪ Language added indicating all screening laboratory values must be met 
without the use of transfusions or growth factors. 
• Additions/Removals/Changes:  
o Synopsis: 
▪ Language regarding enrollment timeline updated to, “Target enrollment 
completion is within 24 months; however, enrollment will proceed until 
met or as determined by the study sponsor (PICI).” 
o Synopsis, Sections 5, 11 and 13:  
▪ Language added regarding exploratory endpoints/assays, as well as 
modified from “will” to “may,” since analysis will depend on sample 
availability and amounts to perform analysis. 
o Section 6.1:  
▪ DLT criteria removed, “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).” 
o Sections 7 and 9:  
▪ Language updated to clarify staggered dosing parameters, “During 
Phase Ib, dosing of the first 3 patients of each cohort will be staggered 
by at least one week. If at one week, and for each of the 3 patients, there 
are no ongoing symptoms of cytokine release related to the infusion, 
and if no DLT occurs, subsequent patients to the cohort may be dosed 
without restriction.” 
o Section 8.6.3:  
▪ Language added about steroid use, “A temporary course of steroids 
may be permitted once discussed and agreed upon by the medical 
monitor.” 
o Section 9: 
▪ An EOS blood sampling for ADA added. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
126 
 
▪ On days APX005M administered, time points for vital collection added 
at EOI, as well as at 2 and 5 hours thereafter. 
▪ Blood sampling for immune biomarkers at screening added. 
▪ A window of -7 days was added for disease assessments. 
▪ After cycle 2, a dosing window of ± 3 days was added for CXD1. 
▪ End of study visits added at 30 and 100 after last dose to assess patients 
for AEs, with a window of ± 7 days, physical exam, serum chemistry, 
vital, AE assessment and thyroid function test 
o Sections 11 and 12:  
▪ Language added regarding how samples may be used in the future. 
▪ Language removed regarding use of plasma for ADA assay. 
▪ Language removed to eliminate redundancy with the PICI0002 
Laboratory Manual. 
o Section 12: 
▪ Requirements for vital sign collection updated to be in line with Table 
10 and Section 9. 
▪ Requirements for physical examination updated. 
o Section 13: 
▪ Language regarding enrollment timelines removed to mirror updated 
language in the synopsis.  
o Table 10: 
▪ Language added regarding review of laboratory assessments, “All 
laboratory assessments should be should be reviewed prior to CXD8.” 
▪ Window of ±10 minutes added for vital sign collection. 
o Table 12: 
▪ Table added to detail specific chemistry, hematology and urinalysis 
assessments, also referenced in Table 10, Table 11 and Section 9. 
• Clarification of Document: 
o Document updated to address administrative changes and typographical errors. 
o Document updated to change “subject(s)” and “patient(s)” to “patient(s)” only, 
for consistency.  
o Document updated to change the naming of treatment cohorts to reflect the 
order in which study drugs are administered. 
o Synopsis, Sections 5, 9 and 11:  
o Updated to clarify time points for PK and ADA sampling. 
o Synopsis, Sections 7.1 and 9: 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
127 
 
▪ Updated to clarify blood sampling for immune biomarkers should only 
be collected at screening if patient has signed informed consent. 
▪ Updated to clarify the requirement of pre-treatment tumor tissue (fresh 
or archival) for trial participation. 
o Sections 7 and 13:  
▪ Language added to clarify staggered dosing, “During Phase Ib, dosing 
of the first 3 patients of each cohort will be staggered by at least one 
week. If at one week, and for each of the 3 patients, there are no ongoing 
symptoms of cytokine release related to the infusion, and if no DLT 
occurs, subsequent patients to the cohort may be dosed without 
restriction.” 
o Section 8.1.5: 
▪ Language added to clarify weight parameters for dosing, “Patient 
weight will be assessed at screening and day 1 of each cycle. Dose 
adjustments are not required unless the subject has a 10% change in 
comparison to their initial weight on Cycle 1, Day 1.” 
o Section 9:  
▪ Instructions for APX005M pre-medication, as described in protocol 
Section 8.2, Table 2, included for clarity. 
▪ Corrected in line with Tables 10 and 11. 
▪ Language added to clarify that blood sampling for immune biomarkers 
should only be collected at screening if patient has signed informed 
consent.  
o Section 12.5: 
▪ Updated to clarify SAE reporting guidelines. 
 
16.4.4 
Key Revisions in Amendment 4 
Text revisions resulting from this amendment are incorporated in the synopsis and body of 
Protocol Amendment 4. Major changes to the protocol are summarized below.  
• Eligibility criteria: 
o Synopsis and Section 7.1: 
▪ Moved the tumor biopsy sample criterion from #8 to #5. 
▪ Updated the AST/ALT criteria to be ≤ 5.0 x ULN for patients with liver 
metastases (#6). 
o Section 7.2: 
▪ Removed the contraception-related exclusion criterion (#17) as it is 
redundant with the inclusion criterion mandating use of contraception. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
128 
 
• Safety assessments: 
o Synopsis, Section 6.1, Section 13.2, and Section 13.6.1: 
▪ Revised definitions for DLTs, DLT-evaluable population, and DLT 
observation period for clarity. 
o Section 12.1: 
▪ Removed the language requiring patients to rest for at least 5 minutes in 
a sitting position. 
o Section 12.4: 
▪ Moved the tabular listing of laboratory assessments from the Section 9 
(Study Procedures) to Section 12.4 (Laboratory Assessments) for clarity.  
o Section 12.5.2: 
▪ Added a new section for reporting of disease progression (titled, 
“Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events) for clarity. 
o Section 12.5.4: 
▪ Updated the fax and telephone numbers for the PICI Pharmacovigilance 
Group due to updated point of contact information. In addition, clarified 
the process for SAE reporting to account for the updated PICI 
Pharmacovigilance Group point of contact information. 
o Section 12.5.5: 
▪ Added a section to clarify the regulatory reporting requirements for 
SAEs as this is a site responsibility and was not previously documented. 
o Section 12.5.6: 
▪ Corrected the reporting of pregnancies to indicate that they will be 
processed as SAEs.  
• Toxicity management 
o Section 8.5.1 (Table 4): 
▪ Added a footnote to clarify that Day 1 toxicity management does not 
apply to Cycle 1 (but begins with Cycle 2 Day 1). 
o Section 8.5.5.1: 
▪ Removed this section (Criteria for Initiation of a New Cycle). 
• Objectives/endpoints: 
o Synopsis and Section 5.2:  
▪ Revised endpoints to align with objectives. 
• Study design 
o Synopsis, Section 6.1, Section 8, Section 8.6.1, and Section 13: 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
129 
 
▪ Removed reference to sequential enrollment in Phase 1b. Specified that 
Phase 1b enrollment may occur concurrently in Cohorts B2 and C1, and 
enrollment in Cohort C2 may begin once enrollment in Cohort C1 has 
been completed. 
o Section 6.1.4: 
▪ Added a new section to allow for treatment beyond unequivocal disease 
progression (per RECIST v1.1). 
• Treatments: 
o Section 6.1, Section 8 (Table 2), Section 8.1.3, Section 8.1.4, Section 8.2.3, 
Section 8.2.4, and Section 8.4 (Table 3): 
▪ Added text to clarify that NP/Gem could be administered on a 3 weeks 
on, 1 week off or 2 weeks on, 1 week off schedule, depending on the 
presence or absence of toxicity. 
o Section 6.1, Section 8 (Table 2), Section 8.1.2, Section 8.2.2, and Section 8.4 
(Table 3): 
▪ Added text to clarify that nivolumab doses should not be administered 
< 2 days apart, and nivolumab should not be administered on Day 15 if 
NP/Gem is held on Day 15. 
o Section 8.2.1: 
▪ Added text to clarify that for each cycle, APX005M should only be 
administered if patients received NP/Gem on Day 1. 
• Study procedures: 
o Section 9: 
▪ Added Cycle 1 and Cycle 2, Day 15 weight assessments for non-
APX005M arms (Table 12). 
o Section 9.1 (Patient Informed Consent): 
▪ Removed this section as informed consent has already been addressed 
by the inclusion criterion. 
o Section 9.2 (Procedures by Study Visit or Period): 
▪ Removed this section as it is redundant given the Schedule of 
Assessments. 
 
In addition to the major changes described above, minor typos were corrected and editorial 
changes were made for clarity. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
130 
 
16.4.5 
Key Revisions in Amendment 5 
Text revisions resulting from this amendment are incorporated in the synopsis and body of 
Protocol Amendment 5. Major changes to the protocol are summarized below.  
• Objectives and Endpoints/Exploratory: 
o Synopsis, Section 5.1.2.3, Section 5.2.2.3, Section 9, Section 11.2, Section 13:  
▪ Added: For Phase 2, evaluation of baseline and on-treatment 
microbiome profiles with treatment outcomes. 
• Eligibility Criteria:  
o Synopsis and Section 7.2:  
▪ Added detail for Hashimoto syndrome: Patients with a history of 
Hashimoto syndrome within 3 years of the first dose of investigational 
agent, which resolved to hypothyroidism alone. 
• Planned Sample Size:  
o Synopsis Section 6.1.2, Section 13.1:  
▪ Deleted: If 10% to 15% of Phase 1 patients are not DLT evaluable, then 
27 patients may need to be enrolled. This text was removed, as 
additional patients may need to be enrolled to meet enrollment 
requirements.  
• Statistical Methods and Planned Analyses: 
o Synopsis, Section 6.1, Section 13:  
▪ Revised text in definition of DLT-evaluable population to clarify 1 dose 
of APX005M required.  
▪ Added: For Phase 2, evaluation of baseline and on-treatment 
microbiome profiles with treatment outcomes. 
• Investigational Plan:  
o Section 6.1, Section 9, Section 11.2:  
▪ Added language regarding timing and mandatory nature and of the on-
treatment tumor biopsy, if medically feasible. 
o Section 6.1.1 
▪ Clarifications to enrollment timeframes for both Phase 1b and 2. 
• Details of Study Treatment:  
o Section 8.1, Section 8.4, Section 8.5 
▪ Added text to permit delay of treatment, as allowed by the protocol, at 
the treating investigator’s discretion (e.g. toxicity, weather).  
▪ Added text to clarify APX005M doses should not be administered <2 
weeks apart. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
131 
 
▪ Added clarification around window for premedication treatment prior 
to APX005M.  
▪ Text added to clarify continuing treatment with other study treatments 
is allowed, with Medical Monitor approval, in the event APX005M is 
discontinued due to drug-related toxicity.  
• Study Procedures: 
o Section 9:  
▪ Table 11 (Arms Including APX005M, Phase 1b):  
• Added pre-infusion vital signs. 
• Added language regarding timing and mandatory nature and of 
the on-treatment tumor biopsy, if medically feasible. 
▪ Table 12 (Arms Including APX005M, Phase 2): 
• Added pre-infusion vital signs. 
• Removed PK collection during Cycle 1, Days 4, 8 and 15. 
• Removed biomarker collection during Cycle 1, Days 4 and 8. 
• Removed biomarker collections after Cycle 4. 
• Added stool collection at screening and on-treatment for 
microbiome profiling. 
• Added language regarding timing and mandatory nature and of 
the on-treatment tumor biopsy, if medically feasible. 
▪ Table 13 (Arms Not Including APX005M, Phase 2): 
• Added pre-infusion vital signs. 
• Removed biomarker collections after Cycle 4. 
• Added stool collection at screening and on-treatment for 
microbiome profiling. 
• Added language regarding timing and mandatory nature and of 
the on-treatment tumor biopsy, if medically feasible. 
 
In addition to the major changes described above, minor typos were corrected and editorial 
changes were made for clarity. 
 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
132 
 
16.4.6 
Key Revisions in Amendment 6 
Text revisions resulting from this amendment are incorporated in the synopsis and body of 
Protocol Amendment 6. Major changes to the protocol are summarized below.  
• Objectives and Endpoints: 
o Synopsis:  
▪ For Phase 2 exploratory objective #4, the specification of “Phase 2” for 
evaluation of baseline and on-treatment microbiome profiles was 
removed. 
o Synopsis and Section 5.2.2.2:  
▪ For Phase 2 secondary endpoint #5, assessment of “unacceptable 
toxicities in Phase 2” was added. 
• Study Design: 
o Synopsis and Section 6.1: 
▪ Figure 1 Study Flow Chart was updated to reflect selection of 
recommended phase 2 dose. 
▪ Added criteria for “unacceptable toxicity”, defined as any ≥ Grade 3 
toxicity that is not treatment-related but not related to the natural 
progression of the tumor and occurs during the Phase 2 period. 
• Study Duration: 
o Synopsis and Section 6.1.1:  
▪ Changed the duration of additional follow-up in Phase 2 from 6 to 12 
months. 
• Discontinuation/Withdrawal of Patients 
o Section 7.3.1:  
▪ Added this subheader (Discontinuation of Study Drug) for clarity. Also, 
specified that the primary reason for study drug discontinuation should 
be documented on the appropriate eCRF page. 
o Section 7.3.2: 
▪ Renamed this subsection as “Withdrawal/Discontinuation of Patients” 
(instead of “Withdrawal and Removal of Patients) for clarity. Added 
text to describe withdrawal/discontinuations of patients. 
o Section 7.5: 
▪ Added this section to describe lost to follow-up. 
• Study Treatments and Toxicity Management: 
o Section 7.4, Section 9 (Table 11, Table 12, and Table 13), Section 11.2:  
▪ Changed “end of study” to “end of treatment” for clarity. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
133 
 
o Section 8.1.1 and Section 8.1.2: 
▪ Revised the storage and stability text for APX005M and nivolumab to 
be consistent with the Pharmacy Manual. 
o Section 8.1.1, Section 8.1.3, Section 8.1.4, Section 8.2.1, Section 8.2.3, and 
Section 8.2.4: 
▪ Specified that patients may only receive a delayed dose of APX005M 
on Day 10 if they have received NP/Gem on Day 8. 
▪ Specified that patients whose Day 8 dose of NP/Gem is delayed due to 
toxicity may receive the dose on Day 22, but they must have received 
APX005M on Day 3. 
o Section 8.2: 
▪ Reduced change in body weight (for dose adjustments) from 10% to 
≥ 5%. 
o Section 8.5: 
▪ Added a statement to clarify that if NP and/or Gem related toxicity leads 
to discontinuation of the chemotherapy, treatment with APX005M and 
nivolumab or either agent alone may be continued with agreement of 
the Medical Monitor. 
• Study Procedures: 
o Section 9: 
▪ Added text to clarify the timing of study assessments for treatment 
delays. 
▪ Table 11 (Arms Including APX005M, Phase 1b): 
• Added follow-up columns (D30, D100, and survival) for clarity. 
• Clarified the timing of study assessments for APX005M 
treatment delays in footnote “b”. 
• Added footnote “h” to clarify the AE collection period, 
particularly for follow-up. 
• Revised footnote “k” for clarity. 
• Revised footnote “m” to specify that the tumor markers, CA19-9 
and CEA, will be collected if performed as part of standard of 
care. 
• Added missing footnotes “q” and “s”. 
▪ Table 12 (Arms Including APX005M, Phase 2) 
• Added follow-up columns (D30, D100, and survival) for clarity. 
• Clarified the timing of study assessments for APX005M 
treatment delays in footnote “b”. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
134 
 
• Added footnote “h” to clarify the AE collection period, 
particularly for follow-up. 
• Revised footnote “l” for clarity. 
• Revised footnote “o” to specify that tumor markers, CA19-9 and 
CEA, are required at Cycle 1 Day 1 for all treatment arms, and 
if the result of either of these markers are not clinically 
significant at Cycle 1 Day 1, further collection will not be 
required. 
• Added footnotes “t” and “u”. 
▪ Table 13 (Arms Not Including APX005M, Phase 2) 
• Added follow-up columns (D30, D100, and survival) for clarity. 
• Revised footnote “f” for clarity. 
• Added footnote “g” to clarify the AE collection period, 
particularly for follow-up. 
• Revised footnote “i” for clarity. 
• Revised footnote “k” to specify that tumor markers, CA19-9 and 
CEA, are required at Cycle 1 Day 1 for all treatment arms, and 
if the result of either of these markers are not clinically 
significant at Cycle 1 Day 1, further collection will not be 
required. 
• Revised footnote “p” for clarity. 
• Safety Assessments: 
o Section 12.5.1: 
▪ Clarified the collection period for AEs and SAEs.  
o Section 2.5.2 and Section 2.5.2.1:  
▪ Clarified the definitions of AEs and SAEs. 
o Section 12.5.2.2: 
▪ Clarified the assessment of events as infusion-related reactions or 
cytokine release syndrome. 
o Section 12.5.2.3: 
▪ Added a definition for immune-mediated AEs. 
o Section 12.5.5: 
▪ Clarified SAE reporting. 
• Statistical Analysis and Sample Size: 
o Synopsis and Section 6.1.2: Corrected the total sample size to show 
“approximately 117” instead of “120” patients. 


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
135 
 
o Synopsis, Section 6.1, Section 13, Section 13.1.2, Section 13.2: 
▪ For 1-year OS rate analysis, text was added to indicate that a 1-sided 1-
sample Z test will also be performed and that the goal is to compare the 
survival probability at 1 year to the historical value of 0.35. 
 
In addition to the major changes described above, minor typos were corrected and editorial 
changes were made for clarity. 
 
16.4.7 
Key Revisions in Amendment 7 
Text revisions resulting from this amendment are incorporated in the synopsis and body of 
Protocol Amendment 7. Major changes to the protocol are summarized below.  
• Study Procedures 
o Sections 6.1, 9 and 11.2 
▪ Added option for tissue collection at the time of disease progression, for 
patients with prolonged stable disease, as well as ad hoc tissue 
collections with Medical Monitor approval 
▪ Added language indicating the first dose of study drug must be 
administered within 3 days of randomization, per a previously-approved 
Note to File 
o Sections 6.1.1, 7.3.2 and 9 
▪ Clarified duration of survival follow-up 
▪ Revised frequency of follow-up for survival and new anti-cancer 
therapy status from Q6M to Q3M with the addition of ad hoc collections  
o Section 8.9.3 
▪ Added language permitting the transient use of steroids to control 
contrast agent allergies for radiographic studies as an exception to the 
Prohibited Medications 
o Section 9 
▪ Revised window for Day 100 Follow-up Visit from  7 days to  14 
days  
▪ Added pregnancy test to the Phase 2 Day 30 Follow-Up Visit to align 
with the Phase 1b safety assessments 
▪ Clarified tumor marker collection requirements for Phase 2  
o Sections 9 and 10 
▪ Added language clarifying the collection requirements for disease 
assessments after treatment discontinuation and during treatment 
beyond radiological progression, per a previously-approved Note to File  


Parker Institute for Cancer Immunotherapy 
PICI0002 
Amendment 7, dated October 11, 2019 
Final Protocol 
 
136 
 
 
o Sections 9, 11.1.1, 11.2.3 
▪ Clarified PK and ADA collection required at EOT 
o Sections 9 and 11.2 
▪ Clarified immune biomarker collection required at EOT  
▪ Added immune biomarker collections for patients on treatment over 12 
months, permitting blood draws at 12 months and Q6M thereafter 
• Safety Assessments: 
o Sections 9 and 12.5.1, 12.5.3 and 12.5.5  
▪ Added language clarifying the collection and reporting periods for AEs, 
AESIs and SAEs 
o Section 12.5.2.2 
▪ Removed text defining infusion-related reaction versus cytokine release 
syndrome to maintain reporting consistency over life of study  
▪ Updated reporting language for Infusion-Related Reactions and 
Cytokine Release Syndrome to clarify all underlying symptom(s) must 
be reported as individual AEs in addition to the applicable syndrome(s) 
o Section 12.5.2.3 
▪ Removed text defining Immune-mediated Adverse Events to maintain 
reporting consistency over life of study  
• Statistical Methods and Planned Analyses: 
o Section 13.1.2 
▪ Removed language specifying an intent-to-treat approach will be used 
for Phase 2 for alignment with the definition of the efficacy population 
indicated in the Synopsis, Section 13 and the Statistical Analysis Plan 
o Section 13.7 
▪ Added language allowing the Sponsor to conduct up to three interim 
analyses of safety and efficacy during the study  
In addition to the major changes described above, minor typos were corrected and editorial 
changes were made for clarity. 
 

SAP_001.pdf: 
11(1 
PARKER 
INSTITUTE 
FOR 
CANCER 
IMMUNOTHERAPY 
Statistical Analysis Plan for 
Protocol Number: PICI0002 
Protocol Title: Open-label, Multicenter, Phase lb/2 Clinical Study to 
Evaluate the Safety and Efficacy of CD40 Agonistic Monoclonal Antibody 
(APX005M) Administered Together with Gemcitabine and nab-Paclitaxel 
with or without PD-1 Blocking Antibody (Nivolumab) in Patients with 
Previously Untreated Metastatic Pancreatic Adenocarcinoma 
IND Number: 
Name of Products: 
Phase of Development: 
Indication: 
Sponsor: 
Date Final: 
132683 
APX005M ( experimental) 
Nivolumab ( experimental) 
Gemcitabine (standard of care) 
nab-Paclitaxel (standard of care) 
lb/2 
Previously untreated metastatic pancreatic cancer 
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Version 1: 26 Sep 2019 
Version 2: 14 Feb 2020 
-CONFIDENTIAL-
This document and its contents are the property of and confidential to Parker Institute for 
Cancer Immunotherapy. Any unauthorized copying or use of this document is prohibited. 
1 
1


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
SPONSOR APPROVAL PAGE 
(
DocuSigned by: 
I (Msfop/w- (Ai,MA-ski 
ll(J 
Signer Name: Christopher Cabanski 
Eigning Reason: I approve this document 
C istcfu~~i i~a~at{§'ftf lpfiljO PM PS I 
D · 
73CCJI.BA74t901463485D6314D83F02F85 
irector, tl10s ausucs 
(
DocuSigned by: 
I 
l~rk ..... 
ll(J 
Signer Name: Ramy Ibrahim 
R 
y lbtrutlifl(Mfil2020 I 4:43:42 AM PST 
Chi 
MeffielfllOfffdel5os7001 o7o9Ec1 c 
PICI0002 
2/14/2020 I 1:10:58 PM PST 
Date: 
2/16/2020 I 4:43:45 AM PST 
Date: 
2 
2


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
1 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
Version 2: 14 Feb 2020 
PICI0002 
The Statistical Analysis Plan was amended to add details about a second interim analysis of 
the Phase 2 portion of the study. Additional minor changes were made to improve clarity and 
consistency. No changes to the study endpoints, population definitions, or statistical methods 
were made. 
3 
3


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
2 
TABLE OF CONTENTS 
PICI0002 
1 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 3 
2 
TABLE OF CONTENTS ................................................................................................ 4 
3 
INTRODUCTION ........................................................................................................... 6 
4 
STUDY DESIGN ............................................................................................................ 6 
4.1 
Protocol Synopsis ................................................................................................. 8 
4.2 
Study Objectives ................................................................................................... 8 
4.2.1 
Phase 1 b ................................................................................................. 8 
4.2.2 
Phase 2 ................................................................................................... 8 
4.3 
Study Endpoints .................................................................................................... 9 
4.4 
Determination of Sample Size .............................................................................. 9 
4.4.1 
Phase 1 b ................................................................................................. 9 
4.4.2 
Phase 2 ................................................................................................. 10 
4.5 
Analysis Timing .................................................................................................. 10 
5 
STUDY CONDUCT ...................................................................................................... 10 
5.1 
Randomization Details ........................................................................................ 10 
5.2 
Blinding .............................................................................................................. 12 
5.3 
Data Monitoring .................................................................................................. 12 
5.3.1 
Early Termination Rules for Unacceptable Toxicity in Phase 2 .......... 12 
6 
STATISTICAL METHODS .......................................................................................... 13 
6.1 
Analysis Populations ........................................................................................... 13 
6.1.1 
Safety Population ................................................................................. 13 
6.1.2 
DLT-evaluable Population ................................................................... 13 
6.1.3 
Efficacy Population .............................................................................. 14 
6.2 
Analysis of Study Conduct ................................................................................. 14 
6.3 
Analysis of Treatment Group Comparability ..................................................... 14 
6.4 
Efficacy Analysis ................................................................................................ 15 
6.4.1 
Comparisons of Interest ....................................................................... 15 
6.4.2 
Type I Error Management .................................................................... 15 
6.4.3 
Covariate Adjustment .......................................................................... 15 
6.4.4 
Primary Efficacy Endpoint .................................................................. 15 
6.4.5 
Secondary Efficacy Endpoints ............................................................. 16 
4 
4


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
PICI0002 
6.4.5.1 
Objective Response Rate ...................................................... 16 
6.4.5.2 Duration ofResponse ............................................................ 16 
6.4.5 .3 
Disease Control Rate ............................................................. 17 
6.4.5.4 Progression-free Survival ...................................................... 17 
6.4.6 
Exploratory Efficacy Endpoints ........................................................... 17 
6.4. 7 
Subgroup Analyses .............................................................................. 17 
6.4.8 
Sensitivity Analyses ............................................................................. 18 
6.5 
Safety Analysis ................................................................................................... 18 
6.5.1 
Exposure to Study Medication ............................................................. 19 
6.5.2 
Adverse Events .................................................................................... 19 
6.5.3 
Laboratory Data ................................................................................... 20 
6.5.4 
Vital Signs ............................................................................................ 20 
6.6 
Missing Data ....................................................................................................... 20 
6.6.1 
Missing and Partial Missing Adverse Event Dates .............................. 20 
6.6.2 
Missing and Partial Missing Death Dates ............................................ 20 
6. 7 
Interim Analyses ................................................................................................. 21 
7 
DIFFERENCES COMPARED TO PROTOCOL ......................................................... 22 
8 
REFERENCES .............................................................................................................. 23 
9 
APPENDICES ............................................................................................................... 24 
9 .1 
Protocol Synopsis ............................................................................................... 24 
LIST OF TABLES 
Table 1 
Probability of Failing to Accept a Dose Level at Different Event Rates .................. 9 
Table 2 
Phase 1 b Treatment Assignment.. ........................................................................... 11 
Table 3 
Phase 2 Design ........................................................................................................ 11 
Table 4 
Bayesian Termination Rules ................................................................................... 12 
LIST OF FIGURES 
Figure 1 Study Flow Chart ...................................................................................................... 6 
5 
5


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
3 
INTRODUCTION 
PICI0002 
The purpose of this document is to provide details of the planned analyses for Protocol 
PICI0002. The analyses specified in this document supersede the high-level analysis plan 
described in the protocol. Statistical analyses will be performed consistent with the principles 
of the ICH/FDA Guidance for Industry E9 Statistical Principles for Clinical Trials. 
4 
STUDY DESIGN 
PICI0002 is a multi-center, open label, Phase 1 b/2 study of the immunotherapy agents 
APX005M and nivolumab, in combination with Gemcitabine (Gem) and nab-Paclitaxel (NP) 
in patients with previously untreated metastatic pancreatic adenocarcinoma. 
Phase 1 b will involve 4 sequential treatment cohorts, and Phase 2 will involve randomization 
to 3 treatment arms, as shown in Figure 1. 
Figure 1 
Study Flow Chart 
Phase lb 
Phase2 
Cohort Bl: 
CohortB2: 
Cohort Cl: 
CohortC2: 
ArmAl: 
-
NP 
NP 
Nivolumab 
Nivolumab 
Nivolumab 
Gem 
Gem 
NP 
NP 
NP 
APX005M 
APX005M 
Gem 
Gem 
Gem 
0.1 mg/kg 
0.3 mg/kg 
APX005M 
APX005M 
-
-
0.1 mg/kg -
0.3 mg/kg 
35 patients 
6 patients 
6 patients 
6 patients 
6 patients 
ArmB2: 
or Arm Bl: 
NP 
NP 
-
Gem 
Gem 
APX005M 
APX005M 
0.3 mg/kg 
0.1 mg/kg 
29 patients 
29 patients 
ArmC2: 
or Arm Cl: 
Nivolumab 
Nivolumab 
-
NP 
NP 
Gem 
Gem 
APX005M 
APX005M 
0.3 mg/kg 
0.1 mg/kg 
29 patients 
29 patients 
Phase lb 
In the Phase 1 b portion of the study, 4 treatment cohorts will be evaluated sequentially for 
feasibility and safety. Each cohort of the study will have 6 DL T-evaluable patients, defined as 
patients who experienced a Dose-Limiting Toxicity (DLT) or who completed the DLT 
observation period, i.e. received at least 2 doses of NP/Gem and 1 dose of APX005M during 
6 
6


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
PICI0002 
Cycle 1. Patients who do not experience a DL T and who do not complete the DL T observation 
period will be replaced. 
In general, a DL T is defined as: (1) any Grade 3 or higher non-hematologic or Grade 4 
hematologic toxicity occurring during the DL T observation period that is considered to be at 
least possibly related to APX005M and/or nivolumab, or (2) an exacerbation of known 
NP/Gem toxicity that is at least possibly related to APX005M and/or nivolumab. A more 
comprehensive definition of a DL T can be found in the protocol. The DL T observation period 
is defined as the time of first administration of investigational agents until Cycle 2 Day 1. 
Dose escalation will proceed if 1 or fewer DL T-evaluable patients experience a DL T during 
this observation period. Dose escalation will cease if 2 or more DL T-evaluable patients in a 
cohort experience a DLT. 
On the basis of discussions among the site Pis, Sponsor, and other stakeholders, concerning 
feasibility, safety, clinical and immune pharmacodynamic (PD) effects (totality of available 
data), the recommended Phase 2 dose is defined by the highest APX00M dose with <2 DLT 
in 6 DL T-evaluable patients, unless the totality of available data suggests a lower APX005M 
dose. 
Randomized Phase 2 
Once the recommended Phase 2 dose (RP2D) of APX005M in combination with nivolumab 
from Cohort C in the Phase 1 b portion of the study is determined, the randomized Phase 2 
portion will commence. Patients will be randomized to Arm Al, Arm B2, or Arm C2, or to 
Arm Al, Arm Bl, or Arm Cl, if Cohort B2 and/or C2 are deemed unsafe in Phase lb. Note 
that the APX005M dose must be the same in Arms B and C, regardless of whether a higher 
APX005M dose was determined to be safe in Arm B. For each regimen, efficacy will be 
evaluated by comparing the I-year overall survival (OS) rate to the historical value for 
NP/Gem. A total of approximately 93 patients will be randomized in Phase 2 (35 Arm Al, 29 
Arm B2, 29 Arm C2). 
All patients will be followed up for survival status until death or a maximum of 5 years. Once 
a patient is in follow-up, follow up can be obtained with a clinic visit or a phone call 
approximately every 6 months. 
It is common for randomized Phase 2 studies that test the addition of an experimental agent to 
a standard of care regimen to include the standard of care arm. However, the setting for this 
study is unique. NP/Gem, the standard of care regimen, was reported recently in a very similar 
patient population, and the I-year OS rate was estimated with extremely high precision (i.e., 
I-year OS rate was 35% with 95% CI 30%-39%) based on 431 treated patients (Von Hoff et 
al.). With hundreds of pancreatic patients treated with NP/Gem since that report, experts in this 
7 
7


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
PICI0002 
field agree that the 1-year OS rate estimate appears to be very robust. Thus, this study will not 
include a standard of care arm. 
The 12 DLT-evaluable patients who were enrolled in Phase 1 b at the recommended Phase 2 
doses (6 on Arm B and 6 on Arm C) will be included in the efficacy evaluation and 93 
additional patients will be randomized in Phase 2, for a total sample size of 105 patients (35 
per treatment arm). 
4.1 
Protocol Synopsis 
The Protocol Synopsis is provided in Section 9 .1. 
4.2 
Study Objectives 
This study will be conducted in two phases, each with its own objectives. 
4.2.1 
Phase lb 
Primary Objectives: 
1. To determine the feasibility, safety, and DLTs of each treatment cohort. 
2. To determine the recommended Phase 2 dose of APX005M when combined with 
NP/Gem. 
3. To determine the recommended Phase 2 dose of APX005M when combined with 
nivolumab/NP/Gem. 
Secondary Objectives: 
1. To determine objective response rate (ORR) and duration of responses (DOR) of each 
treatment cohort. 
Exploratory Objectives: 
1. To assess the pharmacokinetics (PK) of APX005M in Cycles 1 to 4. 
2. To assess immune pharmacodynamic effects of each treatment cohort, in both blood 
and tumor tissue. 
4.2.2 Phase 2 
Primary Objectives: 
1. To estimate the OS of each treatment arm. 
2. To compare 1-year OS rate of each treatment arm to the historical rate for NP/Gem. 
8 
8


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
Secondary Objectives: 
PICI0002 
1. To determine the ORR, disease control rate (DCR), DOR, and progression-free survival 
(PFS) of each treatment arm. 
2. To further characterize the feasibility and safety of each treatment arm. 
Exploratory Objectives: 
1. To assess the PK of APX005M in Cycles 1 to 4 (Arms B and C). 
2. To assess immune pharmacodynamic effects of each treatment arm, in both blood and 
tumor tissue. 
3. To assess associations between immune biomarkers and clinical outcomes. 
4. To evaluate baseline and on-treatment microbiome profiles. 
5. To construct multivariable linear models to dissect the pharmacodynamic effects of 
APX005M and nivolumab on immune biomarkers. 
4.3 
Study Endpoints 
The study endpoints are listed in the Protocol Synopsis (Section 9 .1 ). 
4.4 
Determination of Sample Size 
4.4.1 
Phase lb 
Assuming 4 treatment cohorts will be evaluated sequentially for feasibility, safety, and 
dose-limiting toxicities, 24 DLT-evaluable patients will be enrolled (6 per cohort). Patients 
who do not experience a DL T and who do not complete the DL T observation period will be 
replaced. 
The Phase 1 b sample size was determined by practical considerations and was not based on 
statistical power calculations. Six patients dosed in each group was deemed sufficient to 
characterize the feasibility, safety, and DLTs of each cohort. Based on this sample size, Table 
1 provides the probability of failing to accept a cohort as safe, defined as 2:: 2 DLTs in 6 treated 
patients, assuming different DL T rates. 
Table 1 
Probability of Failing to Accept a Dose Level at Different Event Rates 
DLT Event Rate 
Probability a 
DLT = dose-limiting toxicity 
1% 
0.001 
10% 
0.11 
20% 
0.34 
25% 
0.47 
33% 
0.64 
50% 
0.89 
a Assumes P (X 
2) where X is a binomial random variable with sample size n = 6 and p = DLT event rate. 
9 
9


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
4.4.2 Phase 2 
PICI0002 
The 12 DLT-evaluable patients who were enrolled in Phase 1 b at the recommended Phase 2 
doses (6 on Arm B and 6 on Arm C) will be included in the efficacy evaluation and 
approximately 93 additional patients will be randomized in Phase 2, for a total sample size of 
105 patients (35 per treatment arm). This is a screening study, such that for each treatment arm, 
the I-year OS rate will be estimated and compared with a historical value of35% for NP/Gem 
(Von Hoff et al.). The study is not powered to detect a meaningful difference in OS among the 
3 arms, since these are novel experimental arms and OS is unknown. 
The null hypothesis is a I-year OS rate of 35% and the alternative hypothesis is a I-year OS 
rate of 58%. The I-year OS rate is estimated by the Kaplan-Meier method. A sample size of 
35 patients on each arm provides 88% power to test this hypothesis, using a I-sided one-sample 
Z test with 5% type I error rate, assuming a minimum of 1 year of follow-up for each patient. 
Moreover, the sample size of 3 5 patients on each arm, provides 81 % power to statistically test 
the null hypothesis versus a slightly more conservative alternative hypothesis that the I-year 
OS rate is 55%, given the same design assumptions. 
These calculations assume that 105 patients (35 patients x 3 arms) will be enrolled. There is 
no assumption about the duration of patient enrollment, only that there will be a minimum of 
1 year of follow-up for each patient. 
4.5 
Analysis Timing 
The database lock for analysis of the Phase 2 primary endpoint of I-year overall survival (OS) 
rate will occur approximately one year after the last patient is randomized. No changes to the 
SAP will be allowed at the time of or subsequent to database lock. 
Analysis of the Phase 1 b endpoints may be performed prior to the time of primary analysis. 
These results may be presented and/or published prior to the primary analysis. 
The study will formally end once all patients have been followed for survival status until death 
or a maximum of 5 years, withdrawal of consent, or loss to follow-up. A survival analysis of 
long-term follow-up may be performed after the primary analysis has been completed. 
5 
STUDY CONDUCT 
5.1 
Randomization Details 
In Phase lb, patients will be enrolled sequentially into 4 cohorts (Bl, B2, Cl, and C2) as 
summarized in Table 2. The Phase 1 b portion of the study is non-randomized. Enrollment in 
Cohorts B2 and C 1 may occur concurrently. 
10 
10


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
Table 2 
Phase lb Treatment Assignment 
Arm 
Regimen 
Bl 
NP/Gem/APX005M 0.1 mg/kg 
B2 
NP/Gem/APX005M 0.3 mg/kg 
Cl 
Nivolumab/NP/Gem/APX005M 0.1 mg/kg 
C2 
Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
PICI0002 
Number of DLT-Evaluable 
Patients 
6 
6 
6 
6 
DLT = dose-limiting toxicity; Gem= gemcitabine; NP = nab-paclitaxel 
Once the RP2D of APX005M in combination with nivolumab from Cohort C in the Phase 1 b 
portion of the study is determined, the randomized Phase 2 portion will commence. Patients 
will be randomized to Arm Al, Arm B2, or Arm C2, or to Arm Al, Arm Bl, or Arm Cl, if 
Cohort B2 and/or C2 are deemed unsafe in Phase lb. Note that the APX005M dose must be 
the same in Arms B and C, regardless of whether a higher APX005M dose was determined to 
be safe in Arm B. 
A total of 105 patients will be evaluated in the Phase 2 portion of the study, including 12 DL T-
evaluable patients from Phase 1 b (i.e., 6 patients on B 1 and 6 patients on C 1 or 6 patients on 
B2 and 6 patients on C2). The remaining 93 patients will be randomized and treated only in 
Phase 2. In step 1 of randomization, 12 of the 93 new patients will be randomized to the 3 arms 
in a 4:1:1 ratio in Arms Al, B2, and C2 (or Al, Bl, and Cl), to achieve balance in the total 
number of patients emolled on the arms (since Arm Al does not accrue in Phase 1 b, more 
patients need to be emolled in Arm Al). In step 2 of randomization, 81 patients will be 
randomized to Arms Al, B2, and C2 (or Al, Bl, and Cl) in a 1:1:1 allocation. The 
randomization design is outlined in Table 3. 
Table 3 
Phase 2 Design 
Arm 
Reeimen 
Al 
Nivolumab/NP/Gem 
B2a 
NP/Gem/APX005M 0.3 mwkJi: 
c2a 
Nivolumab/NP/Gem/ APX005M 
0.3 mwkJi: 
a Or Bl and Cl, if either B2 or C2 is not tolerable. 
Gem = gemcitabine; NP = nab-paclitaxel 
Phase lb 
Number 
of patients 
0 
6 
6 
11 
Phase2 
Total 
Step 1 
Step 2 
Number 
Number of 
Number 
of patients 
patients 
of patients 
8 
27 
35 
2 
27 
35 
2 
27 
35 
11


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
PICI0002 
Randomization will be managed by the Parker Institute for Cancer Immunotherapy (PICI), 
using an interactive voice response system (IVRS). The randomization is not stratified by 
baseline patient or tumor characteristics. 
5.2 
Blinding 
This is an open-label study with no blinding. 
5.3 
Data Monitoring 
The study will be closely monitored, and data will be reviewed on an ongoing basis. In order 
to ensure the safety and well-being of participating patients, as well as the validity of data 
during the study, a Data Review Team (DRT) will review the safety and further emerging data 
on a regular basis. The DRT consists of members from the Sponsor, the overall Principal 
Investigator (Pl), the lead statistician, and all active Pis. The DRT will adjudicate DLTs 
relevant for the treatment and will decide by consensus on dose escalation, dose de-escalation, 
prolongation of the DL T observation period, suspension of enrollment based on safety, PK, or 
possibly pharmacodynamic data, and will recommend the dose level for the Phase 2 portion. 
5.3.1 
Early Termination Rules for Unacceptable Toxicity in Phase 2 
A Bayesian rule will be employed to monitor toxicity during Phase 2. A minimally informative 
beta (0.5, 2.5) prior has been assumed, which is information that is equivalent to½ the weight 
of 1 DL T in 6 patients treated, the definition of a safe dose in Phase 1 b. For each treatment 
arm, if the number of patients with an unacceptable toxicity ( defined the Section 6.1 of the 
study protocol) is greater than or equal to the number in Table 4, then termination of that 
particular treatment arm will be considered, as it is likely that the toxicity rate is >30%, as 
noted by the Bayesian posterior probabilities. This rule is intentionally conservative early in 
the enrollment phase. 
Table 4 
Bayesian Termination Rules 
Rules for Unacceptable Toxicity Rate >30% 
Patients treated on an arm 
10 
4 
0.61 
15 
6 
0.69 
20 
9 
0.87 
25 
11 
0.88 
30 
13 
0.90 
Patients with unacceptable toxicity 
Posterior Probability [toxicity rate >30%] 
Action 
Consider termination of arm, re-evaluate study design. 
12 
12


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
6 
STATISTICAL METHODS 
PICI0002 
Summary statistics will be presented by treatment arm. For continuous variables, data will be 
summarized with the number of patients (N), mean, standard deviation, median, minimum, and 
maximum by treatment arm. For categorical variables, data will be tabulated with the number 
and proportion of patients for each category by treatment arm. 
6.1 
Analysis Populations 
6.1.1 
Safety Population 
The safety population consists of all patients who received at least 1 dose of any study drug. 
This is the population for the analyses of safety. A subset of the safety population is the DL T-
evaluable population. 
For the safety analyses, patients will be analyzed according to the treatment regimen actually 
received. Using a conservative approach: 
• 
Phase 1 b patients who receive at least one dose of nivolumab but do not receive 
APX005M will be analyzed under Arm Cl. Phase 2 patients who receive at least one 
dose of nivolumab but do not receive APX005M will be analyzed under Arm Al. 
• 
Phase 1 b patients who receive at least one dose of APX005M but do not receive 
nivolumab will be analyzed under Arm B 1 or B2, depending on the highest dose level 
of APX005M received. Phase 2 patients who receive at least one dose of APX005M 
but do not receive nivolumab will be analyzed under Arm B2 (the dose level selected 
for Phase 2 emollment). 
• 
Phase 1 b patients who receive at least one dose of both APX005M and nivolumab will 
be analyzed under Arm C 1 or C2, depending on the highest dose level of APX005M 
received. Phase 2 patients who receive at least one dose of both APX005M and 
nivolumab will be analyzed under Arm C2 (the dose level selected for Phase 2 
emollment). 
• 
Patients who receive at least one dose of NP/Gem but do not receive APX005M or 
nivolumab will be analyzed under the treatment arm assigned at emollment (Phase 1 b) 
or randomization (Phase 2). 
6.1.2 DL T-evaluable Population 
The DLT-evaluable population consists of patients who (1) were emolled in Phase lb, (2) 
received at least 2 doses of NP/Gem and 1 dose of APX005M during Cycle 1, and (3) 
completed the DL T observation period (i.e. from the time of first administration of study 
13 
13


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
PICI0002 
intervention until Cycle 2 Day 1). Alternatively, patients who did not complete the DLT 
observation period due to a DL T event will also be considered DL T evaluable. 
The DL T-evaluable population is the population for analyses of Phase 1 b efficacy and DL Ts. 
Patients will be grouped according to the treatment arm assigned at emollment, regardless of 
the treatment actually received. 
6.1.3 
Efficacy Population 
The efficacy population consists of (1) all patients who were randomized in Phase 2 and 
received at least 1 dose of any study drug and (2) the 12 DL T-evaluable patients ( 6 on Arm B 
and 6 on Arm C) who were emolled in Phase 1 b at the recommended Phase 2 dose. The 
efficacy population is the population for the primary analyses of efficacy in Phase 2. Patients 
will be grouped according to the treatment arm assigned at emollment/randomization, 
regardless of the treatment actually received. 
6.2 
Analysis of Study Conduct 
The number of patients emolled in Phase 1 b and randomized in Phase 2 will be tabulated by 
treatment arm. Patient disposition ( e.g. the number of patients emolled/randomized, receiving 
at least one dose of study drug) and time on study will be tabulated by treatment arm and may 
be represented graphically (e.g. swim lane plot). Reasons for premature discontinuation from 
study treatment and reasons for premature discontinuation from the study, including the 5-year 
follow-up period, will be summarized. 
Feasibility, defined by the number of Phase 1 b patients who complete the DLT observation 
period and receive the intended therapy without delays or dose modification, will be described 
for each treatment arm. 
6.3 
Analysis of Treatment Group Comparability 
Demographic and baseline characteristics, including but not limited to age, sex, race, ethnicity, 
Eastern Cooperative Oncology Group (ECOG) performance status at baseline, cancer location 
(pancreas body, head, or tail) and cancer stage at initial diagnosis and emollment will be 
summarized by treatment arm using descriptive statistics for all emolled/randomized patients. 
The baseline value of any variable will be defined as the last available value recorded prior to 
the first administration of study drug. 
Previous and concomitant cancer therapy will also be summarized, including radiotherapy and 
surgery, as well as subsequent anti-cancer therapy. Previous and concurrent diseases and 
medications will be listed. 
14 
14


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
6.4 
Efficacy Analysis 
PICI0002 
Phase 2 efficacy analyses will be conducted on the efficacy population (see Section 6.1.3), 
with patients grouped according to the treatment assigned at randomization. Phase 1 b efficacy 
analyses will be conducted on the DL T-evaluable population. 
Efficacy summaries will include data from patients who discontinued study drug early but 
continued with study assessments and may include data collected at unscheduled visits, early 
termination visits, or follow-up visits. 
6.4.1 
Comparisons of Interest 
The 1-year OS rate and I-sided 95% confidence interval will be calculated for each treatment 
arm, to determine whether the lower bound of the confidence interval (Cl) excludes the 
assumed historical value for NP/Gem of 35%. 
This study is not powered for statistical comparisons between arms. 
6.4.2 
Type I Error Management 
Due to the exploratory nature of this study, no control of type I error will be applied for any of 
the endpoints. 
6.4.3 
Covariate Adjustment 
Unless otherwise noted, analyses of primary and secondary efficacy endpoints will not be 
adjusted for additional covariates. 
6.4.4 Primary Efficacy Endpoint 
There is no primary efficacy endpoint for Phase 1 b. The Phase 2 primary efficacy endpoint is 
the 1-year OS rate in each treatment arm. OS is defined as the time from initiation of study 
therapy to date of death due to any cause. Patients who are not reported as having died at the 
time of analysis will be censored at their most recent contact date they were known to be alive. 
Patients who do not have post-baseline survival information will be censored at the date of 
randomization. See Section 6.6.2 for handling of missing or partial death dates. 
OS will be estimated by the Kaplan-Meier method for each treatment arm. For each treatment 
arm, the following parameters and analyses will be provided: Kaplan-Meier product-limit 
estimates of the OS distribution functions, the total number of patients, the total censored, the 
total deaths, the OS time (median and its 95% CI; 25th and 75th percentiles), and the survival 
rates at monthly intervals (i.e. 3, 6, 9, 12, etc. months). 
The 1-year OS rate and I-sided 95% confidence interval will be calculated for each treatment 
arm, to determine whether the lower bound of the confidence interval (Cl) excludes the 
assumed historical value for NP/Gem of 35%. 
15 
15


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
PICI0002 
A 1-sided one-sample Z test will also be conducted. The goal is to compare the survival 
probability at time t to the historical value. The null hypothesis is Ho: S(t) ,:'.S s* at time t. The 
alternative hypothesis is H1: S(t) > s*, a one-sided test. 
The Z test is: 
S(t)- s* 
SE(S(t)) 
where S(t) and SE are sample estimates. For this study, t = l year, S(t) = estimated 1-year OS 
probability from the Kaplan-Meier analysis, SE ( S (t)) = standard error of S (t) and null 
hypothesis s* = 0.35. 
A survival follow-up analysis may be performed based on more mature data. 
6.4.5 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints for Phase 1 b include ORR and DOR. The Phase 1 b efficacy 
endpoints will be analyzed for the DL T-evaluable population. 
Secondary efficacy endpoints for Phase 2 include ORR, DCR, DOR, and PFS. The Phase 2 
efficacy endpoints will be analyzed for the efficacy population. 
6.4.5.1 Objective Response Rate 
ORR, on the basis of investigator assessment, is defined as the proportion of patients who attain 
a complete response (CR) or partial response (PR). Per RECIST vl.1, confirmation of 
objective response is not required for this secondary endpoint. Patients without a post-baseline 
tumor assessment will be considered non-responders, as well as patients with a best overall 
response of stable disease (SD), progressive disease (PD) or not evaluable (NE). For a patient 
to have a best overall response of SD, he/she must have at least one post-baseline tumor 
assessment of SD at least 7 weeks after treatment initiation (8 weeks minus 7-day window; 
study day 49). 
A 95% confidence interval for the rate will be estimated for each treatment arm using the 
Clopper-Pearson method. 
Spider plots and waterfall plots will be generated to visualize changes in the sum of target 
lesions. 
6.4.5.2 Duration of Response 
For patients who have experienced an objective response (CR or PR) during the study as 
assessed by the investigator, DOR is defined as the time from the first tumor assessment that 
documents response (CR or PR, whichever is recorded first) to first documentation of 
16 
16


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
PICI0002 
radiographic PD per RECIST vl.1. Patients who have not progressed at the time of analysis 
will be censored at the last tumor assessment date prior to the start of subsequent systemic anti-
cancer therapy. The Kaplan-Meier method will be used to estimate the median DOR for each 
treatment arm with 95% confidence limits. 
6.4.5.3 Disease Control Rate 
DCR is defined as the proportion of patients who achieve a best response of CR, PR, or SD. 
For a patient to have a best overall response of SD, he/she must have at least one post-baseline 
tumor assessment of SD at least 7 weeks after treatment initiation (8 weeks minus 7-day 
window; study day 49). Patients without a post-baseline tumor assessment will be considered 
non-responders, as well as patients with a best overall response of PD or NE. A 95% confidence 
interval for the rate will be estimated for each treatment arm using the Clopper-Pearson method. 
DCR will also be estimated at 6 and 12 months. For these landmark analyses, DCR is defined 
as the proportion of patients who have a response of CR, PR, or SD at the first tumor 
assessment on or after the landmark time. Accounting for the Q8W (i.e. every 8 weeks) 
schedule and 7-day window for disease assessment, 6-month DCR will consider the first 
evaluable scan after study day 161 (24 weeks - 7 days) and 12-month DCR will consider the 
first evaluable scan after study day 329 (48 weeks - 7 days). Patients without an evaluable 
disease assessment after the landmark time will be considered non-responders. 
6.4.5.4 Progression-free Survival 
PFS is defined as the time from initiation of study therapy to date of first documented 
radiographic progression of disease or date of death due to any cause, whichever occurs first. 
PFS will be determined on the basis of investigator assessment of progression using RECIST 
vl .1. Patients who have not progressed or died at the time of analysis will be censored at the 
last tumor assessment date prior to the start of subsequent systemic anti-cancer therapy. 
Patients with no post-baseline tumor assessment will be censored at the date of study therapy 
initiation. The Kaplan-Meier method will be used to estimate the median PFS for each 
treatment arm with 95% confidence limits. 
PFS will also be estimated at various landmark times (e.g. 6 and 12 months). 
6.4.6 
Exploratory Efficacy Endpoints 
Exploratory endpoints defined in the protocol and listed in Section 9 .1 are outside the scope of 
this SAP. Biomarker analyses will be detailed in a Translational Analysis Plan. 
6.4. 7 
Subgroup Analyses 
For each treatment arm, OS will be analyzed in the subset of patients in the efficacy population 
who remain on treatment for at least 3 cycles (i.e. receive at least one dose of any study drug 
17 
17


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
PICI0002 
in Cycle 4) vs. those who remain on treatment for 3 cycles or less. This subset is in contrast to 
the efficacy population analyzed in the primary analysis. The 1-year OS rate and 1-sided 95% 
confidence interval will be calculated. 
6.4.8 
Sensitivity Analyses 
The following sensitivity analyses will be performed: 
• 
Efficacy analyses will be performed on the Phase 2 Efficacy Population, defined as all 
patients who were randomized in Phase 2 and received at least 1 dose of any study drug. 
This population similar to the Efficacy Population but excludes the 12 DL T-evaluable 
patients who were emolled in Phase 1 b at the recommended Phase 2 dose. 
• If the number of patients dosed in Phase 1 b does not match the DL T-evaluable 
population, ORR and DOR will be calculated for all patients who received at least one 
dose of study drug in Phase 1 b (i.e. the safety population). 
• If any Phase 2 patients were randomized but not dosed, Phase 2 primary and secondary 
efficacy endpoints may be analyzed using an intention-to-treat (ITT) approach. For 
these analyses, all randomized patients will be included, grouped according to the 
treatment assigned at randomization. 
• 
The impact of response confirmation on ORR will be assessed by requmng 
confirmation of CR or PR at least 4 weeks after initial documentation. 
• 
The effect of death on DOR will be assessed by defining DOR as the time from the first 
tumor assessment that documents response ( CR or PR, whichever is recorded first) to 
first documentation of radiographic progressive disease or death, whichever occurs first. 
Patients who have not progressed or died at the time of analysis will be censored at the 
last tumor assessment date prior to the start of subsequent systemic anti-cancer therapy. 
6.5 
Safety Analysis 
Safety will be assessed through the summary of adverse events (AEs), serious adverse events 
(SAEs), DLTs, laboratory test results (hematology and serum chemistry), vital signs, and 
physical examinations. This may include data collected at unscheduled visits, early termination 
visits, or follow-up visits. 
The baseline value of any variable will be defined as the last available value recorded prior to 
the first administration of study medication. If multiple values are available at the same visit, 
the mean of the values will be used for analysis at that timepoint. 
Safety outcomes will be summarized based on the safety population (see Section 6.1.1). Safety 
summaries will be presented by the treatment regimen actually received. 
18 
18


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
6.5.1 
Exposure to Study Medication 
PICI0002 
The number of patients exposed to each study drug and the extent of exposure ( as number of 
doses, cumulative dose received, and relative dose received) will be summarized using 
descriptive statistics. Relative dose received is defined as the total amount of each drug actually 
received divided by the amount of drug the patient would have been expected to receive had 
he/she received all planned doses without any dose modifications until the date of treatment 
discontinuation. 
6.5.2 
Adverse Events 
All reported AEs will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and graded using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03. 
A treatment-emergent adverse event (TEAEs) is defined as any new adverse event or any 
worsening of an existing condition with an onset date on or after the first dose of study drug. 
AEs with relationship to study drug of "Possibly", "Probably", "Definitely" or unknown 
(missing) will be considered treatment related. 
For each patient and each AE, the worst severity/grade recorded will be attributed and used in 
the severity summaries. 
Listings for all AEs, SAEs, and TEAEs will be presented by patient. Listings will include 
information regarding onset day/date, end day/date, duration, relationship to study drug, 
severity, action taken with study drug, whether concomitant medication was administered and 
outcome. 
Summaries of TEAEs (overall, by system organ class and preferred term and by severity) by 
treatment arm will be provided for each of the following categories: 
• 
AEs 
• 
AEs by most extreme severity 
• 
Treatment-related AEs 
• 
SAEs 
• 
Treatment-related SAEs 
• 
AEs leading to discontinuation of study treatment 
• 
DLTs 
• 
AEs from patients enrolled in Phase II that meet the protocol-defined unacceptable 
toxicity criteria 
The proportion of events that are resolved at the time of analysis will be presented. In addition, 
patient deaths and the primary cause of death will be listed, as well as any cases of pregnancy. 
19 
19


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
6.5.3 
Laboratory Data 
PICI0002 
Descriptive summaries of clinical laboratory values at each timepoint, including changes from 
baseline, will be generated for hematology and chemistry parameters by treatment arm. The 
proportion of patients with values outside the normal upper and lower limit at each visit will 
be displayed. 
In addition, select laboratory parameters (including, but not limited to, AST, ALT, alkaline 
phosphatase and total bilirubin) will be summarized by grade using the CTCAE grading scale. 
Missing laboratory values will not be imputed. Analysis will only occur on observed values. 
6.5.4 
Vital Signs 
Vital signs will be summarized by treatment arm using descriptive statistics including mean 
values and mean change from baseline. 
Missing vital signs will not be imputed. Analysis will only occur on observed values. 
6.6 
Missing Data 
6.6.1 
Missing and Partial Missing Adverse Event Dates 
If the AE start date is not a complete date, the following rules will be applied to determine 
whether the event is treatment emergent. 
• If the start date is completely missing: The AE will be assumed to be treatment-
emergent unless the AE stop date is earlier than the date of first dose of study drug. 
• If the day part of the AE start date is missing: If the month and year of the start date are 
later than or equal to the month and year of the date of first dose of study drug, then the 
AE will be assumed to be treatment emergent. If the month and year of the stop date 
are earlier than the month and year of the date of first dose of study drug, then the event 
will be assumed to be non-treatment emergent. 
• If the day and month of the start date are missing: If the year of the start date is later 
than or equal to year of the date of first dose of study drug, then the AE will be assumed 
to be treatment emergent. If the year of the stop date is earlier than the year of the date 
of first dose of study drug, then the event will be assumed to non-treatment emergent. 
6.6.2 
Missing and Partial Missing Death Dates 
For death dates, the following conventions will be used for imputing partial dates: 
• If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known date alive plus 1 
day, and the maximum will be considered as the death date. 
20 
20


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
PICI0002 
• If the month or the year is missing, the death date will be imputed as the last known 
date alive plus 1 day. 
• If the date is completely missing but the reason for death is present, the death date will 
be imputed as the last known date alive plus 1 day. 
6. 7 
Interim Analyses 
Given the hypothesis generating nature of this study, the Sponsor may conduct two interim 
analyses of safety and efficacy during the Phase 1 b and Phase 2 portions of the study. These 
interim analyses are strictly meant to support decision making for future studies. No 
adaptations (e.g. sample size re-estimation, early stopping for futility or efficacy, 
dropping/adding arms, modifying dose levels) will be made to the study based on the interim 
results. The analysis will be performed and interpreted by members of the Sponsor study team 
and management. Full results will be shared with management of the pharmaceutical partners 
of this study (Apexigen and Bristol-Myers Squibb), as their input is critical for decision making 
and design of future studies using this treatment regimen. Safety and limited efficacy results 
will be shared with study Investigators because they are key contributors to the design of an 
in-development clinical trial that may use the treatment regimens being tested in this study. To 
limit potential bias, any interim efficacy data shared with Investigators while patients are still 
receiving study therapy will only be presented as graphical summaries (spider and/or waterfall 
plots of BOR) with cohort names/identifiers masked. 
The first interim analysis will be conducted approximately 3 months after the last patient is 
randomized in the Phase 2 portion. The following endpoints will be summarized for the first 
interim analysis: 
• 
Study conduct including emollment, demographics, and disposition 
• 
Adverse events 
• 
Phase lb efficacy endpoints: ORR, DCR, DOR, OS, PFS 
• 
Phase 2 efficacy endpoints: ORR, DCR 
The second interim analysis will be conducted approximately 8 months after the last patient is 
randomized in the Phase 2 portion. The following endpoints will be summarized for the second 
interim analysis: 
• 
Study conduct including emollment, demographics, and disposition 
• 
Adverse events 
• 
Phase lb efficacy endpoints: ORR, DCR, DOR, OS, PFS 
21 
21


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
• 
Phase 2 efficacy endpoints: ORR, DCR, DOR, PFS 
PICI0002 
The Phase 2 primary endpoint of OS will not be analyzed for Phase 2 patients during either 
interim analysis. Due to the exploratory nature of this study, no control of type I error will be 
applied for any of the endpoints at the interim or final analysis. 
7 
DIFFERENCES COMPARED TO PROTOCOL 
• 
Section 4.4 (Determination of Sample Size): The SAP provides additional justification 
for the Phase 1 b sample size. 
• 
Section 6.1.l(Safety Population): The SAP clarifies that for the safety analyses, 
patients will be analyzed according to the treatment actually received. 
• 
Section 6.1.2 (DL T-evaluable Population): The SAP clarifies that the DL T-evaluable 
population is the population for analyses of Phase lb efficacy and DLTs. 
• 
Section 6.4.7 (Subgroup Analyses): The protocol states that OS will be analyzed in the 
subset of patients who remain on study for at least 6 weeks. The SAP modifies this 
subgroup to patients who remain on treatment for at least 3 cycles. 
• 
Section 6.7 (Interim Analyses): The SAP provides justification for and details about 
the two optional interim analyses of efficacy data. 
22 
22


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan, Version 2 
8 
REFERENCES 
ICH/FDA Guidance for Industry E9 Statistical Principles for Clinical Trials. U.S. 
Department of Health and Human Services, Food and Drug Administration, 
September 1998. 
PICI0002 
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-
paclitaxel plus gemcitabine. N Engl J Med 2013;369(18):1691-703. 
23 
23


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
9 
APPENDICES 
9.1 
Protocol Synopsis 
Title of Study: 
Protocol Number: 
Phase of Development: 
Objectives: 
Open-label, Multicenter, Phase lb/2 Clinical Study to Evaluate the Safety and 
Efficacy of CD40 Agonistic Monoclonal Antibody (APX005M) Administered 
Together with Gemcitabine and nab-Paclitaxel with or without PD-1 Blocking 
Antibody (Nivolumab) in Patients with Previously Untreated Metastatic 
Pancreatic Adenocarcinoma 
PICI0002 
lb/2 
Phase lb: 
Primary: 
1. 
To determine the feasibility, safety and dose-limiting toxicities (DL T) 
of each treatment cohort. 
2. 
To determine the recommended Phase 2 dose (RP2D) of APX005M 
when combined with nab-paclitaxel (NP)/gemcitabine (Gem). 
3. 
To determine the RP2D of APX005M when combined with 
nivolumab/NP/Gem. 
Secondary: 
1. 
To determine objective response (OR) and duration ofresponse (DOR) 
of each treatment cohort. 
Exploratory: 
1. 
To assess the pharmacokinetics (PK) of APX005M in Cycles 1 to 4. 
2. 
To assess immune pharmacodynamic effects of each treatment cohort, 
in both blood and tumor tissue. 
Phase 2: 
Primary: 
1. 
To estimate overall survival (OS) of each treatment arm. 
2. 
To compare 1-year OS rate of each treatment arm to the historical rate 
for NP/Gem. 
Secondary: 
1. 
To determine the objective response rate (ORR), disease control rate 
(DCR), DOR, and progression-free survival (PFS) of each treatment 
arm. 
2. 
To further characterize the feasibility and safety of each treatment arm. 
Exploratory: 
1. 
To assess the PK of APX005M in Cycles 1 to 4 (Arms B and C). 
2. 
To assess immune pharmacodynamic effects of each treatment arm, in 
both blood and tumor tissue. 
3. 
To assess associations between immune biomarkers and clinical 
outcomes. 
4. 
To evaluate baseline and on-treatment microbiome profiles. 
5. 
To construct multivariable linear models to dissect the 
pharmacodynamic effects of APX005M and nivolumab on immune 
biomarkers. 
24 
24


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Study Design: 
1bis is a multicenter, open-label, Phase lb/2 study to evaluate the 
immunotherapy agents APX005M and nivolumab, in combination with Gem and 
NP in patients with previously untreated metastatic pancreatic adenocarcinoma. 
Phase lb 
In the Phase lb portion of the study, the following 4 treatment cohorts will be 
evaluated for feasibility and safety: 
Bl: NP/Gem/APX005M 0.1 mg/kg 
B2: NP/Gem/APX005M 0.3 mg/kg 
Cl: Nivolumab/NP/Gem/APX005M 0.1 mg/kg 
C2: Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
Enrollment in Cohorts B2 and Cl may occur concurrently. Enrollment in 
Cohort C2 may begin once enrollment in Cohort C 1 has been completed. 
Each cohort in the Phase 1 b portion of the study will include approximately 
6 DLT-evaluable patients. A cohort corresponding to Arm A of Phase 2 
(nivolumab/NP/Gem) will not be tested, since an external study is being 
conducted to confirm the safety ofnivolumab in combination with NP/Gem. 
DL T is defined as any Grade 3 or higher toxicity that is treatment-related but not 
related to the natural progression of the tumor and occurs during the DL T 
observation period. 
Phase 2 (Randomized) 
Patients will be randomized to one of three arms: Arm Al, Arm B2, or Arm C2 
(shown below). 
Treatment arms: 
Al: Nivolumab/NP/Gem 
B2: NP/Gem/APX005M 0.3 mg/kg 
C2: Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
A total of approximately 93 patients will be randomized/enrolled in Phase 2 (35 
Arm Al, 29 Arm B2, 29 Arm C2). Twelve DLT-evaluable patients from the 
Phase 1 b study, enrolled at the RP2D of APX005M in Arm C (i.e., 6 patients on 
B2 and 6 patients on C2) will be included in the Phase 2 analysis. Thus, each 
arm will enroll 35 patients, for a total of approximately 105 patients. In the first 
step of randomization, 12 patients will be randomized in a 4: 1: 1 allocation to 
achieve balance in the total number of patients in each arm (since Arm Al did 
not enroll patients in Phase lb, more patients have to be allocated to Arm Al). 
Once the 12 patients are randomized, step 2 will randomize the remaining 
81 patients in a 1 : 1 : 1 allocation. 
25 
25


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Selection of Patients: 
Main Inclusion Criteria: 
1. 
Patient has histologically or cytologically documented diagnosis of 
pancreatic adenocarcinoma with metastatic disease. Locally advanced 
patients are not eligible. 
2. 
Patient must have measurable disease by Response Evaluation Criteria in 
Solid Tumors (RECIST) vl.l. 
3. 
Patients must be age 18 years or older. 
4. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of O or 1. 
5. 
A baseline tumor tissue sample is mandatory for enrollment. If archival 
tumor tissue is not available, then a fresh tumor biopsy must be provided. 
6. 
Patients must have the following laboratory values at Screening, without 
transfusions or growth factors, within 2 weeks of the first dose of 
investigational agents: 
a. 
Absolute neutrophil count (ANC) 2'.1.5 x 109/L (in absence of 
growth factor support) 
b. 
Platelet count 2'.150 x 109/L 
c. 
Hemoglobin 2'.9 g/dL(without transfusion support) 
d. 
Serum creatinine :Sl.5 mg/dL, and creatinine clearance ;?: 50 
ml/min as measured by Cockcroft and Gault formula 
e. 
Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) :s2.5 x institution's ULN for patients 
with no concurrent liver metastases, OR :S5.0 x institution's 
ULN for patients with concurrent liver metastases 
f. 
Total bilirubin :Sl.5 x ULN, except in patients with 
documented Gilbert's Syndrome who must have a total 
bilirubin :S3 x ULN 
7. 
Women of childbearing potential (WOCBP) must have a negative 
pregnancy test (serum or urine) within the 7 days prior to study drug 
administration, and a negative urine pregnancy test within the 3 days 
before the first study drug administration, or a negative serum pregnancy 
test within 24 hours before the first study drug administration. 
8. 
WOCBP and male patients who are sexually active with WOCBP must 
agree before receiving the first dose of study drugs to use 2 highly 
effective methods of contraception (including a physical barrier) during 
the study and for 5 months for women and 7 months for men following the 
last dose of study drug, as described in the body of the protocol. 
9. 
Patients must have the ability to understand and willingness to sign a 
written informed consent document. 
Main Exclusion Criteria: 
1. 
Patient must not have received any prior treatment, including 
chemotherapy, for metastatic pancreatic adenocarcinoma, with the 
following exceptions and notes: 
a. 
Patients who have received prior adjuvant or neoadjuvant 
therapy for pancreatic adenocarcinoma are eligible if the last 
dose of adjuvant therapy was more than 4 months before the 
date of study entry. In this case, prior Gem and/or NP are 
allowable. 
b. 
Prior resection surgery is allowable. 
c. 
Patients initially diagnosed with locally advanced pancreatic 
cancer who have undergone chemotherapy then resection and 
were with no evidence of disease are eligible if metastatic 
relapse of disease has occurred and if the last dose of 
chemotherapy was more than 4 months before the date of study 
entrv. 
26 
26


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
2. 
Patients must not have another active invasive malignancy, with the 
following exceptions and notes: 
a. 
History of a non-invasive malignancy, such as cervical cancer 
in situ, non-melanomatous carcinoma of the skin, in situ 
melanoma, or ductal carcinoma in situ of the breast, is allowed. 
b. 
History of malignancy that is in complete remission after 
treatment with curative intent is allowed. 
c. 
No current or history of a hematologic malignancy is allowed, 
including patients who have undergone a bone marrow 
transplant. 
3. 
History of clinically significant sensitivity or allergy to monoclonal 
antibodies, their excipients or intravenous gamma globulin 
4. 
Previous exposure to CD40, PD-1, PD-Ll, CTLA-4 antibodies or any 
other immunomodulatory agent 
5. 
History of (non-infectious) pneumonitis that required corticosteroids or 
current pneumonitis, or history of interstitial lung disease 
6. 
Patients must not have a known or suspected history of an autoimmune 
disorder, including but not limited to inflammatory bowel disease, celiac 
disease, Wegner syndrome, Hashimoto syndrome, systemic lupus 
erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis, within 
3 years of the first dose of investigational agent, except for the following: 
a. 
Patients with Type 1 diabetes mellitus, hypothyroidism only 
requiring hormone replacement, skin disorders such as vitiligo, 
or alopecia not requiring systemic therapy, or conditions not 
expected to recur in the absence of an external trigger are 
eligible. 
b. 
Patients with a history of Hashimoto syndrome within 3 years 
of the first dose of investigational agent, which resolved to 
hypothyroidism alone. 
7. 
Patients must not have an uncontrolled intercurrent illness, including an 
ongoing or active infection, current pneumonitis, symptomatic congestive 
heart failure (New York Heart Association class III or IV), unstable 
angina, uncontrolled hypertension, cardiac arrhythmia, interstitial lung 
disease, active coagulopathy, or uncontrolled diabetes. 
8. 
Patients must not have a history of myocardial infarction within 6 months 
or a history of arterial thromboembolic event within 3 months of the first 
dose of investigational agent. 
9. 
Patients must not have a history of human immunodeficiency virus, 
hepatitis B (HB), or hepatitis C, except for the following: 
a. 
Patients with anti-RB core antibody but with undetectable HB 
virus deoxyribonucleic acid (DNA) and negative for HB 
surface antigen 
b. 
Patients with resolved or treated hepatitis C virus (HCV) (i.e. 
HCV antibody positive but undetectable HCV RNA) 
10. Patients must not have a history of primary immunodeficiency. 
11. Patients must not receive concurrent or prior use of an immunosuppressive 
agent within 14 days of the first dose of investigational agent, with the 
following exceptions and notes: 
a. 
Systemic steroids at physiologic doses ( equivalent to dose of 
10 mg oral prednisone) are permitted. Steroids as anti-emetics 
for chemotherapy are not allowed. 
b. 
Intranasal, inhaled, topical, 
intra-articular, and ocular 
corticosteroids with minimal systemic absorption are 
permitted. 
27 
27


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
c. 
Patients with a condition with anticipated use of systemic 
steroids above the equivalent of 10 mg prednisone are 
excluded. 
d. 
Transient courses of steroids may be approved by the Medical 
Monitor on a case by case basis, dependent on dose and reason. 
12. Patients must not have a history of clinically manifested central nervous 
system (CNS) metastases. 
a. 
Patients with known or suspected leptomeningeal disease or 
cord compression are not eligible. 
13. Patients must not have had major surgery as determined by the PI within 
4 weeks before the first dose of study drug. 
14. Patients must not have received another investigational agent within the 
shorter of 4 weeks or 5 half-lives before the first dose of investigational 
agent. 
15. Patients must not have received a live attenuated vaccine within 28 days 
before the first dose of investigational agent, and patients, if enrolled, 
should not receive live vaccines during the study or for 180 days after the 
last dose of investigational agent. 
16. Females who are pregnant or lactating or who intend to become pregnant 
during participation in the study are not eligible to participate. 
17. Patients who have any clinically significant psychiatric, social, or medical 
condition that, in the opinion of the investigator, could increase the 
patient's risk, interfere with protocol adherence, or affect the patient's 
ability to give informed consent are ineligible to participate in the study. 
Planned Sample Size: 
Up to 24 DLT-evaluable patients will be enrolled in the Phase lb portion of the 
study. A total of approximately 93 patients will be randomized/enrolled in 
Phase 2. Thus, the total sample size is expected to be approximately 117 
patients. 
Investigational Therapy: 
Phase lb: 
APX005M (0.1 or 0.3 mg/kg) in combination with NP (125 mg/m2) and Gem 
(1000 mg/m2), all administrated intravenously (IV) 
OR 
APX005M (0.1 or 0.3 mg/kg) in combination with nivolumab (240 mg), NP 
(125 mg/m2) and Gem (1000 mg/m2), all administered IV 
Phase 2: 
Nivolumab (240 mg) in combination with NP (125 mg/m2) and Gem 
(1000 mg/m2), all administered IV 
OR 
APX005M (0.3 mg/kg) in combination with NP (125 mg/m2) and Gem 
(1000 mg/m2), all administrated IV 
OR 
APX005M (0.3 mg/kg) in combination with nivolumab (240 mg), NP 
(125 mg/m2) and Gem (1000 mg/m2), all administered IV 
28 
28


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Treatment Duration: 
Study Endpoints: 
Assuming all 4 cohorts are tested, upon completion of enrollment to Phase 1 b, 1 
additional month of follow-up will occur before declaring the RP2D of 
APX005M. Then the Phase 2 portion of the study will have 12 additional 
months of follow-up. Target enrollment completion is within 24 months; 
however, enrollment will proceed until met or as determined by the study 
sponsor (Parker Institute for Cancer lmmunotherapy [PICI]). Considering 
several months for data management and statistical analysis, the total duration 
of the study is likely to be 5 years. 
Patients will undergo screening and, if eligible, will undergo treatment in the 
assigned arm of the study until unacceptable toxicity, progression of disease, or 
withdrawal of consent. All patients will be followed for survival status until 
death or a maximum of 5 years. 
Phase lb: 
Primary: 
• 
The frequency ofDLT 
• 
The RP2D of APX005M when combined with NP/Gem or 
nivolumab/NP/Gem 
• 
The incidence of treatment-emergent AEs (TEAEs), serious adverse 
events (SAEs), and adverse events (AEs) causing discontinuation 
Secondary: 
• 
OR is determined by RECIST vl.1 
• 
DOR is defined as the time from first documentation of response 
(complete response 
[CR] or partial response 
[PR]) to 
first 
documentation of progressive disease (PD) 
Exploratory: 
• 
PK of APX005M will be determined in Cycles 1 to 4. 
• 
Immune pharmacodynamic endpoints may include, but are not limited 
to, the following: 
o Changes in the tumor microenvironment (including cellularity, 
stromal content, cellular infiltration, and tumor apoptosis) may be 
assessed by tumor multiplex immunohistochemistry or other 
appropriate teclmology. Pharmacodynamic and PK parameters, if 
available, may be used to influence the RP2D. 
o Gene expression may be determined by tumor RNA sequencing, 
peripheral blood RNA sequencing, or other appropriate technology. 
Other sequencing technologies, such as ATAC sequencing, may be 
performed. 
o Tumor genomics may be determined when possible by Clinical 
Laboratory Improvement Amendment-certified mutational panel 
assessments and/or by whole exome sequencing. 
o For variant calling and human leukocyte antigen (HLA) 
determination, normal tissue whole exome sequencing may be 
performed. In some cases, data regarding germ-line BRCAl/2 
mutations or microsatellite instability may be incorporated into 
analyses. 
o Cytokine and/or circulating factor analysis may be determined by a 
multiplex assay or other appropriate technology. 
o Flow cytometry or other related technologies, such as CyTof analysis 
of peripheral blood, may be used to assess phenotype, function, and 
other changes in immune cellular subsets. 
o Other markers to measure tumor burden, including circulating tumor 
DNA, tumor cells, and protein markers, may be measured in an 
exploratory fashion if material is available 
29 
29


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Statistical Methods and 
Planned Analyses: 
Phase 2: 
Primary: 
• 
OS is defined as the time from initiation of study therapy to date of death 
due to any cause or date of most recent patient contact. Patients who 
have not died are censored on their most recent contact date. 
• 
1-year OS rate in each treatment arm. 
Secondary: 
• 
Investigators' assessment of OR is determined by RECIST vl.1 and the 
ORR is defined as the proportion of patients who achieve a CR or PR. 
• 
DCR is defined as the proportion of patients who achieve a CR or PR or 
SD. 
• 
DOR is defined as the time from first documentation of response (CR 
or PR) to first documentation of PD. 
• 
PFS is defined as the time from initiation of study therapy to date of first 
documented progression of disease, date of death due to any cause or 
date of most recent patient contact which documented progression-free 
status (i.e., clinic visit date or scan date). Patients who have not 
progressed or died are censored on their most recent progression-free 
date. 
• 
The incidence of AEs defined as unacceptable toxicities in Phase 2, 
TEAEs, SAEs, and AEs causing treatment discontinuation 
• 
Clinical laboratory data and vital signs ( descriptive statistics) and 
numbers of patients with values outside limits of the normal range at 
each time point. 
Exploratory: 
The exploratory endpoints for Phase 2 are the same as those described 
above for Phase 1 b with the addition of evaluation of baseline and on-
treatment microbiome profiles with treatment outcomes. 
This is a multi-center, open-label Phase lb/2 study ofCD40 agonistic 
monoclonal antibody, APX005M, and/or PD-1 blocking antibody, nivolumab, 
in combination with NP and Gem and for patients with newly diagnosed 
metastatic pancreatic cancer. The primary objectives of the Phase lb study are 
to determine the feasibility, safety and DLT of each treatment cohort and to 
determine the RP2D of APX005M in combination with NP/Gem and with 
nivolumab/NP/Gem. The primary objective of the randomized Phase 2 study is 
to evaluate OS in three treatment arms: nivolumab/NP/Gem, 
NP/Gem/ APX005M and nivolumab/NP/Gem/ APX005M by comparing the 
1-year OS rate with the historical value for NP/Gem. 
The safety population consists of all patients who received at least 1 dose of any 
study drug. This is the population for the primary analyses of safety. 
The DLT-evaluable population consists of patients who received 2 or 3 doses 
of NP/Gem and 1 dose of APX005M during Cycle 1, thus have completed the 
DL T observation period (ie, from the time of first administration of study drugs 
until prior to Cycle 2 Day 1 ). Patients who do not meet these criteria will be 
replaced in Phase lb only, to assist with DLT and RP2D decision-making. 
The 
efficacy 
population 
consists 
of (1) 
all 
patients 
who 
were 
randomized/enrolled in Phase 2 and received at least 1 dose of any study drug 
and (2) the 12 DLT-evaluable patients (6 on Arm B and 6 on Arm C) who were 
enrolled in Phase lb at the RP2D. The efficacy population is the population for 
the primary analyses of efficacy. 
Phase lb Design: Four treatment cohorts will be evaluated for feasibility and 
safety. Cohorts Bl and B2 will escalate the dose of APX005M when combined 
with NP/Gem and then Cohorts Cl and C2 will escalate the dose of APX005M 
30 
30


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
when combined with nivolumab/NP/Gem. Enrollment in Cohorts B2 and Cl 
may occur concurrently. Enrollment in Cohort C2 may begin once enrollment in 
Cohort Cl has been completed. Approximately 6 DLT-evaluable patients will be 
enrolled in each cohort. Al (nivolumab/NP/Gem) will not be tested in Phase lb, 
since an external study is being conducted to confirm the safety of nivolumab in 
combination with NP/Gem. 
Statistical analyses will include the following: 
• 
The number of patients treated in each cohort will be reported, and 
reasons why any patient is not DLT evaluable will be summarized. 
• 
Approximately 6 DLT-evaluable patients will be fully analyzed in each 
treatment cohort. 
• 
Feasibility issues will be described for each treatment cohort. 
• 
Toxicities will be graded by NCI-CTCAE, causality attributed, and 
tabulated by treatment cohort. 
• 
RP2D of APX005M when combined with NP/Gem and with 
nivolumab/NP/Gem will be determined. 
• 
RECIST OR will be scored and tabulated along with DOR, by treatment 
cohort. 
• 
PK of APX005M. 
• 
Immune pharmacodynamic effects will be measured, including change 
from baseline, and reported by treatment cohort. 
Phase 2 Design: Once the RP2D of APX005M has been defined, the randomized 
Phase 2 portion of the study will commence. Patients will be randomized to one 
of 3 arms, defined by the addition of one or more immunotherapy agents to 
standard of care NP/Gem. The arms will be either Al vs B2 vs C2 or Al vs Bl 
vs Cl. Note that the APX005M dose must be the same in Arms B and C, 
regardless of whether a higher APX005M dose was determined to be safe in Arm 
B. For each regimen, efficacy will be evaluated by comparing the 1-year overall 
survival (OS) rate to the historical value for NP/Gem. 
Statistical analyses will include the following: 
• 
Thirty-five patients will be analyzed on each treatment arm. Twelve 
DL T-evaluable patients from Phase 1 b (Arms B and C) and 93 patients 
from Phase 2 will comprise the population for the final analysis of 
efficacy. 
• 
OS will be estimated by the Kaplan-Meier method for each treatment 
arm. 
• 
The 1-year OS rate and 1-sided 95% confidence interval (CI) will be 
calculated for each treatment arm, to determine whether the lower bound 
of the CI excludes the historical value for NP/Gem. A 1-sided one-
sample Z test will also be conducted. The goal is to compare the survival 
probability at 1-year to the historical value of0.35. 
• 
ORR and DCR and their 95% Cis will be calculated for each treatment 
arm. 
• 
PFS will be estimated by the Kaplan-Meier method for each treatment 
arm. 
• 
DOR will be calculated from dates of first documented response and 
progression of disease. 
• 
Toxicities will be graded by CTCAE v4.03 and tabulated by treatment 
arm. 
• 
PK of APX005M in Cycles 1 to 4 (Arms B and C). 
• 
Immune pharmacodynamic effects may be measured, including but not 
limited to change from baseline, and reported by treatment arm. 
• 
Test of associations between immune biomarkers and clinical outcomes 
31 
31


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
• 
Construct multivariable linear models to dissect the pharmacodynamic 
effects of APX005M and nivolumab on immune biomarkers. 
32 
32


PARKER INSTITUTE 
for CA N C ER I MMUNOT H ER A PY 
Statistical Analysis Plan for 
Protocol Number: PICI0002 
Protocol Title: Open-label, Multicenter, Phase lb/2 Clinical Study to 
Evaluate the Safety and Efficacy of CD40 Agonistic Monoclonal Antibody 
(APX00SM) Administered Together with Gemcitabine and nab-Paclitaxel 
with or without PD-1 Blocking Antibody (Nivolumab) in Patients with 
Previously Untreated Metastatic Pancreatic Adenocarcinoma 
IND Number: 
Name of Products: 
Phase of Development: 
Indication: 
Sponsor: 
Date Final: 
132683 
APX005M ( experimental) 
Nivolumab ( experimental) 
Gemcitabine ( standard of care) 
nab-Paclitaxel (standard of care) 
lb/2 
Previously untreated metastatic pancreatic cancer 
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
26 Sep 2019 
-CONFIDENTIAL-
This document and its contents are the property of and confidential to Parker Institute for 
Cancer Immunotherapy. Any unauthorized copying or use of this document is prohibited. 
1 
33


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for PICI0002 Protocol 
SPONSOR APPROVAL PAGE 
Christopher Cabanski, PhD 
Director, Biostatistics 
Ramy Ibrahim, MD 
Chief Medical Officer 
2 
PICI0002 
9/26/2019 I 8:45 : 34 AM PDT 
Date: 
9/29/2019 I 5:52 :00 PM PDT 
Date: 
34


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for PICI0002 Protocol 
1 
TABLE OF CONTENTS 
PICI0002 
1 
TABLE OF CONTENTS ................................................................................................ 3 
2 
INTRODUCTION ........................................................................................................... 5 
3 
STUDY DESIGN ............................................................................................................ 5 
3 .1 
Protocol Synopsis ................................................................................................. 7 
3.2 
Study Objectives ................................................................................................... 7 
3.2.1 
Phase lb ................................................................................................. 7 
3.2.2 
Phase 2 ................................................................................................... 7 
3.3 
Study Endpoints .................................................................................................... 8 
3.4 
Determination of Sample Size .............................................................................. 8 
3.4.1 
Phase lb ................................................................................................. 8 
3.4.2 
Phase 2 ................................................................................................... 9 
3.5 
Analysis Timing .................................................................................................... 9 
4 
STUDY CONDUCT ........................................................................................................ 9 
4.1 
Randomization Details .......................................................................................... 9 
4.2 
Blinding .............................................................................................................. 11 
4.3 
Data Monitoring .................................................................................................. 11 
4.3.1 
Early Termination Rules for Unacceptable Toxicity in Phase 2 .......... 11 
5 
STATISTICAL METHODS .......................................................................................... 12 
5.1 
Analysis Populations ........................................................................................... 12 
5.1.1 
Safety Population ................................................................................. 12 
5.1.2 
DLT-evaluable Population ................................................................... 12 
5.1.3 
Efficacy Population .............................................................................. 13 
5.2 
Analysis of Study Conduct ................................................................................. 13 
5.3 
Analysis of Treatment Group Comparability ..................................................... 13 
5.4 
Efficacy Analysis ................................................................................................ 14 
5.4.1 
Comparisons ofinterest ....................................................................... 14 
5.4.2 
Type I Error Management. ................................................................... 14 
5.4.3 
Covariate Adjustment .......................................................................... 14 
5.4.4 
Primary Efficacy Endpoint .................................................................. 14 
5.4.5 
Secondary Efficacy Endpoints ............................................................. 15 
5.4.5.1 
Objective Response Rate ...................................................... 15 
3 
35


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for PICI0002 Protocol 
PICI0002 
5.4.5.2 Duration ofResponse ............................................................ 15 
5.4.5.3 
Disease Control Rate ............................................................. 16 
5.4.5.4 Progression-free Survival ...................................................... 16 
5.4.6 
Exploratory Efficacy Endpoints ........................................................... 16 
5.4.7 
Subgroup Analyses .............................................................................. 16 
5.4.8 
Sensitivity Analyses ............................................................................. 17 
5.5 
Safety Analysis ................................................................................................... 17 
5.5.1 
Exposure to Study Medication ............................................................. 17 
5.5.2 
Adverse Events .................................................................................... 18 
5.5.3 
Laboratory Data ................................................................................... 18 
5.5.4 
Vital Signs ............................................................................................ 19 
5.6 
Missing Data ....................................................................................................... 19 
5.6.1 
Missing and Partial Missing Adverse Event Dates .............................. 19 
5.6.2 
Missing and Partial Missing Death Dates ............................................ 19 
5.7 
Interim Analyses ................................................................................................. 20 
6 
DIFFERENCES COMPARED TO PROTOCOL ......................................................... 21 
7 
REFERENCES .............................................................................................................. 22 
8 
APPENDICES ............................................................................................................... 23 
8.1 
Protocol Synopsis ............................................................................................... 23 
LIST OF TABLES 
Table 1 
Probability of Failing to Accept a Dose Level at Different Event Rates .................. 8 
Table 2 
Phase 1 b Treatment Assignment.. ........................................................................... I 0 
Table 3 
Phase 2 Design ........................................................................................................ 10 
Table 4 
Bayesian Termination Rules ................................................................................... 11 
LIST OF FIGURES 
Figure 1 Study Flow Chart ...................................................................................................... 5 
4 
36


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
2 
INTRODUCTION 
PICI0002 
The purpose of this document is to provide details of the planned analyses for Protocol 
PICI0002. The analyses specified in this document supersede the high-level analysis plan 
described in the protocol. Statistical analyses will be performed consistent with the principles 
of the ICH/FDA Guidance for Industry E9 Statistical Principles for Clinical Trials. 
3 
STUDY DESIGN 
PICI0002 is a multi-center, open label, Phase 1 b/2 study of the immunotherapy agents 
APX005M and nivolumab, in combination with Gemcitabine (Gem) and nab-Paclitaxel (NP) 
in patients with previously untreated metastatic pancreatic adenocarcinoma. 
Phase 1 b will involve 4 sequential treatment cohorts, and Phase 2 will involve randomization 
to 3 treatment arms, as shown in Figure 1. 
Figure 1 
Study Flow Chart 
Phase lb 
Phase2 
Cohort Bl: 
CohortB2: 
Cohort Cl: 
CohortC2: 
ArmAl: 
-
NP 
NP 
Nivolumab 
Nivolumab 
Nivolumab 
Gem 
Gem 
NP 
NP 
NP 
APX005M 
APX005M 
Gem 
Gem 
Gem 
0.1 mg/kg 
0.3 mg/kg 
APX005M 
APX005M 
-
-
0.1 mg/kg -
0.3 mg/kg 
35 patients 
6 patients 
6 patients 
6 patients 
6 patients 
ArmB2: 
or Arm Bl: 
NP 
NP 
-
Gem 
Gem 
APX005M 
APX005M 
0.3 mg/kg 
0.1 mg/kg 
29 patients 
29 patients 
ArmC2: 
or Arm Cl: 
Nivolumab 
Nivolumab 
-
NP 
NP 
Gem 
Gem 
APX005M 
APX005M 
0.3 mg/kg 
0.1 mg/kg 
29 patients 
29 patients 
Phase lb 
In the Phase 1 b portion of the study, 4 treatment cohorts will be evaluated sequentially for 
feasibility and safety. Each cohort of the study will have 6 DL T-evaluable patients, defined as 
patients who experienced a Dose-Limiting Toxicity (DLT) or who completed the DLT 
observation period, i.e. received at least 2 doses of NP/Gem and 1 dose of APX005M during 
5 
37


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Cycle 1. Patients who do not experience a DL T and who do not complete the DL T observation 
period will be replaced. 
In general, a DL T is defined as: (1) any Grade 3 or higher non-hematologic or Grade 4 
hematologic toxicity occurring during the DL T observation period that is considered to be at 
least possibly related to APX005M and/or nivolumab, or (2) an exacerbation of known 
NP/Gem toxicity that is at least possibly related to APX005M and/or nivolumab. A more 
comprehensive definition of a DL T can be found in the protocol. The DL T observation period 
is defined as the time of first administration of investigational agents until Cycle 2 Day 1. 
Dose escalation will proceed if 1 or fewer DL T-evaluable patients experience a DL T during 
this observation period. Dose escalation will cease if 2 or more DL T-evaluable patients in a 
cohort experience a DLT. 
On the basis of discussions among the site Pis, Sponsor, and other stakeholders, concerning 
feasibility, safety, clinical and immune pharmacodynamic (PD) effects (totality of available 
data), the recommended Phase 2 dose is defined by the highest APX00M dose with <2 DLT 
in 6 DL T-evaluable patients, unless the totality of available data suggests a lower APX005M 
dose. 
Randomized Phase 2 
Once the recommended Phase 2 dose (RP2D) of APX005M in combination with nivolumab 
from Cohort C in the Phase 1 b portion of the study is determined, the randomized Phase 2 
portion will commence. Patients will be randomized to Arm Al, Arm B2, or Arm C2, or to 
Arm Al, Arm Bl, or Arm Cl, if Cohort B2 and/or C2 are deemed unsafe in Phase lb. Note 
that the APX005M dose must be the same in Arms B and C, regardless of whether a higher 
APX005M dose was determined to be safe in Arm B. For each regimen, efficacy will be 
evaluated by comparing the I-year overall survival (OS) rate to the historical value for 
NP/Gem. A total of approximately 93 patients will be randomized in Phase 2 (35 Arm Al, 29 
Arm B2, 29 Arm C2). 
All patients will be followed up for survival status until death or a maximum of 5 years. Once 
a patient is in follow-up, follow up can be obtained with a clinic visit or a phone call 
approximately every 6 months. 
It is common for randomized Phase 2 studies that test the addition of an experimental agent to 
a standard of care regimen to include the standard of care arm. However, the setting for this 
study is unique. NP/Gem, the standard of care regimen, was reported recently in a very similar 
patient population, and the I-year OS rate was estimated with extremely high precision (i.e., 
I-year OS rate was 35% with 95% CI 30%-39%) based on 431 treated patients (Von Hoff et 
al.). With hundreds of pancreatic patients treated with NP/Gem since that report, experts in this 
6 
38


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
field agree that the 1-year OS rate estimate appears to be very robust. Thus, this study will not 
include a standard of care arm. 
The 12 DLT-evaluable patients who were enrolled in Phase 1 b at the recommended Phase 2 
doses (6 on Arm B and 6 on Arm C) will be included in the efficacy evaluation and 93 
additional patients will be randomized in Phase 2, for a total sample size of 105 patients (35 
per treatment arm). 
3.1 
Protocol Synopsis 
The Protocol Synopsis is provided in Section 8.1. 
3.2 
Study Objectives 
This study will be conducted in two phases, each with its own objectives. 
3.2.1 
Phase lb 
Primary Objectives: 
1. To determine the feasibility, safety, and DLTs of each treatment cohort. 
2. To determine the recommended Phase 2 dose of APX005M when combined with 
NP/Gem. 
3. To determine the recommended Phase 2 dose of APX005M when combined with 
nivolumab/NP/Gem. 
Secondary Objectives: 
1. To determine objective response rate (ORR) and duration of responses (DOR) of each 
treatment cohort. 
Exploratory Objectives: 
1. To assess the pharmacokinetics (PK) of APX005M in Cycles 1 to 4. 
2. To assess immune pharmacodynamic effects of each treatment cohort, in both blood 
and tumor tissue. 
3 .2.2 Phase 2 
Primary Objectives: 
1. To estimate the OS of each treatment arm. 
2. To compare 1-year OS rate of each treatment arm to the historical rate for NP/Gem. 
7 
39


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
Secondary Objectives: 
PICI0002 
1. To determine the ORR, disease control rate (DCR), DOR, and progression-free survival 
(PFS) of each treatment arm. 
2. To further characterize the feasibility and safety of each treatment arm. 
Exploratory Objectives: 
1. To assess the PK of APX005M in Cycles 1 to 4 (Arms B and C). 
2. To assess immune pharmacodynamic effects of each treatment arm, in both blood and 
tumor tissue. 
3. To assess associations between immune biomarkers and clinical outcomes. 
4. To evaluate baseline and on-treatment microbiome profiles. 
5. To construct multivariable linear models to dissect the pharmacodynamic effects of 
APX005M and nivolumab on immune biomarkers. 
3.3 
Study Endpoints 
The study endpoints are listed in the Protocol Synopsis (Section 8.1 ). 
3.4 
Determination of Sample Size 
3.4.1 
Phase lb 
Assuming 4 treatment cohorts will be evaluated sequentially for feasibility, safety, and 
dose-limiting toxicities, 24 DLT-evaluable patients will be enrolled (6 per cohort). Patients 
who do not experience a DL T and who do not complete the DL T observation period will be 
replaced. 
The Phase 1 b sample size was determined by practical considerations and was not based on 
statistical power calculations. Six patients dosed in each group was deemed sufficient to 
characterize the feasibility, safety, and DLTs of each cohort. Based on this sample size, Table 
1 provides the probability of failing to accept a cohort as safe, defined as 2:: 2 DLTs in 6 treated 
patients, assuming different DL T rates. 
Table 1 
Probability of Failing to Accept a Dose Level at Different Event Rates 
DLT Event Rate 
Probability a 
DLT = dose-limiting toxicity 
1% 
0.001 
10% 
0.11 
20% 
0.34 
25% 
0.47 
33% 
0.64 
50% 
0.89 
a Assumes P (X 
2) where X is a binomial random variable with sample size n = 6 and p = DLT event rate. 
8 
40


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
3.4.2 Phase 2 
PICI0002 
The 12 DLT-evaluable patients who were enrolled in Phase 1 b at the recommended Phase 2 
doses (6 on Arm B and 6 on Arm C) will be included in the efficacy evaluation and 
approximately 93 additional patients will be randomized in Phase 2, for a total sample size of 
105 patients (35 per treatment arm). This is a screening study, such that for each treatment arm, 
the I-year OS rate will be estimated and compared with a historical value of35% for NP/Gem 
(Von Hoff et al.). The study is not powered to detect a meaningful difference in OS among the 
3 arms, since these are novel experimental arms and OS is unknown. 
The null hypothesis is a I-year OS rate of 35% and the alternative hypothesis is a I-year OS 
rate of 58%. The I-year OS rate is estimated by the Kaplan-Meier method. A sample size of 
35 patients on each arm provides 88% power to test this hypothesis, using a I-sided one-sample 
Z test with 5% type I error rate, assuming a minimum of 1 year of follow-up for each patient. 
Moreover, the sample size of 3 5 patients on each arm, provides 81 % power to statistically test 
the null hypothesis versus a slightly more conservative alternative hypothesis that the I-year 
OS rate is 55%, given the same design assumptions. 
These calculations assume that 105 patients (35 patients x 3 arms) will be enrolled. There is 
no assumption about the duration of patient enrollment, only that there will be a minimum of 
1 year of follow-up for each patient. 
3.5 
Analysis Timing 
The database lock for analysis of the Phase 2 primary endpoint of I-year overall survival (OS) 
rate will occur approximately one year after the last patient is randomized. No changes to the 
SAP will be allowed at the time of or subsequent to database lock. 
Analysis of the Phase 1 b endpoints may be performed prior to the time of primary analysis. 
These results may be presented and/or published prior to the primary analysis. 
The study will formally end once all patients have been followed for survival status until death 
or a maximum of 5 years, withdrawal of consent, or loss to follow-up. A survival analysis of 
long-term follow-up may be performed after the primary analysis has been completed. 
4 
STUDY CONDUCT 
4.1 
Randomization Details 
In Phase 1 b, patients will be enrolled sequentially into 4 cohorts (B 1, B2, C 1, and C2) as 
summarized in Table 2. The Phase 1 b portion of the study is non-randomized. Enrollment in 
Cohorts B2 and C 1 may occur concurrently. 
9 
41


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
Table 2 
Phase lb Treatment Assignment 
Arm 
Regimen 
Bl 
NP/Gem/APX005M 0.1 mg/kg 
B2 
NP/Gem/APX005M 0.3 mg/kg 
Cl 
Nivolumab/NP/Gem/APX005M 0.1 mg/kg 
C2 
Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
PICI0002 
Number of DLT-Evaluable 
Patients 
6 
6 
6 
6 
DLT = dose-limiting toxicity; Gem= gemcitabine; NP = nab-paclitaxel 
Once the RP2D of APX005M in combination with nivolumab from Cohort C in the Phase 1 b 
portion of the study is determined, the randomized Phase 2 portion will commence. Patients 
will be randomized to Arm Al, Arm B2, or Arm C2, or to Arm Al, Arm Bl, or Arm Cl, if 
Cohort B2 and/or C2 are deemed unsafe in Phase lb. Note that the APX005M dose must be 
the same in Arms B and C, regardless of whether a higher APX005M dose was determined to 
be safe in Arm B. 
A total of 105 patients will be evaluated in the Phase 2 portion of the study, including 12 DL T-
evaluable patients from Phase 1 b (i.e., 6 patients on B 1 and 6 patients on C 1 or 6 patients on 
B2 and 6 patients on C2). The remaining 93 patients will be randomized and treated only in 
Phase 2. In step 1 of randomization, 12 of the 93 new patients will be randomized to the 3 arms 
in a 4:1:1 ratio in Arms Al, B2, and C2 (or Al, Bl, and Cl), to achieve balance in the total 
number of patients emolled on the arms (since Arm Al does not accrue in Phase 1 b, more 
patients need to be emolled in Arm Al). In step 2 of randomization, 81 patients will be 
randomized to Arms Al, B2, and C2 (or Al, Bl, and Cl) in a 1:1:1 allocation. The 
randomization design is outlined in Table 3. 
Table 3 
Phase 2 Design 
Arm 
Reeimen 
Al 
Nivolumab/NP/Gem 
B2a 
NP/Gem/APX005M 0.3 mwk.J;!; 
c2a 
Nivolumab/NP/Gem/ APX005M 
0.3 mwk.J;!; 
a Or Bl and Cl, if either B2 or C2 is not tolerable. 
Gem = gemcitabine; NP = nab-paclitaxel 
Phase lb 
Number 
of patients 
0 
6 
6 
10 
Phase2 
Total 
Step 1 
Step 2 
Number 
Number of 
Number 
of patients 
patients 
of patients 
8 
27 
35 
2 
27 
35 
2 
27 
35 
42


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Randomization will be managed by the Parker Institute for Cancer Immunotherapy (PICI), 
using an interactive voice response system (IVRS). The randomization is not stratified by 
baseline patient or tumor characteristics. 
4.2 
Blinding 
This is an open-label study with no blinding. 
4.3 
Data Monitoring 
The study will be closely monitored, and data will be reviewed on an ongoing basis. In order 
to ensure the safety and well-being of participating patients, as well as the validity of data 
during the study, a Data Review Team (DRT) will review the safety and further emerging data 
on a regular basis. The DRT consists of members from the Sponsor, the overall Principal 
Investigator (Pl), the lead statistician, and all active Pis. The DRT will adjudicate DLTs 
relevant for the treatment and will decide by consensus on dose escalation, dose de-escalation, 
prolongation of the DL T observation period, suspension of enrollment based on safety, PK, or 
possibly pharmacodynamic data, and will recommend the dose level for the Phase 2 portion. 
4.3.1 
Early Termination Rules for Unacceptable Toxicity in Phase 2 
A Bayesian rule will be employed to monitor toxicity during Phase 2. A minimally informative 
beta (0.5, 2.5) prior has been assumed, which is information that is equivalent to½ the weight 
of 1 DL T in 6 patients treated, the definition of a safe dose in Phase 1 b. For each treatment 
arm, if the number of patients with an unacceptable toxicity ( defined the Section 6.1 of the 
study protocol) is greater than or equal to the number in Table 4, then termination of that 
particular treatment arm will be considered, as it is likely that the toxicity rate is >30%, as 
noted by the Bayesian posterior probabilities. This rule is intentionally conservative early in 
the enrollment phase. 
Table 4 
Bayesian Termination Rules 
Rules for Unacceptable Toxicity Rate >30% 
Patients treated on an arm 
10 
4 
0.61 
15 
6 
0.69 
20 
9 
0.87 
25 
11 
0.88 
30 
13 
0.90 
Patients with unacceptable toxicity 
Posterior Probability [toxicity rate >30%] 
Action 
Consider termination of arm, re-evaluate study design. 
11 
43


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
5 
STATISTICAL METHODS 
PICI0002 
Summary statistics will be presented by treatment arm. For continuous variables, data will be 
summarized with the number of patients (N), mean, standard deviation, median, minimum, and 
maximum by treatment arm. For categorical variables, data will be tabulated with the number 
and proportion of patients for each category by treatment arm. 
5.1 
Analysis Populations 
5 .1.1 
Safety Population 
The safety population consists of all patients who received at least 1 dose of any study drug. 
This is the population for the analyses of safety. A subset of the safety population is the DL T-
evaluable population. 
For the safety analyses, patients will be analyzed according to the treatment regimen actually 
received. Using a conservative approach: 
• 
Phase 1 b patients who receive at least one dose of nivolumab but do not receive 
APX005M will be analyzed under Arm Cl. Phase 2 patients who receive at least one 
dose of nivolumab but do not receive APX005M will be analyzed under Arm Al. 
• 
Phase 1 b patients who receive at least one dose of APX005M but do not receive 
nivolumab will be analyzed under Arm B 1 or B2, depending on the highest dose level 
of APX005M received. Phase 2 patients who receive at least one dose of APX005M 
but do not receive nivolumab will be analyzed under Arm B2 (the dose level selected 
for Phase 2 emollment). 
• 
Phase 1 b patients who receive at least one dose of both APX005M and nivolumab will 
be analyzed under Arm C 1 or C2, depending on the highest dose level of APX005M 
received. Phase 2 patients who receive at least one dose of both APX005M and 
nivolumab will be analyzed under Arm C2 (the dose level selected for Phase 2 
emollment). 
• 
Patients who receive at least one dose of NP/Gem but do not receive APX005M or 
nivolumab will be analyzed under the treatment arm assigned at emollment (Phase 1 b) 
or randomization (Phase 2). 
5.1.2 DLT-evaluable Population 
The DLT-evaluable population consists of patients who (1) were emolled in Phase lb, (2) 
received at least 2 doses of NP/Gem and 1 dose of APX005M during Cycle 1, and (3) 
completed the DL T observation period (i.e. from the time of first administration of study 
12 
44


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
intervention until Cycle 2 Day 1). Alternatively, patients who did not complete the DLT 
observation period due to a DL T event will also be considered DL T evaluable. 
The DL T-evaluable population is the population for analyses of Phase 1 b efficacy and DL Ts. 
Patients will be grouped according to the treatment arm assigned at emollment, regardless of 
the treatment actually received. 
5 .1.3 
Efficacy Population 
The efficacy population consists of (1) all patients who were randomized in Phase 2 and 
received at least 1 dose of any study drug and (2) the 12 DL T-evaluable patients ( 6 on Arm B 
and 6 on Arm C) who were emolled in Phase 1 b at the recommended Phase 2 dose. The 
efficacy population is the population for the primary analyses of efficacy in Phase 2. Patients 
will be grouped according to the treatment arm assigned at emollment/randomization, 
regardless of the treatment actually received. 
5.2 
Analysis of Study Conduct 
The number of patients emolled in Phase 1 b and randomized in Phase 2 will be tabulated by 
treatment arm. Patient disposition ( e.g. the number of patients emolled/randomized, receiving 
at least one dose of study drug) and time on study will be tabulated by treatment arm and may 
be represented graphically (e.g. swim lane plot). Reasons for premature discontinuation from 
study treatment and reasons for premature discontinuation from the study, including the 5-year 
follow-up period, will be summarized. 
Feasibility, defined by the number of Phase 1 b patients who complete the DLT observation 
period and receive the intended therapy without delays or dose modification, will be described 
for each treatment arm. 
5.3 
Analysis of Treatment Group Comparability 
Demographic and baseline characteristics, including but not limited to age, sex, race, ethnicity, 
Eastern Cooperative Oncology Group (ECOG) performance status at baseline, cancer location 
(pancreas body, head, or tail) and cancer stage at initial diagnosis and emollment will be 
summarized by treatment arm using descriptive statistics for all emolled/randomized patients. 
The baseline value of any variable will be defined as the last available value recorded prior to 
the first administration of study drug. 
Previous and concomitant cancer therapy will also be summarized, including radiotherapy and 
surgery, as well as subsequent anti-cancer therapy. Previous and concurrent diseases and 
medications will be listed. 
13 
45


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
5.4 
Efficacy Analysis 
PICI0002 
Phase 2 efficacy analyses will be conducted on the efficacy population (see Section 5.1.3), 
with patients grouped according to the treatment assigned at randomization. Phase 1 b efficacy 
analyses will be conducted on the DL T-evaluable population. 
Efficacy summaries will include data from patients who discontinued study drug early but 
continued with study assessments and may include data collected at unscheduled visits, early 
termination visits, or follow-up visits. 
5.4.1 
Comparisons of Interest 
The 1-year OS rate and I-sided 95% confidence interval will be calculated for each treatment 
arm, to determine whether the lower bound of the confidence interval (Cl) excludes the 
assumed historical value for NP/Gem of 35%. 
This study is not powered for statistical comparisons between arms. 
5.4.2 Type I Error Management 
Due to the exploratory nature of this study, no control of type I error will be applied for any of 
the endpoints. 
5.4.3 
Covariate Adjustment 
Unless otherwise noted, analyses of primary and secondary efficacy endpoints will not be 
adjusted for additional covariates. 
5.4.4 Primary Efficacy Endpoint 
There is no primary efficacy endpoint for Phase 1 b. The Phase 2 primary efficacy endpoint is 
the 1-year OS rate in each treatment arm. OS is defined as the time from initiation of study 
therapy to date of death due to any cause. Patients who are not reported as having died at the 
time of analysis will be censored at their most recent contact date they were known to be alive. 
Patients who do not have post-baseline survival information will be censored at the date of 
randomization. See Section 5.6.2 for handling of missing or partial death dates. 
OS will be estimated by the Kaplan-Meier method for each treatment arm. For each treatment 
arm, the following parameters and analyses will be provided: Kaplan-Meier product-limit 
estimates of the OS distribution functions, the total number of patients, the total censored, the 
total deaths, the OS time (median and its 95% CI; 25th and 75th percentiles), and the survival 
rates at monthly intervals (i.e. 3, 6, 9, 12, etc. months). 
The 1-year OS rate and I-sided 95% confidence interval will be calculated for each treatment 
arm, to determine whether the lower bound of the confidence interval (CI) excludes the 
assumed historical value for NP/Gem of 35%. 
14 
46


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
A 1-sided one-sample Z test will also be conducted. The goal is to compare the survival 
probability at time t to the historical value. The null hypothesis is Ho: S(t) ,:'.S s* at time t. The 
alternative hypothesis is H1: S(t) > s*, a one-sided test. 
The Z test is: 
S(t)- s* 
SE(S(t)) 
where S(t) and SE are sample estimates. For this study, t = l year, S(t) = estimated 1-year OS 
probability from the Kaplan-Meier analysis, SE ( S (t)) = standard error of S (t) and null 
hypothesis s* = 0.35. 
A survival follow-up analysis may be performed based on more mature data. 
5.4.5 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints for Phase 1 b include ORR and DOR. The Phase 1 b efficacy 
endpoints will be analyzed for the DL T-evaluable population. 
Secondary efficacy endpoints for Phase 2 include ORR, DCR, DOR, and PFS. The Phase 2 
efficacy endpoints will be analyzed for the efficacy population. 
5.4.5.1 Objective Response Rate 
ORR, on the basis of investigator assessment, is defined as the proportion of patients who attain 
a complete response (CR) or partial response (PR). Per RECIST vl.1, confirmation of 
objective response is not required for this secondary endpoint. Patients without a post-baseline 
tumor assessment will be considered non-responders, as well as patients with a best overall 
response of stable disease (SD), progressive disease (PD) or not evaluable (NE). 
A 95% confidence interval for the rate will be estimated for each treatment arm using the 
Clopper-Pearson method. 
Spider plots and waterfall plots will be generated to visualize changes in the sum of target 
lesions. 
5.4.5.2 Duration of Response 
For patients who have experienced an objective response (CR or PR) during the study as 
assessed by the investigator, DOR is defined as the time from the first tumor assessment that 
documents response (CR or PR, whichever is recorded first) to first documentation of 
radiographic PD per RECIST v 1.1. Patients who have not progressed at the time of analysis 
will be censored at the last tumor assessment date prior to the start of subsequent systemic anti-
15 
47


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
cancer therapy. The Kaplan-Meier method will be used to estimate the median DOR for each 
treatment arm with 95% confidence limits. 
5.4.5.3 Disease Control Rate 
DCR is defined as the proportion of patients who achieve a best response of CR, PR, or SD. 
For a patient to have a best overall response of SD, he/she must have at least one post-tumor 
assessment of SD at least 7 weeks after treatment initiation (8 week minus 7 day window; study 
day 49). Patients without a post-baseline tumor assessment will be considered non-responders, 
as well as patients with a best overall response of PD or NE. A 95% confidence interval for 
the rate will be estimated for each treatment arm using the Clopper-Pearson method. 
DCR will also be estimated at 6 and 12 months. For these landmark analyses, DCR is defined 
as the proportion of patients who have a response of CR, PR, or SD at the first tumor 
assessment on or after the landmark time. Accounting for the Q8W (i.e. every 8 weeks) 
schedule and 7-day window for disease assessment, 6-month DCR will consider the first 
evaluable scan after study day 161 (24 weeks - 7 days) and 12-month DCR will consider the 
first evaluable scan after study day 329 (48 weeks - 7 days). Patients without an evaluable 
disease assessment after the landmark time will be considered non-responders. 
5.4.5.4 Progression-free Survival 
PFS is defined as the time from initiation of study therapy to date of first documented 
radiographic progression of disease or date of death due to any cause, whichever occurs first. 
PFS will be determined on the basis of investigator assessment of progression using RECIST 
vl .1. Patients who have not progressed or died at the time of analysis will be censored at the 
last tumor assessment date prior to the start of subsequent systemic anti-cancer therapy. 
Patients with no post-baseline tumor assessment will be censored at the date of study therapy 
initiation. The Kaplan-Meier method will be used to estimate the median PFS for each 
treatment arm with 95% confidence limits. 
PFS will also be estimated at various landmark times (e.g. 6 and 12 months). 
5.4.6 Exploratory Efficacy Endpoints 
Exploratory endpoints defined in the protocol and listed in Section 8.1 are outside the scope of 
this SAP. Biomarker analyses will be detailed in a Translational Analysis Plan. 
5.4.7 
Subgroup Analyses 
For each treatment arm, OS will be analyzed in the subset of patients in the efficacy population 
who remain on treatment for at least 3 cycles (i.e. receive at least one dose of any study drug 
in Cycle 4) vs. those who remain on treatment for 3 cycles or less. This subset is in contrast to 
16 
48


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
the efficacy population analyzed in the primary analysis. The 1-year OS rate and 1-sided 95% 
confidence interval will be calculated. 
5.4.8 
Sensitivity Analyses 
The following sensitivity analyses will be performed: 
• 
Efficacy analyses will be performed on the Phase 2 Efficacy Population, defined as all 
patients who were randomized in Phase 2 and received at least 1 dose of any study drug. 
This population similar to the Efficacy Population but excludes the 12 DL T-evaluable 
patients who were emolled in Phase 1 b at the recommended Phase 2 dose. 
• If the number of patients dosed in Phase 1 b does not match the DL T-evaluable 
population, ORR and DOR will be calculated for all patients who received at least one 
dose of study drug in Phase 1 b (i.e. the safety population). 
• If any Phase 2 patients were randomized but not dosed, Phase 2 primary and secondary 
efficacy endpoints may be analyzed using an intention-to-treat (ITT) approach. For 
these analyses, all randomized patients will be included, grouped according to the 
treatment assigned at randomization. 
• 
The impact of response confirmation on ORR will be assessed by requmng 
confirmation of CR or PR at least 4 weeks after initial documentation. 
• 
The effect of death on DOR will be assessed by defining DOR as the time from the first 
tumor assessment that documents response ( CR or PR, whichever is recorded first) to 
first documentation of radiographic progressive disease or death, whichever occurs first. 
Patients who have not progressed or died at the time of analysis will be censored at the 
last tumor assessment date prior to the start of subsequent systemic anti-cancer therapy. 
5.5 
Safety Analysis 
Safety will be assessed through the summary of adverse events (AEs), serious adverse events 
(SAEs), DLTs, laboratory test results (hematology and serum chemistry), vital signs, and 
physical examinations. This may include data collected at unscheduled visits, early termination 
visits, or follow-up visits. 
The baseline value of any variable will be defined as the last available value recorded prior to 
the first administration of study medication. If multiple values are available at the same visit, 
the mean of the values will be used for analysis at that timepoint. 
Safety outcomes will be summarized based on the safety population (see Section 5.1.1 ). Safety 
summaries will be presented by the treatment regimen actually received. 
5.5.1 
Exposure to Study Medication 
17 
49


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
The number of patients exposed to each study drug and the extent of exposure ( as number of 
doses, cumulative dose received, and relative dose received) will be summarized using 
descriptive statistics. Relative dose received is defined as the total amount of each drug actually 
received divided by the amount of drug the patient would have been expected to receive had 
he/she received all planned doses without any dose modifications until the date of treatment 
discontinuation. 
5.5.2 
Adverse Events 
All reported AEs will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and graded using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03. 
A treatment-emergent adverse event (TEAEs) is defined as any new adverse event or any 
worsening of an existing condition with an onset date on or after the first dose of study drug. 
AEs with relationship to study drug of "Possibly", "Probably", "Definitely" or unknown 
(missing) will be considered treatment related. 
For each patient and each AE, the worst severity/grade recorded will be attributed and used in 
the severity summaries. If severity is missing, the event will be considered grade 3. 
Listings for all AEs, SAEs, and TEAEs will be presented by patient. Listings will include 
information regarding onset day/date, end day/date, duration, relationship to study drug, 
severity, action taken with study drug, whether concomitant medication was administered and 
outcome. 
Summaries of TEAEs (overall, by system organ class and preferred term and by severity) by 
treatment arm will be provided for each of the following categories: 
• 
AEs 
• 
AEs by most extreme severity 
• 
Treatment-related AEs 
• 
SAEs 
• 
Treatment-related SAEs 
• 
AEs leading to discontinuation of study treatment 
• 
DLTs 
• 
AEs from patients enrolled in Phase II that meet the protocol-defined unacceptable 
toxicity criteria 
The proportion of events that are resolved at the time of analysis will be presented. In addition, 
patient deaths and the primary cause of death will be listed, as well as any cases of pregnancy. 
5.5.3 
Laboratory Data 
18 
50


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Descriptive summaries of clinical laboratory values at each timepoint, including changes from 
baseline, will be generated for hematology and chemistry parameters by treatment arm. The 
proportion of patients with values outside the normal upper and lower limit at each visit will 
be displayed. 
In addition, select laboratory parameters (including, but not limited to, AST, ALT, alkaline 
phosphatase and total bilirubin) will be summarized by grade using the CTCAE grading scale. 
Missing laboratory values will not be imputed. Analysis will only occur on observed values. 
5.5.4 Vital Signs 
Vital signs will be summarized by treatment arm using descriptive statistics including mean 
values and mean change from baseline. 
Missing vital signs will not be imputed. Analysis will only occur on observed values. 
5.6 
Missing Data 
5.6.1 
Missing and Partial Missing Adverse Event Dates 
If the AE start date is not a complete date, the following rules will be applied to determine 
whether the event is treatment-emergent. 
• If the start date is completely missing: The AE will be assumed to be treatment-
emergent unless the AE stop date is earlier than the date of first dose of study drug. 
• If the day part of the AE start date is missing: If the month and year of the start date are 
later than or equal to the month and year of the date of first dose of study drug, then the 
AE will be assumed to be treatment-emergent. If the month and year of the stop date 
are earlier than the month and year of the date of first dose of study drug, then the event 
will be assumed to be non-treatment-emergent. 
• If the day and month of the start date are missing: If the year of the start date is later 
than or equal to year of the date of first dose of study drug, then the AE will be assumed 
to be treatment-emergent. If the year of the stop date is earlier than the year of the date 
of first dose of study drug, then the event will be assumed to non-treatment-emergent. 
5.6.2 Missing and Partial Missing Death Dates 
For death dates, the following conventions will be used for imputing partial dates: 
• If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known date alive plus 1 
day, and the maximum will be considered as the death date. 
19 
51


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
• If the month or the year is missing, the death date will be imputed as the last known 
date alive plus 1 day. 
• If the date is completely missing but the reason for death is present, the death date will 
be imputed as the last known date alive plus 1 day. 
5. 7 
Interim Analyses 
Given the hypothesis generating nature of this study, the Sponsor may conduct two interim 
analyses of safety and efficacy during the Phase 1 b and Phase 2 portions of the study. Should 
an interim analysis occur, it will be performed and interpreted by members of the Sponsor 
study team. If warranted, interim safety and efficacy results may be shared with study 
Investigators. This SAP will be amended prior to any interim analyses to provide justification 
and document the scope and statistical details. The clinical study report will also document 
that such an interim analysis occurred. 
The first interim analysis will be conducted approximately 3 months after the last patient is 
randomized in the Phase 2 portion. This interim is strictly meant to support decision making 
for future studies. No adaptations (e.g. sample size re-estimation, early stopping for futility or 
efficacy, dropping/adding arms, modifying dose levels) will be made to the study based on the 
interim results. The analysis will be performed and interpreted by members of the Sponsor 
study team and management. Full results will be shared with management of the 
pharmaceutical partners of this study (Apexigen and Bristol-Myers Squibb), as their input is 
critical for decision making and design of future studies using this treatment regimen. Safety 
and limited efficacy results will be shared with study Investigators because they are key 
contributors to the design of an in-development clinical trial that may use the treatment 
regimens being tested in this study. To limit potential bias, any interim efficacy data shared 
with Investigators while patients are still receiving study therapy will only be presented as 
graphical summaries (spider and/or waterfall plots of BOR) with cohort names/identifiers 
masked. 
The following endpoints will be summarized for the first interim analysis: 
• 
Study conduct including emollment, demographics, and disposition 
• 
Adverse events 
• 
Phase 1 b efficacy endpoints: ORR, DCR, DOR, OS, PFS 
• 
Phase 2 efficacy endpoints: ORR, DCR 
20 
52


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
The Phase 2 primary endpoint of OS will not be analyzed for Phase 2 patients during this 
interim analysis. Due to the exploratory nature of this study, no control of type I error will be 
applied for any of the endpoints at the interim or final analysis. 
6 
DIFFERENCES COMPARED TO PROTOCOL 
• 
Section 3.4 (Determination of Sample Size): The SAP provides additional justification 
for the Phase 1 b sample size. 
• 
Section 5.1.l(Safety Population): The SAP clarifies that for the safety analyses, 
patients will be analyzed according to the treatment actually received. 
• 
Section 5.1.2 (DLT-evaluable Population): The SAP clarifies that the DLT-evaluable 
population is the population for analyses of Phase lb efficacy and DLTs. 
• 
Section 5.4.7 (Subgroup Analyses): The protocol states that OS will be analyzed in the 
subset of patients who remain on study for at least 6 weeks. The SAP modifies this 
subgroup to patients who remain on treatment for at least 3 cycles. 
• 
Section 5.7 (Interim Analyses): The SAP provides justification for and details about 
the first optional interim analysis of efficacy data. 
21 
53


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
7 
REFERENCES 
ICH/FDA Guidance for Industry E9 Statistical Principles for Clinical Trials. U.S. 
Department of Health and Human Services, Food and Drug Administration, 
September 1998. 
PICI0002 
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-
paclitaxel plus gemcitabine. N Engl J Med 2013;369(18):1691-703. 
22 
54


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
8 
APPENDICES 
8.1 
Protocol Synopsis 
Title of Study: 
Protocol Number: 
Phase of Development: 
Objectives: 
Open-label, Multicenter, Phase lb/2 Clinical Study to Evaluate the Safety and 
Efficacy of CD40 Agonistic Monoclonal Antibody (APX005M) Administered 
Together with Gemcitabine and nab-Paclitaxel with or without PD-1 Blocking 
Antibody (Nivolumab) in Patients with Previously Untreated Metastatic 
Pancreatic Adenocarcinoma 
PICI0002 
lb/2 
Phase lb: 
Primary: 
1. 
To determine the feasibility, safety and dose-limiting toxicities (DL T) 
of each treatment cohort. 
2. 
To determine the recommended Phase 2 dose (RP2D) of APX005M 
when combined with nab-paclitaxel (NP)/gemcitabine (Gem). 
3. 
To determine the RP2D of APX005M when combined with 
nivolumab/NP/Gem. 
Secondary: 
1. 
To determine objective response (OR) and duration ofresponse (DOR) 
of each treatment cohort. 
Exploratory: 
1. 
To assess the pharmacokinetics (PK) of APX005M in Cycles 1 to 4. 
2. 
To assess immune pharmacodynamic effects of each treatment cohort, 
in both blood and tumor tissue. 
Phase 2: 
Primary: 
1. 
To estimate overall survival (OS) of each treatment arm. 
2. 
To compare 1-year OS rate of each treatment arm to the historical rate 
for NP/Gem. 
Secondary: 
1. 
To determine the objective response rate (ORR), disease control rate 
(DCR), DOR, and progression-free survival (PFS) of each treatment 
arm. 
2. 
To further characterize the feasibility and safety of each treatment arm. 
Exploratory: 
1. 
To assess the PK of APX005M in Cycles 1 to 4 (Arms B and C). 
2. 
To assess immune pharmacodynamic effects of each treatment arm, in 
both blood and tumor tissue. 
3. 
To assess associations between immune biomarkers and clinical 
outcomes. 
4. 
To evaluate baseline and on-treatment microbiome profiles. 
5. 
To construct multivariable linear models to dissect the 
pharmacodynamic effects of APX005M and nivolumab on immune 
biomarkers. 
23 
55


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Study Design: 
1bis is a multicenter, open-label, Phase lb/2 study to evaluate the 
immunotherapy agents APX005M and nivolumab, in combination with Gem and 
NP in patients with previously untreated metastatic pancreatic adenocarcinoma. 
Phase lb 
In the Phase lb portion of the study, the following 4 treatment cohorts will be 
evaluated for feasibility and safety: 
Bl: NP/Gem/APX005M 0.1 mg/kg 
B2: NP/Gem/APX005M 0.3 mg/kg 
Cl: Nivolumab/NP/Gem/APX005M 0.1 mg/kg 
C2: Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
Enrollment in Cohorts B2 and Cl may occur concurrently. Enrollment in 
Cohort C2 may begin once enrollment in Cohort C 1 has been completed. 
Each cohort in the Phase 1 b portion of the study will include approximately 
6 DLT-evaluable patients. A cohort corresponding to Arm A of Phase 2 
(nivolumab/NP/Gem) will not be tested, since an external study is being 
conducted to confirm the safety ofnivolumab in combination with NP/Gem. 
DL T is defined as any Grade 3 or higher toxicity that is treatment-related but not 
related to the natural progression of the tumor and occurs during the DL T 
observation period. 
Phase 2 (Randomized) 
Patients will be randomized to one of three arms: Arm Al, Arm B2, or Arm C2 
(shown below). 
Treatment arms: 
Al: Nivolumab/NP/Gem 
B2: NP/Gem/APX005M 0.3 mg/kg 
C2: Nivolumab/NP/Gem/APX005M 0.3 mg/kg 
A total of 93 patients will be randomized in Phase 2 (35 Arm Al, 29 Arm B2, 
29 Arm C2). Twelve DLT-evaluable patients from the Phase lb study, enrolled 
at the RP2D of APX005M in Arm C (i.e., 6 patients on B2 and 6 patients on C2) 
will be included in the Phase 2 analysis. Thus, each arm will enroll 35 patients, 
for a total of 105 patients. In the first step of randomization, 12 patients will be 
randomized in a 4: 1 : 1 allocation to achieve balance in the total number of patients 
in each arm (since Arm Al did not enroll patients in Phase 1 b, more patients have 
to be allocated to Arm Al). Once the 12 patients are randomized, step 2 will 
randomize the remaining 81 patients in a 1 : 1 : 1 allocation. 
24 
56


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Selection of Patients: 
Main Inclusion Criteria: 
1. 
Patient has histologically or cytologically documented diagnosis of 
pancreatic adenocarcinoma with metastatic disease. Locally advanced 
patients are not eligible. 
2. 
Patient must have measurable disease by Response Evaluation Criteria in 
Solid Tumors (RECIST) vl.l. 
3. 
Patients must be age 18 years or older. 
4. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of O or 1. 
5. 
A baseline tumor tissue sample is mandatory for enrollment. If archival 
tumor tissue is not available, then a fresh tumor biopsy must be provided. 
6. 
Patients must have the following laboratory values at Screening, without 
transfusions or growth factors, within 2 weeks of the first dose of 
investigational agents: 
a. 
Absolute neutrophil count (ANC) 2'.1.5 x 109/L (in absence of 
growth factor support) 
b. 
Platelet count 2'.150 x 109/L 
c. 
Hemoglobin 2'.9 g/dL(without transfusion support) 
d. 
Serum creatinine :Sl.5 mg/dL, and creatinine clearance ;?: 50 
ml/min as measured by Cockcroft and Gault formula 
e. 
Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) :s2.5 x institution's ULN for patients 
with no concurrent liver metastases, OR :S5.0 x institution's 
ULN for patients with concurrent liver metastases 
f. 
Total bilirubin :Sl.5 x ULN, except in patients with 
documented Gilbert's Syndrome who must have a total 
bilirubin :S3 x ULN 
7. 
Women of childbearing potential (WOCBP) must have a negative 
pregnancy test (serum or urine) within the 7 days prior to study drug 
administration, and a negative urine pregnancy test within the 3 days 
before the first study drug administration, or a negative serum pregnancy 
test within 24 hours before the first study drug administration. 
8. 
WOCBP and male patients who are sexually active with WOCBP must 
agree before receiving the first dose of study drugs to use 2 highly 
effective methods of contraception (including a physical barrier) during 
the study and for 5 months for women and 7 months for men following the 
last dose of study drug, as described in the body of the protocol. 
9. 
Patients must have the ability to understand and willingness to sign a 
written informed consent document. 
Main Exclusion Criteria: 
1. 
Patient must not have received any prior treatment, including 
chemotherapy, for metastatic pancreatic adenocarcinoma, with the 
following exceptions and notes: 
a. 
Patients who have received prior adjuvant or neoadjuvant 
therapy for pancreatic adenocarcinoma are eligible if the last 
dose of adjuvant therapy was more than 4 months before the 
date of study entry. In this case, prior Gem and/or NP are 
allowable. 
b. 
Prior resection surgery is allowable. 
c. 
Patients initially diagnosed with locally advanced pancreatic 
cancer who have undergone chemotherapy then resection and 
were with no evidence of disease are eligible if metastatic 
relapse of disease has occurred and if the last dose of 
chemotherapy was more than 4 months before the date of study 
entrv. 
25 
57


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
2. 
Patients must not have another active invasive malignancy, with the 
following exceptions and notes: 
a. 
History of a non-invasive malignancy, such as cervical cancer 
in situ, non-melanomatous carcinoma of the skin, in situ 
melanoma, or ductal carcinoma in situ of the breast, is allowed. 
b. 
History of malignancy that is in complete remission after 
treatment with curative intent is allowed. 
c. 
No current or history of a hematologic malignancy is allowed, 
including patients who have undergone a bone marrow 
transplant. 
3. 
History of clinically significant sensitivity or allergy to monoclonal 
antibodies, their excipients or intravenous gamma globulin 
4. 
Previous exposure to CD40, PD-1, PD-Ll, CTLA-4 antibodies or any 
other immunomodulatory agent 
5. 
History of (non-infectious) pneumonitis that required corticosteroids or 
current pneumonitis, or history of interstitial lung disease 
6. 
Patients must not have a known or suspected history of an autoimmune 
disorder, including but not limited to inflammatory bowel disease, celiac 
disease, Wegner syndrome, Hashimoto syndrome, systemic lupus 
erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis, within 
3 years of the first dose of investigational agent, except for the following: 
a. 
Patients with Type 1 diabetes mellitus, hypothyroidism only 
requiring hormone replacement, skin disorders such as vitiligo, 
or alopecia not requiring systemic therapy, or conditions not 
expected to recur in the absence of an external trigger are 
eligible. 
b. 
Patients with a history of Hashimoto syndrome within 3 years 
of the first dose of investigational agent, which resolved to 
hypothyroidism alone. 
7. 
Patients must not have an uncontrolled intercurrent illness, including an 
ongoing or active infection, current pneumonitis, symptomatic congestive 
heart failure (New York Heart Association class III or IV), unstable 
angina, uncontrolled hypertension, cardiac arrhythmia, interstitial lung 
disease, active coagulopathy, or uncontrolled diabetes. 
8. 
Patients must not have a history of myocardial infarction within 6 months 
or a history of arterial thromboembolic event within 3 months of the first 
dose of investigational agent. 
9. 
Patients must not have a history of human immunodeficiency virus, 
hepatitis B (HB), or hepatitis C, except for the following: 
a. 
Patients with anti-RB core antibody but with undetectable HB 
virus deoxyribonucleic acid (DNA) and negative for HB 
surface antigen 
b. 
Patients with resolved or treated hepatitis C virus (HCV) (i.e. 
HCV antibody positive but undetectable HCV RNA) 
10. Patients must not have a history of primary immunodeficiency. 
11. Patients must not receive concurrent or prior use of an immunosuppressive 
agent within 14 days of the first dose of investigational agent, with the 
following exceptions and notes: 
a. 
Systemic steroids at physiologic doses ( equivalent to dose of 
10 mg oral prednisone) are permitted. Steroids as anti-emetics 
for chemotherapy are not allowed. 
b. 
Intranasal, inhaled, topical, 
intra-articular, and ocular 
corticosteroids with minimal systemic absorption are 
permitted. 
26 
58


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
c. 
Patients with a condition with anticipated use of systemic 
steroids above the equivalent of 10 mg prednisone are 
excluded. 
d. 
Transient courses of steroids may be approved by the Medical 
Monitor on a case by case basis, dependent on dose and reason. 
12. Patients must not have a history of clinically manifested central nervous 
system (CNS) metastases. 
a. 
Patients with known or suspected leptomeningeal disease or 
cord compression are not eligible. 
13. Patients must not have had major surgery as determined by the PI within 
4 weeks before the first dose of study drug. 
14. Patients must not have received another investigational agent within the 
shorter of 4 weeks or 5 half-lives before the first dose of investigational 
agent. 
15. Patients must not have received a live attenuated vaccine within 28 days 
before the first dose of investigational agent, and patients, if enrolled, 
should not receive live vaccines during the study or for 180 days after the 
last dose of investigational agent. 
16. Females who are pregnant or lactating or who intend to become pregnant 
during participation in the study are not eligible to participate. 
17. Patients who have any clinically significant psychiatric, social, or medical 
condition that, in the opinion of the investigator, could increase the 
patient's risk, interfere with protocol adherence, or affect the patient's 
ability to give informed consent are ineligible to participate in the study. 
Planned Sample Size: 
Up to 24 DLT-evaluable patients will be enrolled in the Phase lb portion of the 
study. A total of93 patients will be randomized in Phase 2. Thus, the total 
sample size is expected to be approximately 117 patients. 
Investigational Therapy: 
Phase lb: 
APX005M (0.1 or 0.3 mg/kg) in combination with NP (125 mg/m2) and Gem 
(1000 mg/m2), all administrated intravenously (IV) 
OR 
APX005M (0.1 or 0.3 mg/kg) in combination with nivolumab (240 mg), NP 
(125 mg/m2) and Gem (1000 mg/m2), all administered IV 
Phase 2: 
Nivolumab (240 mg) in combination with NP (125 mg/m2) and Gem 
(1000 mg/m2), all administered IV 
OR 
APX005M (0.3 mg/kg) in combination with NP (125 mg/m2) and Gem 
(1000 mg/m2), all administrated IV 
OR 
APX005M (0.3 mg/kg) in combination with nivolumab (240 mg), NP 
(125 mg/m2) and Gem (1000 mg/m2), all administered IV 
27 
59


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Treatment Duration: 
Study Endpoints: 
Assuming all 4 cohorts are tested, upon completion of enrollment to Phase 1 b, 1 
additional month of follow-up will occur before declaring the RP2D of 
APX005M. Then the Phase 2 portion of the study will have 12 additional 
months of follow-up. Target enrollment completion is within 24 months; 
however, enrollment will proceed until met or as determined by the study 
sponsor (Parker Institute for Cancer lmmunotherapy [PICI]). Considering 
several months for data management and statistical analysis, the total duration 
of the study is likely to be 3 years. 
Patients will undergo screening and, if eligible, will undergo treatment in the 
assigned arm of the study until unacceptable toxicity, progression of disease, or 
withdrawal of consent. All patients will be followed for survival status until 
death or a maximum of 5 years. 
Phase lb: 
Primary: 
• 
The frequency ofDLT 
• 
The RP2D of APX005M when combined with NP/Gem or 
nivolumab/NP/Gem 
• 
The incidence of treatment-emergent AEs (TEAEs), serious adverse 
events (SAEs), and adverse events (AEs) causing discontinuation 
Secondary: 
• 
OR is determined by RECIST vl.1 
• 
DOR is defined as the time from first documentation of response 
(complete response 
[CR] or partial response 
[PR]) to 
first 
documentation of progressive disease (PD) 
Exploratory: 
• 
PK of APX005M will be determined in Cycles 1 to 4. 
• 
Immune pharmacodynamic endpoints may include, but are not limited 
to, the following: 
o Changes in the tumor microenvironment (including cellularity, 
stromal content, cellular infiltration, and tumor apoptosis) may be 
assessed by tumor multiplex immunohistochemistry or other 
appropriate teclmology. Pharmacodynamic and PK parameters, if 
available, may be used to influence the RP2D. 
o Gene expression may be determined by tumor RNA sequencing, 
peripheral blood RNA sequencing, or other appropriate technology. 
Other sequencing technologies, such as ATAC sequencing, may be 
performed. 
o Tumor genomics may be determined when possible by Clinical 
Laboratory Improvement Amendment-certified mutational panel 
assessments and/or by whole exome sequencing. 
o For variant calling and human leukocyte antigen (HLA) 
determination, normal tissue whole exome sequencing may be 
performed. 
In some cases, data regarding germ-line BRCAl/2 
mutations or microsatellite instability may be incorporated into 
analyses. 
o Cytokine and/ or circulating factor analysis may be determined by a 
multiplex assay or other appropriate technology. 
o Flow cytometry or other related technologies, such as CyTof analysis 
of peripheral blood, may be used to assess phenotype, function, and 
other changes in immune cellular subsets. 
o Other markers to measure tumor burden, including circulating tumor 
DNA, tumor cells, and protein markers, may be measured in an 
exploratory fashion if material is available 
28 
60


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
Phase 2: 
Primary: 
• 
OS is defined as the time from initiation of study therapy to date of death 
due to any cause or date of most recent patient contact. Patients who 
have not died are censored on their most recent contact date. 
• 
1-year OS rate in each treatment arm . 
Secondary: 
• 
Investigators' assessment of OR is determined by RECIST vl.1 and the 
ORR is defined as the proportion of patients who achieve a CR or PR. 
• 
DCR is defined as the proportion of patients who achieve a CR or PR or 
SD. 
• 
DOR is defined as the time from first documentation of response (CR 
or PR) to first documentation of PD. 
• 
PFS is defined as the time from initiation of study therapy to date of first 
documented progression of disease, date of death due to any cause or 
date of most recent patient contact which documented progression-free 
status (i.e., clinic visit date or scan date). Patients who have not 
progressed or died are censored on their most recent progression-free 
date. 
• 
The incidence of AEs defined as unacceptable toxicities in Phase 2, 
TEAEs, SAEs, and AEs causing treatment discontinuation 
• 
Clinical laboratory data and vital signs ( descriptive statistics) and 
numbers of patients with values outside limits of the normal range at 
each time point. 
Exploratory: 
• The exploratory endpoints for Phase 2 are the same as those described 
above for Phase 1 b with the addition of evaluation of baseline and on-
treatment microbiome profiles with treatment outcomes. 
Statistical Methods and 
This is a multi-center, open-label Phase lb/2 study ofCD40 agonistic 
Planned Analyses: 
monoclonal antibody, APX005M, and/or PD-1 blocking antibody, nivolumab, 
in combination with NP and Gem and for patients with newly diagnosed 
metastatic pancreatic cancer. The primary objectives of the Phase lb study are 
to determine the feasibility, safety and DLT of each treatment cohort and to 
determine the RP2D of APX005M in combination with NP/Gem and with 
nivolumab/NP/Gem. The primary objective of the randomized Phase 2 study is 
to evaluate OS in three treatment arms: nivolumab/NP/Gem, 
NP/Gem/ APX005M and nivolumab/NP/Gem/ APX005M by comparing the 
1-year OS rate with the historical value for NP/Gem. 
The safety population consists of all patients who received at least 1 dose of any 
study drug. This is the population for the primary analyses of safety. 
The DLT-evaluable population consists of patients who received 2 or 3 doses 
of NP/Gem and 1 dose of APX005M during Cycle 1, thus have completed the 
DL T observation period (ie, from the time of first administration of study drugs 
until prior to Cycle 2 Day 1) Patients who do not meet these criteria will be 
replaced in Phase lb only, to assist with DLT and RP2D decision-making. 
The efficacy population consists of (1) all patients who were randomized in 
Phase 2 and received at least 1 dose of any study drug and (2) the 12 DLT-
evaluable patients ( 6 on Arm B and 6 on Arm C) who were enrolled in Phase 1 b 
at the RP2D. The efficacy population is the population for the primary analyses 
of efficacy. 
Phase lb Design: Four treatment cohorts will be evaluated for feasibility and 
safety. Cohorts Bl and B2 will escalate the dose of APX005M when combined 
with NP/Gem, and then Cohorts Cl and C2 will escalate the dose of APX005M 
29 
61


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
when combined with nivolumab/NP/Gem. Enrollment in Cohorts B2 and Cl 
may occur concurrently. Enrollment in Cohort C2 may begin once enrollment in 
Cohort Cl has been completed. Approximately 6 DLT-evaluable patients will be 
enrolled in each cohort. A 1 (nivolumab/NP /Gem) will not be tested in Phase 1 b, 
since an external study is being conducted to confirm the safety of nivolumab in 
combination with NP/Gem. 
Statistical analyses will include the following: 
• 
The number of patients treated in each cohort will be reported, and 
reasons why any patient is not DLT evaluable will be summarized. 
• 
Approximately 6 DLT-evaluable patients will be fully analyzed in each 
treatment cohort. 
• 
Feasibility issues will be described for each treatment cohort. 
• 
Toxicities will be graded by NCI-CTCAE, causality attributed, and 
tabulated by treatment cohort. 
• 
RP2Ds of APX005M when combined with NP/Gem and with 
nivolumab/NP/Gem will be determined. 
• 
RECIST OR will be scored and tabulated along with DOR, by treatment 
cohort. 
• 
PK of APX005M. 
• 
Immune pharmacodynamic effects will be measured, including change 
from baseline, and reported by treatment cohort. 
Phase 2 Design: Once the RP2D of APX005M has been defined, the randomized 
Phase 2 portion of the study will commence. Patients will be randomized to one 
of 3 arms, defined by the addition of one or more immunotherapy agents to 
standard of care NP/Gem. The arms will be either Al vs B2 vs C2 or Al vs Bl 
vs Cl. Note that the APX005M dose must be the same in Arms B and C, 
regardless of whether a higher APX005M dose was determined to be safe in Arm 
B. For each regimen, efficacy will be evaluated by comparing the 1-year overall 
survival (OS) rate to the historical value for NP/Gem. 
Statistical analyses will include the following: 
• 
Thirty-five patients will be analyzed on each treatment arm. Twelve 
DLT-evaluable patients from Phase 1 (Arms Band C) and 93 patients 
from Phase 2 will comprise the population for the final analysis of 
efficacy. 
• 
OS will be estimated by the Kaplan-Meier method for each treatment 
arm. 
• 
The 1-year OS rate and 1-sided 95% confidence interval (CI) will be 
calculated for each treatment arm, to determine whether the lower bound 
of the CI excludes the historical value for NP/Gem. A 1-sided one-
sample Z test will also be conducted. The goal is to compare the survival 
probability at 1-year to the historical value of0.35. 
• 
ORR and DCR and their 95% Cis will be calculated for each treatment 
arm. 
• 
PFS will be estimated by the Kaplan-Meier method for each treatment 
arm. 
• 
DOR will be calculated from dates of first documented response and 
progression of disease. 
• 
Toxicities will be graded by CTCAE v4.03 and tabulated by treatment 
arm. 
• 
PK of APX005M in Cycles 1 to 4 (Arms B and C). 
• 
Immune pharmacodynamic effects may be measured, including but not 
limited to change from baseline, and reported by treatment arm. 
• 
Test of associations between immune biomarkers and clinical outcomes 
30 
62


Parker Institute for Cancer Immunotherapy 
Statistical Analysis Plan for Protocol PICI0002 
PICI0002 
• 
Construct multivariable linear models to dissect the pharmacodynamic 
effects of APX005M and nivolumab on immune biomarkers. 
31 
63