Clinical trial NCT03502330
Conditions: Advanced Melanoma Non-small Cell Lung Cancer Renal Cell Carcinoma
Sponsor: Yale University
Start date: 2018-06-09; Completion date: 2024-05-15
Enrollment: 42 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This trial is a phase 1/1b study to evaluate the safety, efficacy, and tolerability of APX005M in combination with nivolumab and cabiralizumab.

The phase 1 dose escalation portion of the study will enroll patients with advanced solid tumors melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) in 6 cohorts to determine the recommended phase II dose (RP2D) of APX005M.

The phase 1b dose expansion portion will study the triple drug combination separately in the three disease cohorts: melanoma, NSCLC, and RCC.

Detailed description:

Arms: arm 1: Cabiralizumab 4mg/kg plus APX005M 0.03 mg/kg administered in 14 day cycles. arm 2: Nivolumab 240 mg plus Cabiralizumab 4mg/kg plus APX005M 0.03 mg/kg administered in 14 day cycles. arm 3: Cabiralizumab 4mg/kg plus APX005M 0.1 mg/kg administered in 14 day cycles. arm 4: Nivolumab 240 mg plus Cabiralizumab 4mg/kg plus APX005M 0.1 mg/kg administered in 14 day cycles. arm 5: Cabiralizumab 4mg/kg plus APX005M 0.3 mg/kg administered in 14 day cycles. arm 6: Nivolumab 240 mg plus Cabiralizumab 4mg/kg plus APX005M 0.3 mg/kg administered in 14 day cycles. arm 7: Patients will be treated at the estimated APX005M RP2D in combination with nivolumab 240 mg IV and cabiralizumab 4 mg/kg on day 1 of each 14-day cycle. arm 8: Patients will be treated at the estimated APX005M RP2D in combination with nivolumab 240 mg IV and cabiralizumab 4 mg/kg on day 1 of each 14-day cycle. arm 9: Patients will be treated at the estimated APX005M RP2D in combination with nivolumab 240 mg IV and cabiralizumab 4 mg/kg on day 1 of each 14-day cycle.
Interventions: intervention 1: APX005M intervention 2: Cabiralizumab intervention 3: Nivolumab
Intervention descriptions: intervention 1: APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion. intervention 2: Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion. intervention 3: Nivolumab is a humanized IgG4 monoclonal antibody directed against programmed cell death 1 (PD-1). Nivolumab is administered by intravenous infusion.

Protocol documents:
Prot_SAP_000.pdf: 
ClinicalTrials.gov ID: NCT03502330 
Title: APX005M With Nivolumab and Cabiralizumab in Advanced Melanoma, Non-small Cell Lung Cancer 
or Renal Cell Carcinoma 
Document Type: Protocol and SAP 
Date: 3/21/2022 


 
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A Phase I/Ib Study of APX005M in Combination with Nivolumab and 
Cabiralizumab in Patients with Advanced Melanoma, Non-small Cell Lung 
Cancer or Renal Cell Carcinoma Whose Disease Has Progressed on Anti-PD- 
1/PD-L1 Therapy 
 
BMS Protocol Number: 
Institutional Protocol Number 
CA025-007 
HIC #2000021757 
Investigational Products: 
APX005M, Cabiralizumab (FPA008), and Nivolumab 
IND Number: 
139038 
Development Phase: 
Phase 1/1b 
Indications Studied: 
Melanoma, NSCLC, RCC 
Protocol Version: 
10 
Date of Protocol: 
21 Mar-2022 
Sponsor: 
Industry Collaborators: 
Yale Cancer Center 
Bristol-Myers Squibb, Apexigen, Inc. 
Principal Investigator: 
Co-Principal Investigators 
Harriet Kluger, MD 
Yale Cancer Center 
harriet.kluger@yale.edu 
203-737-2572 
Scott Gettinger, MD  
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Bristol-Myers Squibb 
and Apexigen. Any unauthorized use or disclosure of such information without the prior written authorization of 
Bristol-Myers Squibb and Apexigen is prohibited. 


 
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Study Synopsis 
 
Title: 
A Phase 1/1b Study of APX005M in Combination with Nivolumab and 
Cabiralizumab in Patients with Advanced Melanoma, Non-small Cell Lung 
Cancer or Renal Cell Carcinoma Whose Disease Has Progressed on Anti-PD- 
1/PD-L1 Therapy 
Protocol Number: 
CA025-007 
Clinical Phase: 
1/1b 
Sponsor: 
Industry 
Collaborators: 
Yale Cancer Center 
Bristol-Myers Squibb, Apexigen, Inc. 
Study Center: 
Yale Cancer Center 
Background: 
Objectives: 
New combinatorial therapeutic strategies are needed to overcome resistance to 
immune checkpoint inhibitors in a number of malignancies.  We hypothesize 
that manipulation of the innate immune system by targeting macrophage 
activity will assist in reversing local immune suppression and overcome 
resistance to PD-1/PD-L1 inhibition. 
Phase 1 Objectives 
Primary 
• To assess the safety and tolerability of APX005M in combination with 
cabiralizumab 
• To assess the safety and tolerability of APX005M in combination with 
cabiralizumab and nivolumab 
• To determine the recommended phase 2 dose (RP2D) of APX005M in 
combination with a fixed dose of cabiralizumab and nivolumab 
Secondary 
• To determine the adverse event (AE) profile of this combination 
Exploratory 
• To characterize the pharmacokinetic (PK) profile of APX005M when 
administered in combination with cabiralizumab and nivolumab 
• To characterize the pharmacodynamic (PD) profile of APX005M when 
administered in combination with cabiralizumab and nivolumab 
• To further characterize the PD profile and immunogenicity of APX005M in 
combination with cabiralizumab and nivolumab by analyses of pre- 
treatment and on-treatment tumor biopsies and blood collection 
Phase 1b Objectives 


 
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Primary 
• Determine the objective response rate (ORR) using RECIST v1.1 to 
APX005M in combination with cabiralizumab and nivolumab in patients 
with advanced melanoma, non-small cell lung cancer (NSCLC), and renal 
cell carcinoma (RCC) whose tumors are resistant to anti-PD-1/PD-L1 
therapy 
• Evaluate the safety and tolerability of the RP2D of APX005M in 
combination with cabiralizumab and nivolumab 
Secondary 
• To determine the progression-free survival (PFS) of patients with 
melanoma, NSCLC or RCC treated with APX005M in combination with 
cabiralizumab and nivolumab whose tumors are resistant to anti-PD-1/PD- 
L1 therapy. 
• To determine the overall survival (OS) of patients with melanoma, NSCLC 
or RCC treated with APX005M in combination with cabiralizumab and 
nivolumab whose tumors are resistant to anti-PD-1/PD-L1 therapy. 
• To assess the association of selected biomarker measures and clinical 
efficacy measures using pre-treatment and on-treatment tumor biopsies 
Exploratory 
• To identify immune correlates that are associated with clinical response or 
resistance to the triple combination.  Biomarker analyses will include study 
of pre-treatment and on-treatment biopsies as well as analyses of select 
serum and PBMC markers. 
Investigational 
Products 
• APX005M Solution for Intravenous Infusion 
• Cabiralizumab Solution for Intravenous Infusion 
• Nivolumab Solution for Intravenous Infusion 
Study Design 
This trial is a phase 1/1b study to evaluate the safety, efficacy, and tolerability 
of APX005M in combination with nivolumab and cabiralizumab.  The phase 1 
dose escalation portion will enroll patients with advanced solid tumors 
(melanoma, NSCLC, and RCC) to determine the RP2D of APX005M. The 
phase 1b dose expansion portion will study the triple drug combination in three 
disease cohorts. APX005M is a humanized IgG1 agonistic monoclonal 
antibody that binds CD40. Nivolumab is a humanized IgG4 monoclonal 
antibody directed against PD-1. Cabiralizumab is a humanized IgG4 
monoclonal antibody directed against CSF1R. 


 
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Phase 1: Dose 
Escalation 
 
Patients with advanced solid tumors will be sequentially enrolled in 6 cohorts 
using a standard 3 + 3 dose escalation design to determine safety, characterize 
the AEs, and establish the RP2D of APX005M in combination with nivolumab 
and cabiralizumab.  A minimum of 48 hours observation will be required after 
each patient is enrolled in cohorts 1-6, before a subsequent patient can be 
enrolled. Approximately 3 patients will be enrolled per cohort. Cohorts 1, 3, 
and 5 will include cabiralizumab at 4 mg/kg and dose escalation of APX005M. 
Cohorts 2, 4, and 6 will include nivolumab at 240 mg, cabiralizumab at 4 
mg/kg, and dose escalation of APX005M. Each cycle will be 14 days with 
anticipated dosing as follows: 
 
Phase 1 Dose Escalation Cohorts 
Cohort 
Nivolumab 
(mg) 
Cabiralizumab 
(mg/kg) 
APX005M 
(mg/kg) 
1 
Not given 
4 
0.03 
2 
240 
4 
0.03 
3 
Not given 
4 
0.1 
4 
240 
4 
0.1 
5 
Not given 
4 
0.3 
6 
240 
4 
0.3 
 
If none of the first 3 evaluable patients in a dose cohort experience a dose- 
limiting toxicity (DLT) in the first two cycles, then the next 3 patients will be 
treated at the next higher dose cohort. If 1 of 3 patients within a cohort 
experiences a DLT in the first two cycles, then 3 additional patients will be 
added to that cohort. If a second patient experiences a DLT at that dose level 
in the first two cycles, the next cohort will not be initiated, and the dose of one 
or more drugs will be de-escalated.  Patients at each dose level will be 
evaluated for at least 4 weeks from the start of treatment before additional 
patients can be treated at a higher dose level.  If DLTs are observed in 2 or 
more patients within a cohort, the maximum tolerated dose (MTD) will have 
been exceeded and no further patients will be treated at that dose level.  At 8 
weeks, imaging studies will be performed to assess for response.  Of note, 2 
sets of cohorts will be conducted simultaneously:  Cohorts 2 and 3, and 
Cohorts 4 and 5, as depicted below. 


 
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Dose escalation will be based on the number of DLTs experienced during the 
DLT evaluation interval as determined by dose escalation meetings attended 
by the PIs and Industry Collaborators (see Section 3.1.2.1.1 for DLT criteria). 
The DLT evaluation interval begins on the first day of treatment and continues 
for 28 days. 
Algorithm for Dose-Escalation Decisions 
 
Number of 
Patients with 
DLT at a Given 
Dose Level 
Dose Escalation Decision Rule 
0/3 
Escalation will occur into the next highest dose 
cohort 
1/3 
Enroll 3 additional patients at current dose level 
>2/3 
Stop enrolment.  Enroll 3 more patients at the lower 
dose level, if only 3 were previously entered, or at 
an intermediate dose level. 
1/6 
Open next cohort 
>2/6 
Stop enrolment.  Enter 3 more patients at the lower 
dose level or at an intermediate dose level. 
 
 
 
Phase 1b Study 
Once a specific dose regimen is determined to be safe as determined by the 
Sponsors and Industry Collaborators, the phase 1b portion will follow and will 
enroll additional patients in three disease-specific cohorts, all of whom who 
have progressed on prior PD-1/PD-L1 therapy: advanced melanoma, NSCLC, 


 
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and RCC who have progressed on prior PD-1/PD-L1 therapy. Patients will be 
treated at the estimated APX005M RP2D in combination with nivolumab 240 
mg IV and cabiralizumab 4 mg/kg on day 1 of each 14-day cycle. 
 
 
Number of Patients 
 In the Phase 1 dose escalation portion, at least 3 patients with advanced solid 
tumors will be enrolled per cohort using a standard 3+3 design. There are a 
total of 6 cohorts.  In the Phase 1b portion, a Simon’s two-stage design will be 
used to study 3 disease cohorts: advanced melanoma, NSCLC, and RCC.  The 
null hypothesis that the true response rate is 10% will be tested against a one- 
sided alternative. In the first stage, 13 patients in each disease cohort will be 
accrued.  If there are 1 or fewer responses in these 13 patients, the enrollement 
in that disease cohort will be stopped.  Otherwise, 21 additional patients will be 
accrued for a total of 34 patients per disease cohort. The null hypothesis     
will be rejected if 6 or more responses are observed in 34 patients. This design 
yield a type I error rate of 0.1 and a power of 80% when the true response rate 
is 25%. 


 
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Study Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria 
 
The phase 1 dose escalation portion will include patients with advanced 
melanoma, NSCLC, and RCC with the same criteria as listed below for the 
phase 1b portion. 
 
The Phase 1b dose expansion portion of the trial studying APX005M at the 
RP2D in combination with cabiralizumab and nivolumab will consist of three 
solid tumor cohorts. All patients in all tumor types are required to have 
progressed while on anti-PD(L)-1 therapy without any intervening therapy. 
Additional descriptions are below: 
 
Melanoma: 
• 
Unresectable stage III or stage IV melanoma, irrespective of BRAF 
status, with histologic or cytologic confirmation 
 
RCC: 
• 
Histologic or cytologically documented, locally advanced unresectable 
or metastatic RCC irrespective of histologic subtype 
 
NSCLC: 
• 
Histologic or cytologically documented, locally advanced or 
metastatic (i.e. Stage IIIB not eligible for definitive 
chemoradiotherapy, stage IV, or recurrent) NSCLC. 
• 
Patients known to harbor an ALK rearrangement or EGFR mutation 
known to be sensitive to FDA-approved tyrosine kinase inhibitors 
(TKI), are only eligible after experiencing disease progression (during 
or after treatment) or intolerance to an FDA approved ALK TKI or 
EGFR TKI, respectively. 
• 
Patients with TKI-treated EGFR mutant NSCLC harboring the 
secondary EGFR T790M tumor must have received prior osimertinib. 
• 
Patients with crizotinib-treated ALK rearranged NSCLC must have 
received a next generation ALK inhibitor. 
 
1. Biopsy proven metastatic melanoma, NSCLC or RCC whose disease has 
progressed on a prior regimen containing a PD-1 or PD-L1 inhibitor, without 
intervening therapy. Progression will be determined by the 
investigator based on clinical and/or radiographic features. 
 
2. At least 1 site of disease must be accessible to provide repeat biopsies 
for tumor tissue. This site may be a target lesion as long as it will not 
be made unmeasurable by the biopsy procedure 
 
3. Age ≥18, able to understand and sign the informed consent form 
 
4. ECOG performance status < 2 
 
5. Any number of previous treatments. Other prior systemic therapies must 
have been administered at least 4 weeks before administration of the study 
drugs; the exception to this is small molecule inhibitors, which must be 


 
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stopped at least 2 weeks or after five half-lives of the drug, whichever is 
shorter, prior to the start of the study drugs. 
 
6. Life expectancy of at least 6 months 
 
7. A history of previously treated brain metastases is allowed, provided that 
they are stable for at least 4 weeks. 
 
8. Willingness to undergo mandatory tumor biopsy prior to initiation of 
therapy and before the fifth cycle. 
 
9. Willingness to provide an archival specimen block, if available, for research. 
 
10. Patients must have normal organ and marrow function (as outlined in 
Section 3.2.2) 
 
11. Female subject of childbearing potential should have a negative urine or 
serum pregnancy within 24 hours prior to receiving the first dose of study 
medication.  If the urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required. 
 
12. Female subjects of childbearing potential should be willing to use a highly 
effective contraception (hormonal or IUD) or be surgically sterile, or abstain 
from heterosexual activity for a period of at least 5 months after the last dose 
of study drug. Subjects of childbearing potential are those who have not 
been surgically sterilized or have not been free from menses for > 1 year. 
 
13. Male subjects should agree to use an adequate method of contraception 
starting with the first dose of study therapy through at least 7 months after 
the last dose of study drug. 
 
14. Patients must have at least one measurable lesion at baseline by computed 
tomography (CT) or magnetic resonance imaging (MRI) as per RECIST 
v1.1 criteria. 
 
a. Tumor sites situated in a previously irradiated area, or in an area 
subjected to other loco-reginal therapy, are not considered 
measurable unless there has been demonstrated progression in the 
lesion. 
15. Prior focal radiotherapy is allowed. Radiation to brain, pulmonary or 
intestinal sites must be completed at least 4 weeks prior to study Day 1. 
There is no time restriction prior to study Day 1 for patients who have 
received 
radiation 
to 
bone, 
soft 
tissue 
or 
other 
sites. 
No 
radiopharmaceuticals (strontium, samarium) within 8 weeks before first 
dose of study drug administration. 
 
16. Major surgery must be completed at least 4 weeks prior to the first dose of 
study drug administration. Surgery requiring local/epidural anesthesia must 


 
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be completed at least 72 hours before first dose of study drug administration 
and patients should have recovered. Wounds must be healed. 


 
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Exclusion Criteria 
1. Untreated brain metastases. 
2. A patient who has had prior immune therapy or chemotherapy, within 4 
weeks prior to study Day 1, or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent will 
be excluded.  The exception is  targeted  therapy  that  must  have  been 
completed at least 2 weeks or after 5 half-lives, which ever is shorter, prior 
to study Day 1. Patients who have had prior ipilimumab must have received 
their last dose no less than 4 weeks prior to study Day 1. 
a. Note: If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the 
intervention prior to starting therapy. 
b. Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it 
meets the inclusion requirements for laboratory parameters. 
 
3. Has had prior treatment with any other CSF1R inhibitor or CD40 agonist 
4. Use of corticosteroids to control immune related adverse events at 
enrollment will not be allowed, and patients who previously required 
corticosteroids for symptom control must be off steroids for at least 2 
weeks.  Low-dose steroid use (≤10 mg of prednisone or equivalent) as 
corticosteroid replacement therapy for primary or secondary adrenal 
insufficiency is allowed. 
5. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
prior treatments with the exception of clinically insignificant adverse events 
such as alopecia, clinically insignificant laboratory abnormalities, clinically 
insignificant rash and Grade 2 neuropathy.  
6. History of grade 3-4 neurologic or cardiac toxicity or life-threatening liver 
toxicity poorly responsive to steroids with prior anti-PD-1/anti-PDL1 
monotherapy. 
7. Presence of leptomeningeal disease. 
8. Has active autoimmune disease unrelated to use of immune checkpoint 
inhibitors that has required systemic treatment in the past year (i.e. with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
9. Pregnancy or breast feeding. Should a woman become pregnant or suspect 
she is pregnant while participating in this study, she should inform her 
treating physician immediately. Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the 
mother with nivolumab, cabiralizumab or APX005M, breastfeeding must 
be discontinued if the mother is enrolled on this trial. 


 
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10. Patients may not be receiving any other investigational agents and may not 
have participated in a study of an investigational agent or using an 
investigational device within 4 weeks of the first dose of treatment. 
 
11. Either a concurrent condition (including medical illness, such as active 
infection requiring treatment with intravenous antibiotics or the presence of 
laboratory abnormalities) or history of a prior condition that places the 
patient at unacceptable risk if he/she were treated with the study drug or a 
medical condition that confounds the ability to interpret data from the study. 
 
12. Concurrent, active malignancies in addition to those being studied. 
 
13. Active (non-infectious) pneumonitis. 
 
14. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), 
or Hepatitis C (HCV) acute or chronic infection. 
 
15. Has received a live vaccine within 30 days prior to the first dose of trial 
treatment. 
 
16. History of myocardial infarction or unstable angina within 3 months prior 
to Cycle 1, Day 1. 
 
17. Prisoners, or subjects who are under compulsory detention 
 
18. Current or history of clinically significant muscle disorders (e.g., myositis), 
recent unresolved muscle injury, or any condition known to elevate serum 
CK levels 
 
19. History of anti-drug antibodies, severe allergic, anaphylactic, or other 
infusion-related reaction to a previous biologic agent 
 
20. Concomitant use of statins while on study. However, a patient using statins 
for over 3 months prior to study drug administration and in stable status 
without CK rise may be permitted to enroll 
 
21. Open wounds and active skin infections 
 
22. Uveal melanoma in the Phase Ib dose expansion trial 


 
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Concomitant 
Medications 
All medications taken within 28 days before the administration of the first dose 
of any study drug and all concomitant therapy administered during the study 
until 100 (±7) days after last dose of any study drug (or use of subsequent anti- 
cancer therapy) will be collected. All subsequent anti-cancer therapy will be 
collected in the Long-Term Follow-up Period. 
Information on all prior treatments indicated for advanced cancer, including 
chemotherapy, biochemotherapy, immunotherapy, radiation, surgery, biologic, 
and experimental therapy will be collected. 
No concomitant medication information will be collected following patient 
discontinuation from the study except for concomitant medication use 
associated with study drug-related AEs or AEs that lead to discontinuation 
from the study. 
Withdrawal 
Criteria 
Patients must discontinue study drugs for any of the following reasons: 
• Withdrawal of informed consent (patient’s decision to withdraw for any 
reason) 
• Any clinically significant AE, abnormal laboratory test results, or 
intercurrent illness which, in the opinion of the Investigator, indicates that 
continued participation in the study is not in the best interest of the patient 
• Patients who are required to have prohibited concomitant medications 
• Pregnancy 
• Termination of the study by the Sponsor 
• Loss of ability to freely provide consent through imprisonment or 
involuntary incarceration for treatment of a psychiatric or physical (e.g., 
infectious disease) illness 
• Documented disease progression or clinical deterioration while receiving 
active study therapy 
• Non-compliance by the patient 


 
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List of Key Study Personnel 
 
 
 
 
Sponsor: 
Industry Collaborators: 
Principal Investigator: 
Co-Principal Investigators: 
Co-Investigators: 
Yale Cancer Center 
Bristol-Myers Squibb, Apexigen, Inc. 
Harriet Kluger, MD 
Scott Gettinger, MD 
Anne Chiang, MD 
Sarah Goldberg, MD 
Roy Herbst, MD, PhD 
Michael Hurwitz, MD, PhD 
Mario Sznol, MD 
Serious Adverse Event Reporting: 
Bristol-Myers Squibb 
Apexigen, Inc. 
FDA 


 
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Table of Contents 
Study Synopsis.................................................................................................................... 2 
List of Key Study Personnel ........................................................................................... 13 
Table of Contents ............................................................................................................. 14 
List of Abbreviations and Definitions ............................................................................ 20 
1. Introduction and Study Rationale ......................................................................... 26 
1.1 
Introduction ............................................................................................................. 26 
1.2 
Rationale for Combination of APX005M with nivolumab and cabiralizumab..26 
1.3 
Target Receptor Background ................................................................................. 30 
1.3.1 
Tumor-Associated Macrophages and Colony Stimulating Factor 1 Receptor 
.......................................................................................................................30 
1.3.2 
Programmed Cell Death-1 (PD-1; CD279)...................................................31 
1.3.3 
CD40 ............................................................................................................ 33 
1.3.4 
Product Development Background .............................................................. 33 
1.3.4.1 
Mechanism of Action ............................................................................ 33 
1.3.4.1.1 
Cabiralizumab ............................................................................... 33 
1.3.4.1.2 
Nivolumab ..................................................................................... 34 
1.3.4.1.3 
APX005M ..................................................................................... 35 
1.3.5 
Preclinical Summary .................................................................................... 36 
1.3.5.1 
Cabiralizumab ....................................................................................... 36 
1.3.5.2 
Nivolumab ............................................................................................. 37 
1.3.5.3 
APX005M ............................................................................................. 38 
1.3.6 
Clinical Summary ........................................................................................ 39 
1.3.6.1 
Cabiralizumab ....................................................................................... 39 
1.3.6.1.1 
Clinical Study Summary of Cabiralizumab ................................... 39 
1.3.6.1.2 
Clinical Pharmacology Summary (Pharmacokinetics, 
Immunogenicity, and Pharmacodynamics) of Cabiralizumab ....... 39 
1.3.6.1.3 
Clinical Safety Summary of Cabiralizumab .................................. 39 
1.3.6.2 
Nivolumab ............................................................................................. 41 
1.3.6.2.1 
Clinical Pharmacology Summary of Nivolumab ........................... 41 
1.3.6.2.2 
Safety Summary of Nivolumab ..................................................... 41 
1.3.6.3 
APX005M ............................................................................................. 43 


 
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1.3.6.3.1 
Clinical Pharmacology Summary of APX005M ........................... 43 
1.3.6.3.2 
Pharmacokinetics of APX005M .................................................... 43 
1.3.6.3.3 
Safety Summary of APX005M ..................................................... 44 
1.4 
Clinical Experience Involving Serum Enzyme Elevations ................................... 45 
1.4.1 
Serum Enzyme Elevations with Cabiralizumab ........................................... 45 
1.4.2 
Serum Enzyme Elevations with Nivolumab ................................................. 46 
1.4.3 
Serum Enzyme Elevations in APX005M ..................................................... 46 
2. 
Objectives................................................................................................................. 47 
2.1 
Phase 1a Objectives ................................................................................................. 47 
2.1.1 
Primary ......................................................................................................... 47 
2.1.2 
Secondary ..................................................................................................... 47 
2.1.3 
Exploratory .................................................................................................. 47 
2.2 
Phase 1b Objectives ................................................................................................. 47 
2.2.1 
Primary ......................................................................................................... 47 
2.2.2 
Secondary ..................................................................................................... 47 
2.2.3 
Exploratory .................................................................................................. 48 
3. 
Investigational Plan ................................................................................................ 49 
3.1 
Study Design and Duration ..................................................................................... 49 
3.1.1 
Screening Period .......................................................................................... 50 
3.1.2 
Treatment Period .......................................................................................... 50 
3.1.2.1 
Phase 1 Cohorts and Combination Dose Escalation Cohorts ................. 50 
3.1.2.1.1 
Dose Limiting Toxicity ................................................................. 53 
3.1.2.2 
Phase 1 Dose Escalation Extended Treatment Period ........................... 54 
3.1.2.3 
Phase 1b Expansion Cohorts ................................................................. 54 
3.1.3 
End-of-Treatment Follow-up Period ............................................................ 55 
3.1.4 
Long-Term Follow-up .................................................................................. 55 
3.1.5 
Study Duration ............................................................................................. 55 
3.1.6 
Stopping Rules ............................................................................................. 55 
3.1.6.1 
Stopping Rules for All Cohorts ............................................................. 55 
3.1.6.2 
Treatment Beyond Progression ............................................................. 56 


 
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3.2 
Study Population ...................................................................................................... 56 
3.2.1 
Planned Number of Patients ......................................................................... 56 
3.2.2 
Inclusion Criteria for All Cohorts ................................................................ 56 
3.2.3 
Exclusion Criteria for All Cohorts ............................................................... 58 
3.2.4 
Women of Childbearing Potential ................................................................ 60 
3.3 
Concomitant Medications ....................................................................................... 61 
3.3.1 
Prohibited and/or Restricted Treatments ...................................................... 61 
3.3.2 
Permitted Therapy ........................................................................................ 61 
3.4 
Long-Term Follow-up ............................................................................................. 62 
4. 
Study Drugs ............................................................................................................. 63 
4.1 
Investigational Products .......................................................................................... 63 
4.2 
Handling and Dispensing ........................................................................................ 63 
4.2.1 
Cabiralizumab .............................................................................................. 64 
4.2.2 
Nivolumab .................................................................................................... 64 
4.2.3 
APX005M .................................................................................................... 65 
4.3 
Method of Assigning Patient Identification ........................................................... 65 
4.4 
Study Drug Dosing and Dose Modification ........................................................... 66 
4.4.1 
Dosing .......................................................................................................... 66 
4.4.1.1 
Nivolumab Dosing ................................................................................ 67 
4.4.1.2 
Cabiralizumab Dosing ........................................................................... 67 
4.4.1.3 
APX005M Dosing ................................................................................. 68 
4.5 
Blinding/Unblinding ................................................................................................ 69 
4.6 
Dose Modifications, Delays or Discontinuation ..................................................... 69 
4.7 
Criteria to Resume Treatment with APX005M, Cabiralizumab and Nivolumab 
....................................................................................................................................69 
4.8 
Management of Adverse Events and Supportive Care Guidelines...................... 70 
4.9 
Criteria for Holding, Discontinuing, or Modifying Study Drug .......................... 74 
4.10 Dose Reduction ........................................................................................................ 78 
4.11 Treatment Discontinuation Criteria ...................................................................... 79 


 
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4.12 Infusion Delays and Missed Doses with Nivolumab, Cabiralizumab and 
APX005M ................................................................................................................. 80 
4.13 Treatment Beyond Progression .............................................................................. 80 
4.14 Treatment Compliance ............................................................................................ 81 
4.15 Destruction of Study Drug ...................................................................................... 82 
4.16 Return of Study Drug .............................................................................................. 82 
5. 
Study Assessments and Procedures ...................................................................... 83 
5.1 
Schedule of Assessments.......................................................................................... 83 
5.2 
Study Procedures by Visit ....................................................................................... 83 
5.2.1 
Phase 1 Dose Escalation ............................................................................... 83 
5.2.1.1 
Screening Period (Day –28 to Day 0) .................................................... 83 
5.2.1.2 
Cycle 1, Day 1 ....................................................................................... 84 
5.2.1.3 
Cycle 1, Day 2 ....................................................................................... 85 
5.2.1.4 
Cycle 1, Day 3 ....................................................................................... 85 
5.2.1.5 
Cycle 1, Day 8 ....................................................................................... 86 
5.2.1.6 
Cycle 2, Day 1 ....................................................................................... 86 
5.2.1.7 
Cycle 2, Day 2 ....................................................................................... 87 
5.2.1.8 
Cycle 2, Day 3 ....................................................................................... 88 
5.2.1.9 
Cycle 2, Day 8 ....................................................................................... 88 
5.2.1.10 
Subsequent Cycles, Day 1 ..................................................................... 88 
5.2.1.11 
End-of-Treatment Follow-up Period ..................................................... 89 
5.2.2 
Phase 1b ....................................................................................................... 90 
5.2.2.1 
Screening Period (Day -28 to Day 0) ..................................................... 90 
5.2.2.2 
Cycle 1, Day 1 ....................................................................................... 91 
5.2.2.3 
Cycle 1, Day 2 ....................................................................................... 92 
5.2.2.4 
Cycle 2, Day 1 ....................................................................................... 93 
5.2.2.5 
Cycle 2, Day 2 ....................................................................................... 94 
5.2.2.6 
Phase 1b, Subsequent Cycles, Day 1 ..................................................... 94 
5.2.2.7 
End of Treatment Follow-up Period ...................................................... 95 
5.2.3 
Long-Term Follow-up for All Patients ........................................................ 95 
5.3 
Study Assessments ................................................................................................... 95 
5.3.1 
Safety Assessments ...................................................................................... 95 


 
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5.3.2 
Efficacy Assessments ................................................................................... 96 
5.3.2.1 
Primary Efficacy Parameters ................................................................. 96 
5.3.2.1.1 
Tumor Assessment ........................................................................ 97 
5.3.2.2 
Additional Efficacy Parameters ............................................................. 97 
5.3.2.3 
Tumor Biopsy for Fresh Tumor Tissue Collection ................................ 97 
5.3.3 
Pharmacokinetic Assessments ...................................................................... 98 
5.3.4 
Biomarker Assessments ............................................................................... 98 
5.3.4.1 
Tumor Tissue Specimens .......................................................................... 98 
5.3.4.2 
Flow Cytometry ..................................................................................... 99 
6. 
Adverse Events ...................................................................................................... 100 
6.1 
Collection of Adverse Events ................................................................................ 100 
6.2 
Serious Adverse Events ......................................................................................... 100 
6.2.1 
Serious Adverse Event Reporting .............................................................. 101 
6.3 
Non-Serious Adverse Events ................................................................................. 105 
6.3.1 
Non-serious Adverse Event Reporting ....................................................... 105 
6.4 
Laboratory Test Result Abnormalities ................................................................ 105 
6.5 
Pregnancy ............................................................................................................... 106 
6.6 
Overdose ................................................................................................................. 106 
6.7 
Potential Drug Induced Liver Injury ................................................................... 106 
7. 
Statistical Considerations ..................................................................................... 108 
7.1 
Sample Size Determination ................................................................................... 108 
7.2 
Demographics and Baseline Characteristics ....................................................... 108 
7.3 
Efficacy Analyses ................................................................................................... 108 
7.4 
Safety Analyses ...................................................................................................... 109 
7.5 
Pharmacokinetic Analyses .................................................................................... 109 
7.6 
Biomarker Analyses............................................................................................... 109 
8. 
Ethical Considerations ......................................................................................... 111 
8.1 
Good Clinical Practice ........................................................................................... 111 
8.2 
Institutional Review Board/Independent Ethics Committee ............................. 111 


 
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8.3 
Informed Consent .................................................................................................. 111 
9. 
Study Management ............................................................................................... 113 
9.1 
Compliance ............................................................................................................. 113 
9.1.1 
Compliance with the Protocol and Protocol Revisions .............................. 113 
9.1.2 
Yale Safety Reporting and Monitoring (DSMP) ........................................ 113 
9.1.2.1 
Source Documentation ........................................................................ 114 
9.1.3 
Investigational Site Training ...................................................................... 114 
9.2 
Records ................................................................................................................... 115 
9.2.1 
Records Retention ...................................................................................... 115 
9.2.2 
Study Drug Records ................................................................................... 115 
9.2.2.1 
Case Report Forms .................................................................................. 116 
10. References .............................................................................................................. 117 
11. Appendices ............................................................................................................. 122 


 
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List of Abbreviations and Definitions 
 
ACTH 
Adrenocorticotropic hormone 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antibody 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AT 
Aminotransferase 
AUC 
Area under the concentration-time curve 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Bis in die; twice daily 
BMI 
Body mass index 
BMS 
Bristol-Myers Squibb 
BOR 
Best overall response 
BP 
Blood pressure 
BTLA 
B- and T-lymphocyte attenuator 
BUN 
Blood urea nitrogen 
ºC 
Degrees Celsius 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
CEA 
Carcinoembryonic antigen 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CI 
Confidence interval 
CK 
Creatine kinase 
CL 
Clearance 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response 


 
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CRC 
Colorectal cancer 
CRF 
Case report form, may be paper or electronic 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CSF1 
Colony stimulating factor 1 
CSF1R 
Colony stimulating factor 1 receptor 
CSR 
Clinical study report 
CT 
Computed tomography 
CTA 
Clinical trials agreement 
CTCAE v 5.0 
Common Terminology Criteria for Adverse Events, version 5.0 
CTLA-4 
Cytotoxic T lymphocyte antigen 4 
CTX 
C-terminal collagen crosslink peptides 
CV 
Coefficient of variation 
DC 
Dendritic cell 
DILI 
Drug-induced liver injury 
dL 
Deciliter 
DLT 
Dose-limiting toxicity 
DMARD 
Disease-modifying anti-rheumatic drug 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
dt-TGCT 
Diffuse-type tenosynovial giant-cell tumor 
EC50 
Half-maximal effective concentration 
ECG 
Electrocardiogram 
ECLA 
Electrochemiluminescence assay 
ECM 
Extracellular matrix 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylene diamine tetraacetic acid 
e.g. 
exempli gratia (for example) 
ELISA 
Enzyme-linked immunosorbent assay 
ePPND 
Enhanced pre- and post-natal development 


 
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ESR 
Erythrocyte sedimentation rate 
ºF 
Degrees Fahrenheit 
FACS 
Fluorescent-activated cell sorter 
Fc 
Fragment crystallizable 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin-embedded 
FISH 
Fluorescent in situ hybridization 
FivePrime 
Five Prime Therapeutics, Inc. 
FOXP3+ 
Forkhead box p3 
FSH 
Follicle stimulating hormone 
g 
Gram 
GBM 
Malignant glioma 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
h 
Hour 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
Half-maximal inhibitory concentration 
ICD 
Implantable cardioverter defibrillator 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICOS 
Inducible co-stimulator 
i.e. 
id est (that is) 
IEC 
Independent ethics committee 
IFN 
Interferon 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 


 
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IL 
Interleukin 
IM 
Intramuscular 
IMP 
Investigational medicinal product 
IND 
Investigational new drug 
INR 
International normalized ratio 
I-O 
Immuno-oncology 
irAE 
Immune-related adverse event 
IRB 
Institutional review board 
ITIM 
Immunoreceptor tyrosine inhibitory motif 
ITSM 
Immunoreceptor tyrosine-based switch motif 
IU 
International unit 
IV 
Intravenous 
IXRS 
Integrated voice and web response system 
kg 
Kilogram 
KM 
Kaplan-Meier 
LAG-3 
Lymphocyte-activate gene 3 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
LOQ 
Limit of quantitation 
MABEL 
Minimum anticipated biological effect level 
mCRPC 
Metastatic castration-resistant prostate cancer 
MDSC 
Myeloid-derived suppressor cell 
mg 
Milligram 
min 
Minute 
µL 
Microliter 
mL 
Milliliter 
MLR 
Mixed lymphocyte reaction 
µM 
Micrometer 
mM 
Millimolar 
mm3 
Cubic millimeters 
mmHg 
Millimeters of mercury 
MRI 
Magnetic resonance imaging 


 
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MSD 
Meso Scale Discovery 
MTD 
Maximum tolerated dose 
N 
Number of patients or observations 
NCI 
National Cancer Institute 
ng 
Nanogram 
NOAEL 
No-observable-adverse-effect level 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
NSAID 
Non-steroidal, anti-inflammatory drug 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamics 
PD-1 
Programmed cell death 1 
PDAC 
Pancreatic ductal adenocarcinoma 
PD-L1 
Programmed death ligand 1 
PD-L2 
Programmed death ligand 2 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PO 
Per os; by mouth 
PPK 
Population pharmacokinetics 
PR 
Partial response 
PT 
Prothrombin time 
PTT (aPTT) 
Partial thromboplastin time 
PVC 
Polyvinyl chloride 
q2w 
Every two weeks 
PVNS 
Pigmented villonodular synovitis 
qPCR 
Quantitative real-time polymerase chain reaction 
qRT-PCR 
Quantitative reverse-transcription polymerase chain reaction 
QTcF 
Fridericia’s correction formula for QT interval 
RA 
Rheumatoid arthritis 
RBC 
Red blood cell 


 
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RCC 
Renal cell carcinoma 
RD 
Recommended Dose 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCCHN 
Squamous-cell carcinoma of the head and neck 
SD 
Stable disease 
SkTnI 
Skeletal troponin 
SOP 
Standard operating procedure 
Src 
Sarcoma homology protein 
T3 
Triiodothyronine 
T4 
Thyroxine 
TAM 
Tumor-associated macrophage 
TB 
Tuberculosis 
TCR 
T-cell receptor 
TIL 
Tumor-infiltrating lymphocyte 
Tmax 
Time of maximum observed concentration 
TNF 
Tumor necrosis factor 
Trap5b 
Tartrate resistant acid phosphatases 5b 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
Vss 
Volume of distribution at steady state 
Vz 
Volume of distribution of terminal phase (if IV and if multi-exponential decline) 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


 
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1. 
Introduction and Study Rationale 
1.1 
Introduction 
Immunotherapies including PD-1/PD-L1 inhibitors have become effective standard therapies in 
several advanced cancers. Objective response rates (ORR) for advanced melanoma patients 
treated with dual (ipilimumab and nivolumab) or single agent (nivolumab) immune checkpoint 
inhibitors have reached up to 57.6% and 43.7%, respectively [1-4]. However, not all patients 
respond and after 2 years of monotherapy, approximately half of the responders have progressed. 
Similarly, in advanced non-small cell lung cancer (NSCLC) patients with greater than 50% tumor 
PD-L1 positivity, pembrolizumab is used in the front-line setting with a 44.8% response rate [5]. 
Nivolumab and atezolizumab are also approved for NSCLC patients who have progressed on 
platinum-based chemotherapy and who are not candidates for EGFR or ALK inhibitors [6, 7]. 
Additionally, nivolumab is approved in second-line treatment of advanced renal cell carcinoma 
(RCC) with a 25% ORR [8]. In the absence of targetable driver mutations, limited treatment 
options exist for next-line therapy in patients who do not initially respond to or who develop 
acquired resistance to PD-1 inhibitors. New combinatorial therapeutic strategies are needed to 
overcome this resistance. 
 
Proposed mechanisms for resistance to anti-PD-1/PD-L1 therapy include lack of or inactivation of 
T cells, T cell exhaustion, loss of antigen presentation, or expression of other immunosuppressive 
molecules. Tumor-associated macrophages (TAMs) comprise up to 30% of innate immune cells 
in the tumor microenvironment [9] and can serve as both negative (M1) and positive (M2) 
regulators 
of 
tumor 
growth. M2 
macrophages 
are 
anti-inflammatory 
and 
secrete 
immunosuppressive growth factors that negatively impact cytotoxic T-cell capabilities [10-13] and 
promote tumorigenesis, invasion, and metastasis [14, 15]. We hypothesize that manipulation of 
the innate immune system by targeting macrophage activity will assist in reversing local immune 
suppression and overcome resistance to PD-1/PD-L1 inhibition. 
 
1.2 
Rationale for Combination of APX005M with nivolumab and cabiralizumab 
Immunotherapies including CSF1R inhibitors (CSF1Ri) and CD40 agonists (CD40α) target innate 
immune cells. Researchers including those at Yale have shown these agents to suppress poorly T- 
cell infiltrated melanomas in a T-cell independent fashion. Macrophage colony-stimulating factor 
1 (CSF-1) is chemotactic signal that stimulates monocyte tumor infiltration and differentiation into 
M2 macrophages [10, 16] and elevated expression of CSF-1 and CSF1R is associated with poor 
prognosis [17]. For example, in a melanoma mouse model, CSF1Ri improved efficacy of adoptive 
cell therapy by increasing T-cell tumor infiltration and decreasing immunosuppressive 
macrophage infiltration [18]. CD40 is similarly expressed on macrophages and other antigen 
presenting cells, and interacts with its ligand, CD40L, on T cells. CD40α have also been shown to 
increase tumoricidal activity of macrophages and stimulate maturation of antigen presenting cells. 
In a pancreatic mouse model, combination PD-1 blockade and CD40α improved anti-tumor 
immunity compared to either agent alone [19]. Clinical trials of CD40α have shown activity in 
melanoma, including durable responses [20]. 
 
Pre-clinical studies at Yale in the Kaech and Bosenberg laboratories have supported the notion that 
TAMs may confer resistance to PD-1/PD-L1 inhibition [21]. Using the BrafV600E/Pten-/- 
genetically engineered mouse melanoma model (GEMM), we have generated a series of cell lines 


 
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(YUMM for Yale University Mouse Melanoma) and irradiated derivatives (YUMMER for Yale 
University Mouse Melanoma Exposed to UVB Radiation). These models are unique in that they 
are driven by mutations relevant to human melanomas and can be studied in immune competent 
mice. YUMM tumors tend to be resistant to PD-1/PD-L1 inhibitors, while the YUMMER tumors 
are less resistant, but do develop resistance over time, mimicking primary and acquired resistance 
seen in humans. We have found that the 
predominant immune population present in tumors with poor cytotoxic T cell infiltration are 
TAMs. TAMs are particularly in abundance relative to CD8+ T cells in YUMM tumors, with the 
inverse being observed  in  YUMMER  tumors 
(Figure 1). 
 
Tumor infiltrating neutrophils (TINs) and CD4 T cells are present as well, but mostly at the tumor 
margin. Tumor growth in this model is not responsive to anti-PD-1/PD-L1 treatment alone, but 
combination therapy with CSF1Ri slows tumor growth significantly compared to the control (data 
not shown). Treatment with combined CSF1Ri/CD4α slows tumor growth more than either agent 
alone (Figure 2 upper panel). The combination therapy also resulted in increased tumor infiltrating 
immune cells, clearly impacting the TAM population (Figure 2 lower panel). 
 
Figure 1. Content of immune infiltrating cells in 
the 
BrafV600E/Pten-/- 
genetically 
engineered 
mouse melanoma models (GEMM), a cell line 
model derived from these GEMM tumors, YUMM 
1.7, and a model generated by exposure to UVB 
radiation (YUMMER1.7), which is more sensitive 
to PD-1/PD-L1 inhibitors, but develops resistance 
over time. TAM content is abundant in the former, 
whereas more CD8 cells are infiltrating the latter. 


 
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Additional detailed mechanistic studies have been conducted supporting the combination of 
CD40α and CSF1Ri in these animal models and their role in activating the innate immune 
system (Perry CJ et al, submitted). Combined treatment with CD40α and CSF1Ri alters the 
composition of TAMs, increases Type I inflammation and chemokine expression, and enhances 
CD8 T-cell infiltration and PD-1 expression. 
 
As shown in the flow plots in Figure 3 for example, the expression TNF-α on TAMs significantly 
increases with combined CSF1Ri/CD40α. 
 
 
Figure 2. Upper panel: Groups of 12 mice were treated with control vehicle, CD40 agonist alone, CSF1R inhibitor 
alone, or the combination 30 days after tumor induction. The combination resulted in significant inhibition of tumor 
growth compared with either drug alone. 
Lower Panel: Treatment of mice with CD40 agonists, CSF1R inhibitors or the combination thereof impacted tumor 
infiltrating immune cells, particularly tumor associated macrophages (TAM) and neutrophils (TAN). 


 
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Inflammatory cytokines including TNFα and IFNγ appear to be necessary for anti-tumor immunity 
provided by combined CSF1Ri and CD4α therapy. As shown in the Kaplan-Meier curves (Figure 
4 upper panel) and the associated log-rank p values (Mantel-Cox) (Figure 4 lower panel), TNFα 
and IFNγ blocking therapy actually interferes with tumor growth suppression from combined 
CSF1Ri and CD40α therapy. Data are from one experiment (n=3-6), representative of three 
independent experiments (total n=6-15). 
 
 
 
 
 
In pilot experiments, we have shown that mice (n=11) treated with the triple combination of anti- 
PD-1/CSF1Ri/CD40α had superior survival compared to treatment with anti-PD-1/CSF1Ri or 
anti-PD-1/CD40α (Figure 5). 
Figure 3. Treatment with CSF1Ri and CD40α in combination alters the macrophage content to a greater degree 
than either drug alone. 
Figure 4. Kaplan Meier survival curves (upper panel) and associated statistical comparisons (lower panel) show 
that TNFα and IFNγ are necessary for anti-tumor immunity provided by combined CSF1Ri and CD40α therapy, as 
blocking them interferes with the inhibition of tumor growth by these drugs. 


 
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Thus, based on the above pre-clinical data, we hypothesize that addition of CSF1Ri/CD40α to PD- 
1 blockade may further disengage T cell suppression and potentiate the anti-tumor immune 
response. We therefore propose a phase I/Ib clinical trial of the CD40α APX005M in combination 
with cabiralizumab (CSF1Ri) and nivolumab in advanced solid tumors including melanoma, 
NSCLC, and RCC. Our preliminary data from immune profiling of murine tumors treated with 
CSF1Ri and CD40α indicate that biomarkers of response include TNFα, IL-6, CCL3,4,5 and 
CD8+ T cell/neutrophil recruitment. We aim to identify immune correlates that are associated 
with clinical response to the triple combination and to develop biomarkers of response using 
mandatory pre-treatment and on-treatment biopsies. 
 
Seeing that APX005M and cabiralizumab have not been used in combination, and both drugs 
activate macrophages, we propose an initial cohort of the APX005M and cabiralizumab. This 
cohort will be followed by the addition of fixed dose nivolumab. APX005M will then be slowly 
dose escalated in combination with cabiralizumab, with and without nivolumab, to establish safety 
and to establish the RP2D of APX005M in combination with nivolumab and cabiralizumab. 
 
1.3 
Target Receptor Background 
 
1.3.1 Tumor-Associated Macrophages and Colony Stimulating Factor 1 Receptor 
Macrophages are myeloid-derived cells that carry out a variety of functions in the human body. 
They can colonize tissues and tumors through two distinct mechanisms: hematogenous seeding 
from circulating monocytes or local self-renewal in the form of tissue-resident macrophages 
[22]. Recent studies have shown that macrophages exert their physiological effect within, and 
play roles unique to, the tissues in which they are active [23]. Macrophage regulation is complex 
as these cells actively secrete and respond to multiple cytokine and chemokine gradients within 
their local environment. 
Figure 5. YUMM 1.7 bearing mice were treated with control vehicle, CD40 agonistic antibodies (CD40α), 
CSF1R inhibitors (CSF1Ri) or anti-PD-1/L1. These tumors are resistant to any of the three 
monotherapies, and survival was clearly superior with triplet therapy compared with doublets of CSF1Ri 
or CD40α and PD-1 axis inhibitors. 


 
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Macrophages are among the most abundant immune cell types in the tumor microenvironment. 
Based on their opposing functions, macrophages can be classified into two major phenotypes, 
M1 and M2. M1 macrophages are immunostimulatory and tumor suppressive, while M2 
macrophages are immunosuppressive and tumor promoting. Substantial evidence suggests that 
tumor-associated macrophages (TAMs) are polarized towards an anti-inflammatory M2 
phenotype [24]. Consistent with this, increased levels of TAMs are associated with a poor 
prognosis in the majority of cancers [25]. Based on their tumor-promoting phenotype TAMs 
have become an attractive therapeutic target. 
 
Colony stimulating factor 1 receptor (CSF1R) signaling plays a fundamental role in the 
differentiation, maintenance, and function of macrophages [26]. There are two ligands for 
CSF1R: CSF1 and IL34. These agonists bind to overlapping regions of CSF1R with similar 
affinity (reviewed in Masteller and Wong [27]). Mice lacking CSF1R, CSF1, or IL34 have 
deficiencies in macrophages, underscoring the essential role of the CSF1R pathway in the 
biology of this cell type [27, 28]. Pharmacologic treatments that block CSF1R in cancer settings 
are expected to reduce or reprogram M2 TAMs and reduce immune suppression. Following 
treatment with anti-CSF1R agents, the remaining macrophage compartment may be repolarized 
from an M2 immunosuppressive state to an M1 anti-tumor state, which would support T-cell 
responses. This conversion associated with concurrent treatment modalities, such as anti-PD-1 
treatment, could have an increased effect on reduction of tumor growth [29]. 
 
Support for targeting CSF1R in cancer comes from animal studies in which antibody or small 
molecule inhibition of CSF1R decreases M2 TAMs resulting in decreased immune suppression 
and a more robust cytotoxic T-cell response [30-32]. Cabiralizumab is a recombinant, humanized 
immunoglobulin G4 (IgG4) monoclonal antibody that binds to human CSF1R. The interaction of 
cabiralizumab and CSF1R antagonizes the binding of both CSF1 and IL34 to CSF1R, thereby 
preventing receptor activation. In vitro, cabiralizumab inhibits CSF1 and IL34-induced 
proliferation and survival of peripheral blood monocytes. In vivo, cabiralizumab inhibits the 
survival of subsets of monocytes and macrophages. 
Taken together, these and other emerging data suggest that blocking CSF1R with cabiralizumab 
treatment may reduce immunosuppression in the tumor environment generated by TAMs and 
enhance the efficacy of immune-based anti-cancer therapies. 
 
1.3.2 Programmed Cell Death-1 (PD-1; CD279) 
PD-1 is a cell surface signaling receptor that delivers inhibitory signals to regulate the balance 
between T-cell activation and tolerance by interacting with its ligands, PD-L1 (CD274; B7-H1) 
and PD-L2 (B7-DC/CD273). It is a 55 kDa type I transmembrane protein that is a member of the 
CD28 family of T-cell costimulatory receptors, which also includes inducible co-stimulator 
(ICOS), cytotoxic T lymphocyte antigen-4 (CTLA-4), and B- and T-lymphocyte attenuator 
(BTLA) [33]. PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine 
inhibitory motif (ITIM) and a membrane distal immunoreceptor tyrosine-based switch motif 
(ITSM). PD-1 is primarily expressed on activated T cells, B cells, and myeloid cells [34]. Its 
ligands, PD-L1 and PD-L2, have been shown to down-regulate T-cell activation upon binding to 


 
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PD-1 in both murine and human systems [35, 36]. PD-1 delivers a negative signal by the 
recruitment of Src homology region 2 domain-containing phosphatase-2 (SHP-2) to the 
phosphorylated tyrosine residue in the ITSM in its cytoplasmic region [37, 38]. 
 
Evidence for a negative regulatory role of PD-1 comes from studies of PD-1-deficient mice, 
which develop various autoimmune phenotypes, including dilated cardiomyopathy and a lupus- 
like syndrome with arthritis and nephritis [39-41]. The emergence of these autoimmune 
phenotypes is dependent on the genetic background of the mouse strain; many of these 
phenotypes emerge at different times and show variable penetrance. In addition to the 
phenotypes of null mutations, PD-1 inhibition by antibody-mediated blockade in several murine 
models has been found to play a role in the development of autoimmune diseases such as 
encephalomyelitis, graft-versus-host disease, and type I diabetes [42-44]. Taken together, these 
results suggest that PD-1 blockade has the potential to activate anti-self T-cell responses, but 
these responses are variable and dependent upon various host genetic factors. Thus, PD-1 
deficiency or inhibition is not accompanied by a universal loss of tolerance to self-antigens. 
 
The PD-1 targeting agent, nivolumab has been investigated clinically in several tumor types 
including non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC), 
Classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, and urothelial 
carcinoma as a single agent or in combination with other treatments. A selection of efficacy data 
is described in the Nivolumab Investigator’s Brochure).. As a single agent, nivolumab shows 
remarkably durable efficacy in responding patients. 
 
Nivolumab is currently approved in the US for the following indications [45]: 
 
• BRAF V600 wild-type unresectable or metastatic melanoma, as a single agent. 
• BRAF V600 mutation-positive unresectable or metastatic melanoma, as a single agent. 
• Unresectable or metastatic melanoma, in combination with ipilimumab. 
• Metastatic non-small cell lung cancer and progression on or after platinum-based 
chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have 
disease progression on FDA-approved therapy for these aberrations. 
• Advanced renal cell carcinoma for patients who have received prior anti-angiogenic 
therapy. 
• Classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous 
hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab 
vedotin or 3 or more lines of therapy that includes autologous HSCT. 
• Recurrent or metastatic squamous cell carcinoma of the head and neck with disease 
progression on or after a platinum-based therapy. 
• Locally advanced or metastatic urothelial carcinoma who: 
– have disease progression during or following platinum-containing chemotherapy 


 
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– have disease progression within 12 months of neoadjuvant or adjuvant treatment with 
platinum-containing chemotherapy. 
 
 
 
1.3.3 CD40 
Apexigen has developed the mAb APX005M, which binds and activates CD40, a costimulatory 
molecule expressed by antigen presenting cells (APC). As such, APX005M is a CD40 agonistic 
antibody. The cell surface molecule CD40, a member of the tumor necrosis factor receptor 
(TNFR) superfamily, plays an important role in induction of tumor apoptosis and regulation of 
immune activation, especially in crosstalk between T cells and APCs [46]. CD40 is expressed by 
dendritic cells (DC), B cells, monocytes, and some non-lymphoid cells [47]. The natural ligand 
(CD40L) for CD40 is CD154, which is expressed on activated T cells and provides a major 
component of T cell “help” for immune response. Agonistic CD40 antibodies can substitute for 
the function of CD154 on T cells to boost immunity. Signaling through CD40 on APCs, 
including dendritic cells (DCs), monocytes, and B cells, can, in turn, enhance the T cell response 
via improvement in antigen processing and presentation and through the release of cytokines 
from activated APCs [48, 49]. Therefore, an agonistic CD40 antibody can activate and stimulate 
both innate and adaptive immunity. 
 
CD40 is also expressed on many tumor cells and can mediate a direct cytotoxic effect. In 
addition to B cell lymphoma, CD40 expression has been reported in 30−70% of primary human 
solid tumor samples including melanoma and carcinomas [50]. Activation of CD40 on tumor 
cells results in tumor cell apoptosis and inhibition of tumor growth [12]. Due to its action on both 
immune and tumor cells, CD40 has been studied as a target for novel cancer immunotherapy; 
agonistic anti-CD40 antibodies have been demonstrated to be potent stimulators of tumor 
immune responses in both animal models and cancer subjects [50-53]. 
 
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. 
 
1.3.4 Product Development Background 
 
1.3.4.1 Mechanism of Action 
 
1.3.4.1.1 Cabiralizumab 
Cabiralizumab is a recombinant, humanized IgG4 monoclonal antibody that binds to human 
CSF1R. Cabiralizumab contains a single amino acid substitution in the hinge region to prevent 
hemi-dimer exchange. Binding of cabiralizumab to CSF1R antagonizes its natural ligands, CSF1 
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Cabiralizumab inhibits both CSF1 and IL34-induced CSF1R phosphorylation in a cell line 
engineered to overexpress CSF1R (CHO-CSF1R), demonstrating that cabiralizumab blocks the 
activation of ligand-induced CSF1R signaling pathways. Cabiralizumab also inhibits CSF1 and 
IL34-induced proliferation and survival of peripheral blood monocytes in vitro, demonstrating 
that cabiralizumab inhibits not only the initiation of CSF1 and IL34 signaling pathways, but also 
the subsequent physiologic responses of primary human monocytes to these ligands. 
 
CSF1R is expressed on cells of the monocyte/macrophage lineage and signaling through CSF1R 
via its ligands, CSF1 and IL34, supports differentiation, maintenance, and function of 
monocytes, macrophages, and osteoclasts. TAMs are among the most abundant immune cell 
types in the tumor microenvironment. Substantial evidence suggests that TAMs are polarized 
towards an anti-inflammatory phenotype (M2 TAMs) and through both cell surface inhibitors 
and soluble factors, such as immunosuppressive cytokines, play a major role in inhibiting anti- 
tumor immune responses [24]. CSF1 is a major survival factor for TAMs and targeting CSF1R 
through cabiralizumab should reduce TAM-mediated immune suppression resulting in 
strengthening the anti-tumor response to immunotherapy. Therefore, a drug that inhibits CSF1R 
should limit the immune-suppressive influence of TAMs on the tumor microenvironment and 
could be complementary and augment current cancer therapies. 
 
1.3.4.1.2 Nivolumab 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immuno-surveillance and escape effective innate and adaptive immune responses [54-57]. 
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. 
 
T-cell stimulation is a complex process involving the integration of numerous positive as well as 
negative co-stimulatory signals in addition to antigen recognition by the T-cell receptor (TCR) 
[58]. Collectively, these signals govern the balance between T-cell activation and tolerance. PD- 
1 signaling has been shown to inhibit CD28-mediated upregulation of IL2, IL10, IL13, 
interferon-γ (IFN-γ) and Bcl-xL. PD-1 signaling has also been noted to inhibit T-cell activation, 
and expansion of previously activated cells. Evidence for a negative regulatory role of PD-1 
comes from studies of PD-1 deficient mice, which develop a variety of autoimmune phenotypes 
[59]. These results suggest that PD-1 blockade has the potential to promote anti-self T-cell 
responses, but these responses are variable and dependent upon various host genetic factors. 
Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to self 
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In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibits the 
binding of PD-1 to its ligands, PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab binds specifically to 
PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. 
Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement of both 
proliferation and IFN-γ release in a mixed lymphocyte reaction (MLR). Using a cytomegalovirus 
(CMV) re-stimulation assay with human peripheral blood mononuclear cells (PBMCs), the effect 
of nivolumab on antigen-specific recall response is indicative of nivolumab-augmented IFN-γ 
secretion from CMV-specific memory T cells in a dose-dependent manner versus an isotype- 
matched control. In vivo blockade of PD-1 by a murine analog of nivolumab enhances the anti- 
tumor immune response and results in tumor rejection in several immunocompetent mouse tumor 
models (MC38, SA1/N, and PAN02) [60]. 
 
1.3.4.1.3 APX005M 
The agonistic CD40 mAb, APX005M, a humanized IgG1 mAb with a mutation in the Fc portion, is 
engineered to enhance interaction with Fc receptors to mediate antibody crosslinking. APX005M has 
demonstrated biological activity in human subjects and a favorable toxicity profile when given IV at 
doses up to 1 mg/kg body weight. 
 
Recently, Zippelius and co-authors [61] showed in preclinical models that CD40 engagement with an 
agonistic mAb leads to a T cell and IFN-γ dependent upregulation of PD-L1 on tumor infiltrating 
monocytes and macrophages, thereby feeding into a negative feedback loop, which hampers CD40 
induced T-cell responses. This resistance mechanism was successfully circumvented by co- 
administration of PD-1/PD-L1 blocking antibodies. 
 
Similarly, other groups showed in preclinical models of pancreatic cancer that CD40 activation drove 
T-cell immunity and reversed the complete resistance of pancreatic tumors to checkpoint blockade. 
Combining a CD40 agonistic antibody with PD-1/PD-L1 blockade enhanced anti-tumor immunity 
and improved overall survival versus either monotherapy [19, 62, 63]. 
 
Studies elucidating the mechanism of APX005M action showed that it activates the CD40 signaling 
pathway, leading to APC activation, as seen in increased CD80, CD83, and CD86 expression and 
release of cytokines from human lymphocytes and monocytes. In particular, APX005M induced 
interleukin (IL)-12 p(70), TNF-α and IL-6 secretion from DCs. The CD40-agonistic activity of 
APX005M can be further enhanced by a toll-like receptor (TLR) 4 agonist. In comparison with 3 
other CD40-agonistic antibody analogs (CP-870,893, SGN-40, and ADC-1013), APX005M is the 
most potent CD40 agonist. APX005M’s CD40-agonistic activity depends on its ability to bind  
FcγRs. In in vitro cultures with T cells and DCs, APX005M was able to enhance antigen-specific T- 
cell proliferation and promote IFN-γ secretion. In combination with an antibody against programmed 
cell death ligand-1 (PD-L1), APX005M synergistically enhances antigen-specific T-cell responses. 
Upon binding to CD40-expressing tumor cells, APX005M was capable of inducing ADCP and tumor 
cell apoptosis. APX005M did not appear to have a substantive effect on normal human DC and T- 
cell counts, but could partially reduce B-cell counts in vitro [64]. 


 
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1.3.5 Preclinical Summary 
 
1.3.5.1 Cabiralizumab 
The PK profile of cabiralizumab is complex and characterized by nonlinear clearance that is 
likely mediated by binding to CSF1R on cells. As monocyte and macrophage cells are dependent 
on CSF1R for viability, these target-bearing cells are reduced in number following cabiralizumab 
treatment, resulting in a decrease of target-mediated clearance. As target-mediated clearance 
becomes saturated at high or repeat doses, cabiralizumab clearance is similar to other human IgG 
antibodies. 
 
Three PD biomarkers correlate with cabiralizumab exposure in nonclinical studies: CSF1 serum 
levels, circulating CD16-positive peripheral blood monocytes (CD16+ monocytes), and serum 
markers of bone resorption (Trap5b and CTX). CSF1 serum levels rapidly rise and CD16+ 
monocyte levels rapidly fall in a dose-dependent manner that correlates closely with 
cabiralizumab plasma concentration. Saturation of the PD response is achieved at a low dose of 
cabiralizumab (3 mg/kg weekly) in cynomolgus monkeys. The half-maximal response (IC50) for 
reduction of CD16+ monocytes occurs at a serum concentration of approximately 3 µg/mL and 
the maximal response occurs at approximately 10 µg/mL. The level of CD16-negative (CD16–) 
monocytes does not change with exposure to cabiralizumab. 
 
In the in vivo toxicology studies in cynomolgus monkeys, cabiralizumab was generally well 
tolerated. The most prominent clinical observation was reversible periorbital edema, seen after 
prolonged exposure to cabiralizumab. The onset of the edema did not show a clear relationship to 
exposure levels, but edema resolved after systemic clearance of the drug. Periorbital edema is a 
known side effect of drugs affecting the CSF1 pathway [31, 65]. The main hematologic change 
was a reversible decrease in circulating CD16+ monocytes, which was considered a PD effect. 
 
Cabiralizumab-related clinical chemistry effects included reversibly increased ALT, AST, CK, 
and LDH serum levels. These laboratory abnormalities were not associated with any 
histopathological evidence of liver, cardiac, or muscle tissue injury. Additionally, cardiac 
troponin, skeletal troponin (SkTnI), myoglobin, and aldolase did not show any changes further 
confirming the lack of any liver or muscle injury. The increased serum levels are attributed to 
diminished clearance of ALT, AST, CK, and LDH molecules from serum due to a reduced 
number of liver Kupffer cells.  Kupffer cells are the normal clearance mechanism for these serum 
enzymes so a loss of macrophages leads to an elevation of these serum enzymes [66]. 
Accordingly, ALT, AST, CK, and LDH elevations are considered non-toxic and an indirect PD 
effect of cabiralizumab exposure. 
 
One histopathological finding was the reversible expansion of the submucosal collagen fibers by 
clear space and varying amounts of a blue, granular extracellular matrix (ECM) in a variety of 
tissues. This change was neither associated with inflammatory cells nor with any sign of 
degeneration or other alteration of the collagen fibers, fibroblasts, or the smooth muscle cells 
within the area of expansion. Because it was not associated with clinical signs and was 


 
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reversible, it was deemed to be a non-adverse event. A similar observation was also seen in 
op/op mice that lack functional CSF1. The reduction of tissue macrophages is the likely cause of 
the observed accumulation of ECM due to a decreased clearance of glycosaminoglycans, 
especially hyaluronic acid, that are prominent in connective tissue and are normally catabolized 
by macrophages [67]. This change is also considered to be an indirect PD effect of 
cabiralizumab. 
 
The no-observable-adverse-effect level (NOAEL) for cabiralizumab was determined to be 
100 mg/kg when administered for 13 weekly doses to cynomolgus monkeys, which provides a 
32-fold safety factor based on body surface area calculation for the starting dose of 1 mg/kg in 
humans. 
 
For more detailed information or background on cabiralizumab, please refer to the 
Cabiralizumab Investigator’s Brochure. 
 
1.3.5.2 Nivolumab 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related 
members of the CD28 family, such as ICOS, CTLA-4, and BTLA(Nivolumab Investigator’s 
Brochure) . Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, 
resulting in enhanced T-cell proliferation and IFN-γ release in vitro[68] (Nivolumab 
Investigator’s Brochure). Fluorescent-activated cell sorter (FACS) analysis confirmed that 
nivolumab binds to transfected Chinese hamster ovary (CHO) with human or cynomolgus 
monkey PD-1, but not to rat or rabbit PD-1 molecules. Nivolumab has also been shown to bind 
to PD-1 on activated human T cells expressing cell surface PD-1 or on virus-specific CD8+ T 
cells from chronically infected hepatitis C virus patients [69, 70]. 
 
PD-1 inhibition in an MLR resulted in a reproducible concentration-dependent enhancement of 
IFN-γ release in the MLR up to 50 µg/mL. No effect was observed with a human IgG4 isotype 
control or CD4+ T cells and dendritic cell (DC) controls [71]. 
 
In intravenous repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was well 
tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 50 mg/kg, 
administered twice weekly for 27 doses. Nivolumab-related findings were limited to a reversible 
decrease of 28% in triiodothyronine (T3) among the females administered 27 doses of 50 mg/kg 
nivolumab. No corresponding changes in the level of thyroxine (T4), thyroid-stimulating 
hormone (TSH), or histologic changes in the thyroid were observed. While nivolumab alone was 
well tolerated in cynomolgus monkeys, combination studies have highlighted the potential for 
enhanced toxicity when combined with other immunostimulatory agents[45]. 
 
Ipilimumab (BMS-734016), an anti-CTLA-4 monoclonal antibody that blocks the 
downregulation of T-cell activation, was used in combination with nivolumab to investigate the 
effects of concurrent inhibition of the PD-1 and CTLA-4 receptors in nonhuman primates[68]. 
Although gastrointestinal (GI) toxicity has not been observed in cynomolgus monkeys treated 
with nivolumab alone, dose-dependent GI toxicity was evident in cynomolgus monkeys treated 


 
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weekly for 4 weeks with a combination of nivolumab and ipilimumab at combinations of 
10 mg/kg and 3 mg/kg and 50 mg/kg and 10 mg/kg, respectively. GI effects have also been 
observed at a low incidence after ipilimumab administration [68]. 
 
In addition, an enhanced pre- and post-natal development (ePPND) study in pregnant 
cynomolgus monkeys with nivolumab was conducted [68]. Administration of nivolumab at up to 
50 mg/kg every 2 weeks was well tolerated by pregnant monkeys; however, nivolumab was 
determined to be a selective developmental toxicant when administered from the period of 
organogenesis to parturition at ≥ 10 mg/kg (area under the concentration-time curve [AUC] from 
time zero to 168 hours [AUC(0-168 h)] 117,000 µg•h/mL). Specifically, increased developmental 
mortality (including late gestational fetal losses and extreme prematurity with associated 
neonatal mortality) was noted in the absence of overt maternal toxicity. There were no 
nivolumab-related changes in surviving infants tested throughout the 6-month postnatal period. 
Although the cause of these pregnancy failures was undetermined, nivolumab-related effects on 
pregnancy maintenance are consistent with the established role of PD-L1 in maintaining 
fetomaternal tolerance in mice [72]. 
 
For more detailed information or background on nivolumab, please refer to the Nivolumab 
Investigator’s Brochure. 
 
1.3.5.3 APX005M 
Preclinical experiments with APX005M showed that it activates the CD40 signaling pathway, 
leading to APC activation, as demonstrated by an increased expression of CD80, CD83, and 
CD86 and by expression and release of cytokines from human DCs and lymphocytes. As a result 
of APC activation, APX005M enhances T-cell proliferation to alloantigen, triggers production of 
IFN-γ in response to viral antigens, and enhances T-cell response to tumor antigens. APX005M 
combined with a TLR 4 agonist or an antibody against programmed death ligand 1 (PD-L1) 
synergistically enhances T-cell responses. 
 
In comparison with other CD40-agonistic antibodies, such as CP-870,893, SGN-40, and ADC- 
1013 analogs, APX005M is the most potent CD40 agonist. APX005M did not appear to have a 
substantive effect on normal human DC and T-cell counts, but could partially reduce B cell 
counts in vitro. The potential for APX005M to induce expression of cytokines was evaluated 
with peripheral blood mononuclear cells (PBMC) obtained from normal humans and treatment 
naïve cynomolgus monkeys, including anti CD3 antibody as a positive control. Cytokine 
secretion differed significantly between species with much less secretion from monkey PBMCs 
compared with human PBMCs. These data suggest that APX005M is a strong CD40-agonistic 
antibody that can activate APCs (DCs, B cells, and monocytes) and in turn stimulate T-cell 
response. 
 
For more detailed information or background on APX005M, please refer to the APX005M 
Investigator’s Brochure. 


 
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1.3.6 Clinical Summary 
 
1.3.6.1 Cabiralizumab 
 
1.3.6.1.1 Clinical Study Summary of Cabiralizumab 
The clinical summary is based on three clinical studies: 
 
1. Study FPA008-001 evaluated the safety of cabiralizumab as single or dual escalating 
doses in 48 healthy volunteers (36 cabiralizumab and 12 placebo). This study also 
evaluated the safety and efficacy of cabiralizumab administered as two or three doses, 14 
days apart, in 18 rheumatoid arthritis patients. This study has been completed. 
 
2. Study FPA008-002 is evaluating the safety and efficacy of cabiralizumab monotherapy 
for six months in approximately 40 patients with pigmented villonodular synovitis 
(PVNS). 
 
3. Study FPA008-003 is evaluating the safety and efficacy of cabiralizumab as monotherapy 
and in combination with nivolumab in approximately 295 patients with advanced cancers. 
 
1.3.6.1.2 Clinical Pharmacology Summary (Pharmacokinetics, Immunogenicity, and 
Pharmacodynamics) of Cabiralizumab 
The available PK, ADA, and nonclassical CD16+ monocyte status following cabiralizumab 
treatment with either monotherapy or in combination with nivolumab were characterized in three 
trials: FPA008 001, FPA008-002, and FPA008-003. The PK, ADA, and nonclassical CD16+ 
monocyte data from Study FPA008-003 are summarized below; data from Studies FPA008 001 
and FPA008-002 are presented in the cabiralizumab IB. 
 
The PK profile of cabiralizumab is characterized by linear and nonlinear clearance pathways, 
with the latter likely mediated by binding to CSF1R on cells. As monocyte and macrophage cells 
are dependent on CSF1R for viability, these target-bearing cells are reduced in number following 
cabiralizumab treatment, resulting in a decrease of target-mediated clearance. Once target 
mediated clearance is saturated at high or repeat doses, cabiralizumab clearance is similar to 
other human IgG antibodies. 
 
1.3.6.1.3 Clinical Safety Summary of Cabiralizumab 
1.3.6.1.3.1 Study FPA008-001 – Healthy Volunteers and Rheumatoid Arthritis 
Thirty six healthy volunteers and 18 RA subjects received cabiralizumab in Study FPA008 001. 
No dose-limiting toxicities (DLTs) were reported and no unexpected treatment related adverse 
events (AEs) have been reported from RA subjects treated with three doses up to 6 mg/kg. 


 
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1.3.6.1.3.2 Study FPA008-002 – Pigmented Villonodular Synovitis 
Study FPA008-002 is currently ongoing and is evaluating cabiralizumab as monotherapy in 
subjects with PVNS. Details relating to safety are included in the latest version of the 
cabiralizumab IB (FivePrime, 2017). 
 
1.3.6.1.3.3 Study FPA008-003 – Advanced Cancers 
As of August 1, 2017, cabiralizumab-related AEs were reported in 169 of 195 subjects (87%) 
treated Q2W in Phase 1b of Study FPA008-003. The AEs reported in more than 10% of the 
subjects included: CK increased (77 subjects, 40%); periorbital edema (73 subjects, 73%); AST 
increased (65 subjects, 33%); fatigue (61 subjects, 31%); ALT increased and pruritus (32 
subjects each, 16%); amylase increase and rash (30 subjects each, 15%); lipase increase (29 
subjects, 15%); nausea (27 subjects, 14%); and LDH increased (20 subject, 10%). 
 
Cabiralizumab-related Grade 3 AEs in Phase 1b were predominantly enzyme elevations of CK 
(14 Grade 3 and 14 Grade 4 events), LDH (one Grade 3 and one Grade 4 event), Alkaline 
phosphate ([ALP] two Grade 3 events), ALT (two Grade 3 events), and AST (10 Grade 3 
events). Other related AEs that were Grade 3 and reported in 2 or subjects included 13 events of 
amylase increased (12 Grade 3 and one Grade 4), 15 events of Grade 3 lipase increased (14 
Grade 3 and one Grade 4), 11 events of Grade 3 Fatigue, and three events of Grade 3 
hypertension. 
 
Twenty-six of 195 subjects (13%) experienced a cabiralizumab-related SAE in Phase 1b. The 
SAEs reported in two or more subjects included: CK increased (three subjects, 3%), brain 
edema, pneumonitis, hyponatremia (two subjects each, 1%). Also SAEs included one event of 
Grade 4 CK increased (related to cabiralizumab and nivolumab), one event of Grade 3 
autoimmune colitis (related to nivolumab), and one event of Grade 3 hypopituitarism (related to 
cabiralizumab and nivolumab). 
 
Two Grade 5 SAEs prior to study treatment discontinuation have occurred in Phase 1a of Study 
FPA008-003: one subject had a Grade 5 pulmonary embolus (not related) and a Grade 5 
pneumonitis (related to both drugs; refer to Appendix 7 for management recommendations in 
cases of pneumonitis) and the other subject had a Grade 5 hypoxic respiratory failure secondary 
to pneumonia (not related). Six Grade 5 SAEs prior to study treatment discontinuation were 
reported in Phase 1b of this study. These included 1 sudden cardiac death (unrelated), 1 death 
due to tumor thrombus blocking a major blood vessel (unrelated), 2 patients with respiratory 
failure (unrelated), 1 patient with acute respiratory distress (related), and 1 patient with acute 
respiratory failure (related). 
Data from the Phase 1 dose escalation study of cabiralizumab +/- nivolumab in advanced solid 
tumors was presented at the Society for Immunotherapy of Cancer’s 2017 Annual Meeting. 
Cabiralizumab administered at 4 mg/kg every 2 weeks depleted circulating non-classical 
monocytes and had a tolerable safety profile when administered with or without nivolumab. The 
most common treatment-related adverse events attributed to cabiralizumab were elevations in 
LDH, CK, and serum transaminases without elevation of bilirubin. Grade 3-4 serum enzyme 
elevations occurred in 9/24 (38%) patients on the cabiralizumab monotherapy arm and in 40/205 


 
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(20%) patients on the cabiralizumab plus nivolumab arm.  All cases of periorbital edema except 
for one was grade 1-2, occurring in 5/24 (21%) patients on the cabiralizumab monotherapy arm 
and in 84/205 (41%) patients on the cabiralizumab plus nivolumab arm.  In heavily pre-treated 
patients with pancreatic cancer, durable clinical benefit was observed in 5/31 (16%) patients with 
a confirmed ORR of 13%.  All confirmed responses occurred in patients with MSS disease who 
historically have not received benefit from anti-PD-1/PD-L1 agents and a study of cabiralizumab 
plus nivolumab with or without chemotherapy in pancreatic cancer (NCT03336216) is planned. 
 
 
1.3.6.2 Nivolumab 
 
1.3.6.2.1 Clinical Pharmacology Summary of Nivolumab 
The pharmacokinetics (PK) of nivolumab was studied in subjects over a dose range of 0.1 to 
20 mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. 
Based on a population pharmacokinetic (PPK) analysis using data from patients with various 
tumor types, including melanoma, NSCLC, and RCC and a time varying CL model, nivolumab 
clearance was shown to decrease over time, with a median maximal reduction from baseline 
values of approximately 25% resulting in a geometric mean steady state clearance (CLss) 
(% coefficient of variation [CV%]) of 8.2 mL/h [53.9%]. The decrease in CLss is not considered 
to be clinically relevant. The geometric mean [CV%] volume of distribution at steady state (Vss) 
is 6.8 L (27.3%), and elimination half-life (t1/2) is 25 days (77.5%). Steady-state concentrations 
of nivolumab were reached by approximately 12 weeks when administered at 3 mg/kg every 2 
weeks, and systemic accumulation was approximately 3.7-fold. The exposure to nivolumab 
increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 
weeks. The clearance of nivolumab increased with increasing body weight. The PPK analysis 
suggested that the following factors had no clinically important effect on the CL of nivolumab: 
age (29 to 87 years), gender, race, baseline LDH, PD-L1 status, solid tumor type, baseline tumor 
size, and hepatic impairment. 
The effect of renal impairment on the CL of nivolumab was evaluated in subjects with mild 
(GFR < 90 and ≥ 60 mL/min/1.73 m2; n=379), moderate (GFR < 60 and ≥ 30 mL/min/1.73 m2; 
n=179), or severe (GFR <30 and ≥ 15 mL/min/1.73 m2; n=2) renal impairment compared to 
subjects with normal renal function (GFR ≥ 90 mL/min/1.73 m2; n=342) in the PPK analysis. No 
clinically important differences in the CL of nivolumab were found between subjects with mild 
or moderate renal impairment and subjects with normal renal function. Data from subjects with 
severe renal impairment are too limited to draw conclusions on this population [45]. 
 
1.3.6.2.2 Safety Summary of Nivolumab 
Overall, the safety profile of nivolumab monotherapy as well as combination therapy is 
manageable and generally consistent across completed and ongoing clinical trials with no 
maximum tolerated dose (MTD) reached at any dose tested up to 10 mg/kg. There was no pattern 
in the incidence, severity, or causality of AEs to the nivolumab dose level. Most AEs were low- 


 
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grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. Most high-grade 
events were manageable with the use of corticosteroids or hormone replacement therapy 
(endocrinopathies) as instructed in the management algorithms provided in the Nivolumab 
Investigator’s Brochure. 
 
A total of 39 and 306 patients with selected recurrent or treatment-refractory malignancies have 
been treated in a completed Phase 1 single-dose study (CA209001) and an ongoing Phase 1 
multi-dose study (CA209003), respectively. As the safety profile from CA209003 to date is 
consistent with that observed for CA209001, only data from the larger and more recent study, 
CA209003, are presented below. 
 
In CA209003 (n=306, including 129 patients with NSCLC), as of the 05-Mar-2013 database 
lock, drug-related AEs of any grade occurred in 75% of patients. The most frequent drug-related 
AEs occurring in at least 5% of patients included fatigue (28%), rash (15%), diarrhea (13%), 
pruritus (11%), nausea (9%), decreased appetite (9%), decreased hemoglobin (6%), and pyrexia 
(6%). The majority of events were low grade, with Grade 3/4 drug-related AEs observed in 17% 
of patients. The most common Grade 3/4 drug-related AEs occurring in at least 1% of patients 
were fatigue (2%), pneumonitis (1%), diarrhea (1%), abdominal pain (1%), hypophosphatemia 
(1%), and lymphopenia (1%). Drug-related SAEs occurred in 14% of patients; 8% were Grade 
3/4 including pneumonitis (1%) and diarrhea (1%). The spectrum, frequency, and severity of 
drug-related AEs were generally similar across the dose levels tested. A review of the safety data 
by tumor type (RCC, NSCLC, metastatic castration-resistant prostate cancer [mCRPC], 
colorectal cancer [CRC], and melanoma) also did not show any clinically meaningful differences 
in the proportion of patients with AEs noted across tumor type. 
 
Select AEs with potential immune-related causality, previously termed “immune-related adverse 
events” or “adverse events of special interest” were also analyzed taking into account multiple 
events, with rates adjusted for treatment duration. Most events occurred within the first 6 months 
of therapy; cumulative or novel toxicities were not observed with prolonged drug exposure. 
Nineteen of 306 patients (6%) experienced Grade 3/4 treatment-related select AEs. Fifty-two of 
230 patients (23%) with drug-related AEs required management with systemic glucocorticoids 
and/or other immunosuppressive agents. Twenty-one of 52 (40%) resumed nivolumab therapy 
after toxicity resolved, while the others discontinued therapy. 
 
Although tumor progression was the most common cause of mortality, there were 3 drug-related 
deaths associated with Grade 3/4 pneumonitis. Pneumonitis (any grade) occurred in 12 of 
306 patients (4%), and Grade 3/4 pneumonitis occurred in 4 patients (1%), with clinical 
presentations ranging from asymptomatic radiographic abnormalities to progressive, diffuse 
pulmonary infiltrates associated with cough, fever, and/or dyspnea. No clear relationship 
between the occurrence of pneumonitis and tumor type, dose level, or treatment duration was 
noted. In 9 of 12 patients, pneumonitis was reversible after treatment discontinuation and/or with 
immunosuppressive therapy (glucocorticoids, infliximab, or mycophenolate). 


 
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Additional details on the safety profile of nivolumab, including results from other clinical 
studies, are also available in the nivolumab IB and Opdivo® package insert [45]. 
 
1.3.6.3 APX005M 
 
1.3.6.3.1 Clinical Pharmacology Summary of APX005M 
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 [73]. 
 
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 [64]. These data suggest that APX005M, as a single agent, 
can induce potent growth inhibition of CD40-expressing human tumors. 
 
Preliminary human data shows that APX005M induces a dose-dependent activation of APCs (as 
demonstrated by increases in expression of activation markers such as CD54, CD70, CD80, 
CD86, HLA-DR), T cell activation and increases in circulating levels of IL12, INF-γ, TNF-α and 
IL6. 
 
1.3.6.3.2 Pharmacokinetics of APX005M 
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) [16]. Based on these results, the no observed adverse effect level 
(NOAEL) was considered 30 mg/kg. 
 
There are limited human PK data with APX005M at this time. Exposures to APX005M at dose 
levels of 0.03 mg/kg or less were for the most part below the limit of quantitation (BLOQ). IV 
administration of APX005M at doses between 0.1 and 1 mg/kg lead to rapid increase in serum 
concentrations, reaching a maximum just after the end of the infusion. Levels declined rapidly 
thereafter and were for the most part BLOQ between 24 and 168 hours after the start of dosing. 


 
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Increases in the dose of APX005M (0.1 mg/kg to 1 mg/kg) led to approximately dose- 
proportional increases in maximum serum concentration (Cmax) and area under the curve at the 
last measurable time point (AUC0–t). No accumulation of APX005M was observed with every 
21 days dosing. 
 
1.3.6.3.3 Safety Summary of APX005M 
Study APX005M-001 is a first in human phase 1 dose escalation study of APX005M with 8 pre- 
planned dose levels. APX005M was administered to study subjects at doses up to 1 mg/kg. At 
the 1 mg/kg dose level, 1 out of 6 dose limiting toxicity (DLT)-evaluable subjects experienced a 
DLT (grade 4 cytokine release syndrome). Two additional subjects at the 1mg/kg dose level 
experienced serious adverse events (SAE) in later cycles (Grade 3 cytokine release syndrome 
and Grade 4 thrombocytopenia). On May 2, 2016 Apexigen decided to discontinue dose 
escalation and enroll up to 6 subjects in dose level 0.6 mg/kg (originally designed as an 
intermediate de-escalation dose level) and an additional 3 subjects at the previously completed 
dose level 0.3 mg/kg to better characterize the safety and pharmacodynamics (PDn) of 
APX005M and to help establish the single agent recommended phase 2 dose (RP2D). The RP2D 
for APX005M as a single agent every 21 days is 0.3 mg/kg body weight. 
 
As of the data cutoff date of 14 April 2017, 432 AEs have been reported in the 30 subjects enrolled in 
Study APX005M-001. The majority of AEs (371/432 [85.9%]) were mild or moderate (≤ Grade 2) in 
severity, 44 events (10.2%) were reported as Grade 3, and 8 events (1.9%) were reported as Grade 4. 
No Grade 5 events have been reported. 
 
As of 14 August 2017, 17 SAEs had been reported in 6 subjects. With the exception of cytokine 
release syndrome and thrombocytopenia, all SAEs were considered unrelated to APX005M. 
Cytokine release syndrome is an expected on-target side effect of CD40 agonists. No 
thromboembolic or bleeding events have been reported to date for APX005M. 
 
APX005M demonstrated a dose-dependent activation of APCs (as demonstrated by increases in 
expression of activation markers such as CD54, CD70, CD80, CD86, HLA-DR), T cell 
activation and increases in circulating levels of IL12, INF-γ, TNF-α and IL6. 
 
For further details on the APX005M-001 study please refer to latest version of the APX005M 
Investigator’s Brochure [64]. 
 
Symptoms associated with cytokine release syndrome (including but not limited to flushing, 
itchiness, chills, fever, rash, tachycardia, hypotension, hypertension, rigor, and myalgia) after 
administration of APX005M are possible and have been observed in some of the subjects 
receiving APX005M. Guidance for monitoring and management of cytokine release syndrome 
are included in this protocol and in the APX005M Investigator’s Brochure. 
 
Transient transaminase elevations (≤ Grade 2) have been observed in several subjects with liver 
metastases, which were not associated with a particular dose of APX005M. Six subjects with 


 
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liver metastases enrolled in the study experienced a transient increase in total bilirubin. Liver 
function test abnormalities tend to resolve to baseline within 7 days from APX005M 
administration. 
 
Transient decreases in peripheral blood lymphocyte count in general and B-cell count in 
particular have been observed for APX005M as well as for other CD40-agonistic mAbs and are 
believed to be a PDn effect. Transient decreases in platelet counts were observed for some of the 
subjects receiving higher doses of APX005M but were not associated with bleeding or other 
clinical manifestations. 
 
Other symptoms might also occur, including allergic reactions, which could be severe, 
pulmonary edema, and rarely, thromboembolic events, myocardial infarction and/or death. 
In the 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 1mg/kg body weight 
suggest a best in class profile for APX005M and the possibility of a safe and tolerable 
combination with other immunomodulatory antibodies such as nivolumab. 
 
1.4 
Clinical Experience Involving Serum Enzyme Elevations 
 
The safety and preliminary efficacy of cabiralizumab is currently being evaluated in 3 clinical 
trials. A common feature observed across the clinical trials is an elevation of AST, CK, and LDH 
after the administration of cabiralizumab. These alterations are the consequence of the direct 
effect of anti-CSF1R antibodies on the Kupffer cell in the liver that results in a depletion of these 
cells. Depletion of Kupffer cells allows the enzymes, which are released following normally 
occurring liver cell turnover, to enter circulation (where they are measured by routine laboratory 
assessment) rather than being absorbed by the Kupffer cells. Elevated liver enzymes, thus, 
represent a PD marker rather than a safety signal. The observed elevations were asymptomatic 
not permanent and not associated with clinical sequelae. Similar effects have been observed 
across other CSF1R targeted agents (see cabiralizumab IB for additional details). There is a 
significant body of evidence from the cabiralizumab preclinical and clinical experience as well 
as from others in the field that suggest elevations of serum enzymes caused by inhibition of the 
CSF1R pathway are reversible and are not associated with clinical sequelae [66, 74-78]. 
 
1.4.1 Serum Enzyme Elevations with Cabiralizumab 
In Study FPA008-003, 34 subjects have been dosed as part of Phase 1a dose escalation (24 in 
cabiralizumab monotherapy and 10 in cabiralizumab + nivolumab combination therapy) and 195 
subjects have been dosed as part of Phase 1b dose expansion as of 1 August 2017. In Phase 1a, 
CK was elevated in 11 of 34 subjects (32%), and 3 events (1%) were Grade 3 or higher. AST 
was elevated in 16 of 34 subjects (47%), and 10 events (29%) were Grade 3 or higher. ALT was 
elevated in 4 of 34 subjects (17%), and none of these were Grade 3 or higher. In Phase 1b, CK 
was elevated in 82 of 195 subjects (42%), and 29 events (15%) were Grade 3 or higher. AST was 
elevated in 76 of 195 subjects (39%), and 14 events (7%) were Grade 3 or higher. ALT was 


 
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elevated in 39 of 195 subjects (20%), and five events (3%) were Grade 3 or higher. 
The serum enzyme elevations for Studies FPA008-001 and FPA008-002 follow a similar pattern. 
 
Please refer to the cabiralizumab IB for more detailed information about these serum enzyme 
elevations. 
 
1.4.2 Serum Enzyme Elevations with Nivolumab 
 
The hepatic enzyme changes caused by cabiralizumab and nivolumab are due to different 
mechanisms that should not be additive. For cabiralizumab, the elevations are hypothesized to be 
due to the on-target effect of Kupffer cell reduction and not to liver cell toxicity. Hepatic AEs, 
including possible drug induced liver injury (DILI) cases, have been managemable using an 
established management algorithm and thus do not meaningfully alter the benefit/risk of 
nivolumab in the advanced malignancy populations.  Guidelines for management and safety 
assessments focused on the liver can be found in Section 4.8 and Section 4.9. 
 
1.4.3 Serum Enzyme Elevations in APX005M 
Transient transaminase elevations (≤ Grade 2) with APX005M administration have been 
observed in several subjects with liver metastases, which were not associated with a particular 
dose of APX005M. Six subjects with liver metastases enrolled in the study experienced a 
transient increase in total bilirubin. Liver function test abnormalities tend to resolve to baseline 
within 7 days from APX005M administration. Elevations of ALT, AST, CK, and LDH were not 
associated with signs or symptoms of hepatic or muscle injury as demonstrated by concurrent 
normal total bilirubin, INR, aldolase, and troponin levels. 
 
Please refer to the APX005M Investigator’s Brochure for more detailed information about serum 
liver ezyme elevations and their management, as outlined in Section 4.8 and Section 4.9. 
Additional laboratory abnormality management algorithms are included to help manage 
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2. 
Objectives 
2.1 
Phase 1a Objectives 
 
2.1.1 Primary 
• To assess the safety and tolerability of APX005M in combination with cabiralizumab 
• To assess the safety and tolerability of APX005M in combination with cabiralizumab and 
nivolumab 
• To determine the recommended RP2D of APX005M in combination with a fixed dose of 
cabiralizumab and nivolumab in advanced melanoma, NSCLC, and RCC 
 
2.1.2 Secondary 
• To determine the AE profile of this combination 
 
2.1.3 Exploratory 
 
• To characterize the pharmacokinetic (PK) profile of APX005M when administered in 
combination with cabiralizumab and nivolumab 
• To characterize the pharmacodynamic (PD) profile of APX005M when administered in 
combination with cabiralizumab and nivolumab 
• To further characterize the PD profile and immunogenicity of APX005M in combination 
with cabiralizumab and nivolumab by analyses of pre-treatment and on-treatment tumor 
biopsies and blood collection 
 
2.2 
Phase 1b Objectives 
 
2.2.1 Primary 
• To determine the objective response rate (ORR) using RECIST v1.1 to APX005M in 
combination with cabiralizumab and nivolumab in 3 separate patient cohorts: advanced 
melanoma, NSCLC, and RCC whose tumors are resistant to anti-PD-1/PD-L1 therapy 
• To evaluate the safety and tolerability of the RP2D of APX005M in combination with 
cabiralizumab and nivolumab 
 
2.2.2 Secondary 
• To determine the PFS of patients with melanoma, NSCLC or RCC treated with 
APX005M in combination with cabiralizumab and nivolumab whose tumors are 
resistant to anti-PD-1/PD-L1 therapy. 
• To determine the OS of patients with melanoma, NSCLC or RCC treated with 
APX005M in combination with cabiralizumab and nivolumab whose tumors are 
resistant to anti-PD-1/PD-L1 therapy. 
• To assess the association of selected biomarker measures and clinical efficacy 
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2.2.3 Exploratory 
• To identify immune correlates that are associated with clinical response or resistance to 
the triple combination. Biomarker analyses will include study of pre-treatment and on- 
treatment biopsies as well as analyses of select serum and PBMC markers. 


 
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3. 
Investigational Plan 
3.1 
Study Design and Duration 
This study is a Phase 1/1b, open-label, single institution, dose escalation and dose expansion 
study to evaluate the efficacy, safety, and tolerability of APX005M in combination with 
nivolumab and cabiralizumab in patients with advanced melanoma, NSCLC, and RCC. 
Nivolumab is a fully human monoclonal antibody directed against PD-1. Cabiralizumab is a 
humanized monoclonal antibody directed against CSF1R. APX005M is a humanized IgG1 
agonistic monoclonal antibody that binds CD40. 
 
Patients will be sequentially enrolled in the phase 1 dose escalation portion in 6 cohorts using a 
standard 3 + 3 design to determine safety, characterize the adverse events, and establish the 
MTD of APX005M in combination with cabiralizumab and nivolumab. A minimum of 48 hours 
observation will be required after each patient is enrolled in cohorts 1-6, before a subsequent 
patient can be enrolled. Approximately 3 patients will be enrolled into each cohort. Cohorts 1, 3, 
and 5 will include cabiralizumab at the fixed RP2D of 4 mg/kg and dose escalation of 
APX005M.  Cohorts 2, 4, and 6 will include nivolumab at 240 mg, cabiralizumab at 4 mg/kg, 
and dose escalation of APX005M. 
 
All study drugs will will be given on Day 1 of each 14-day treatment cycle.  Pre-medications will 
be given before nivolumab.  Nivolumab will be administered as an IV infusion over 30 minutes 
first followed by a 30-minute break and then cabiralizumab will be administered as an IV 
infusion over 30 minutes. After another 30-minute break, APX005M will be administered as an 
IV infusion over 60 minutes.  Patients must remain near the vicinity of a hospital with rapid 
access to an intensive care unit setting during the initial 48 hour period after treatment for the 
first two treatment cycles. 
 
Dose escalation will be based on the number of DLTs experienced during the DLT evaluation 
interval as determined by the PI and Industry Collaborators (see Section 3.1.2.1.1 for DLT 
criteria). The DLT evaluation interval begins on the first day of treatment and continues for 28 
days. 
 
The phase 1b portion will enroll patients in three cohorts (advanced melanoma, NSCLC, and 
RCC) to study the RP2D of APX005M in combination with nivolumab and cabiralizumab. 
 
3.1.1 Screening Period 
All screening evaluations must be completed and reviewed by the Investigator for the enrollment 
process to confirm that patients meet all eligibility criteria before the first infusion of study drug. 
Written informed consent for participation in the study must be obtained before performing any 
study specific screening tests or procedures. Screening assessments will be performed within 28 
days prior to the first dose of study drug unless otherwise specified. 
 
The Investigator may repeat qualifying lab tests and vitals/ECGs prior to enrollment if a non- 
qualifying finding is considered an error or an acute finding is likely to meet eligibility criteria 
upon repeat testing. 
 


 
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Study procedure-related AEs that occur after signing of the ICF and before administration of the 
first study drug dose will be collected during this period. 
 
3.1.2 Treatment Period 
 
3.1.2.1 Phase 1 Cohorts and Combination Dose Escalation Cohorts 
Phase 1 consists of three dose escalation cohorts of APX005M in combination with 
cabiralizumab alone, and three dose-escalation cohorts of APX005M in combination with 
nivolumab and cabiralizumab.  A minimum of 3 patients will be enrolled in each cohort. The 
planned dose levels and schedules for the Phase 1 dose escalation cohorts are as follows in Table 
2: 
Table 2 
 
Cohort 
Nivolumab 
(mg) 
Cabiralizumab 
(mg/kg) 
APX005M 
(mg/kg) 
1 
Not given 
4 
0.03 
2 
240 
4 
0.03 
3 
Not given 
4 
0.1 
4 
240 
4 
0.1 
5 
Not given 
4 
0.3 
6 
240 
4 
0.3 
 
A minimum of 48 hours observation will be required after each patient is enrolled in cohorts 1-6, 
before a subsequent patient can be enrolled. As depicted in Figure 6, accrual to cohorts 2 and 3 
will only start after the last patient in cohort 1 has been observed for toxicity for at least two 14- 
day cycles (28 days in total); accrual to cohort 4 will commence when the last patients on cohorts 


 
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2 and 3 have been observed for at least two 14-day cycles, accrual to cohort 5 will commence 
only after the last patient on cohort 3 has been observed for at least two 14 day cycles, and 
accrual to cohort 6 will accrue once the last patients on cohorts 4 and 5 have been observed for at 
least two 14-day cycles. Doses will be de-escalated as determined by toxicities. 
 
Figure 6 
 
 
 
All dose escalation decisions will be based on assessment of toxicity, overall safety, and 
tolerability. Dose escalation decisions will be agreed upon by the PIs and study collaborators. 
Prior to initiating each new dose level or expanding an existing dose level, a safety 
teleconference will be held wherein the PIs and study collaborators will review patient data, 
including but not limited to the available demographics, dosing, concomitant medications, 
hematology, serum chemistry, and AEs; and confer and document agreement that dose escalation 
or expanding an existing dose level is considered appropriate. If the PIs collectively agree, 
following review of safety, PK, and PD data (if available), that a different dose escalation 
scheme should be used than the one outlined, this will be permitted. Review of safety, PK, and 
PD profiles may inform decisions to add cohorts with alternative dose levels or dose regimens 
(e.g., less frequent dosing) in order to reach an optimal target exposure. 
 
For the purpose of dose escalation, we will require a 28 day observation period from the 
time the last patient in a given cohort was treated. For the purpose of calculating the MTD, 
we will require a minimum of 28 days of observation for each patient. 
 
Dose escalation in Phase 1 will proceed as follows: 


 
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If none of the first 3 evaluable patients in a dose cohort experience a DLT in the first two cycles, 
then the next 3 patients will be treated at the next higher dose cohort.  If 1 of 3 patients within a 
cohort experiences a DLT in the first two cycles, then 3 additional patients will be added to that 
cohort.  If a second patient experiences a DLT at that dose level in the first two cycles, the next 
cohort will not be initiated, and the dose of one or more drugs will be de-escalated. Patients at 
each dose level will be evaluated for at least 28 days from the start of treatment before additional 
patients can be treated at a higher dose level.  If DLTs are observed in 2 or more patients within 
a cohort, the maximum tolerated dose (MTD) will have been exceeded and no further patients 
will be treated at that dose level. 
 
DLT evaluation and enrollment decisions will follow the guidance in Table 3. 
 
Table 3: Algorithm for Dose-Escalation Decisions 
 
Number of 
Patients with 
DLT at a Given 
Dose Level 
Dose Escalation Decision Rule 
0/3 
Escalation will occur into the next highest dose 
cohort 
1/3 
Enroll 3 additional patients at current dose level 
>2/3 
Stop enrollment.  Enroll 3 more patients at the lower 
dose level, if only 3 were previously entered, or at 
an intermediate dose level. 
1/6 
Open next cohort 
>2/6 
Stop enrollment.  Enter 3 more patients at the lower 
dose level at an intermediate dose level. 
 
 
Dose escalation will continue until either the MTD or maximum planned dose of APX005M is 
reached, with a minimum of 3 patients enrolled in each cohort. 
 
The MTD is defined as the highest dose associated with DLTs in less than or equal to 33% of 
patients receiving APX005M in combination with cabiralizumab or with cabiralizumab and 
nivolumab, administered during the DLT period. This will normally be the dose recommended 
for further study; however, based on review of safety, PK, and PD (if available) data, the RP2D 
could be lower than the MTD. If the MTD is not reached, and the highest evaluated APX005M 
dose in combination with cabiralizumab and nivolumab is well tolerated, the data will be 
reviewed to assess whether further dose escalations of APX005M are warranted. 
 
In order to calculate the MTD and RP2D, every patient included in this calculation must have 
received at least 2 doses of study drugs and have been monitored for at least 2 full cycles (28 
days).  If a patient does not receive 2 doses of study drugs and does not complete safety 
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related AEs (e.g., disease progression or withdrawal of consent), then an additional patient will 
be enrolled into the cohort so that the cohort has at least 3 patients evaluable for 28 days. All 
such discussions and decisions will be documented as part of the dose escalation decision- 
making process. 
 
3.1.2.1.1  Dose Limiting Toxicity 
A DLT is defined as any of the following AE (graded using National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] v5.0), which occurs during the first 
28-days of cabiralizumab/APX005M or nivolumab/cabiralizumab/APX005M administration 
that is not clearly due to a cause other than the study medication (e.g., disease under study, car 
accident). 
 
1. Grade 4 neutropenia or grade 4 thrombocytopenia lasting ≥ 7 days 
2. Neutropenic fever of any duration 
3. Grade > 3 thrombocytopenia if associated with: 
a. Clinically significant bleeding or requirement for platelet transfusion, or 
b. A life-threatening bleeding event which results in urgent intervention and admission to 
an Intensive Care Unit 
4. Any grade ≥3 non-hematologic toxicity (not laboratory) with the exception of: 
• Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor) 
• Grade 3 joint pain 
• Grade 3 fatigue lasting less than 1 week 
• Serum elevations of CK > 15X ULN and < 20X ULN that last for < 7 days 
• Grade 3 or Grade 4 electrolyte abnormalities that are not complicated by associated 
clinical adverse experiences, last less than 72 hours and either resolve spontaneously 
or respond to conventional medical intervention 
• Grade 3 nausea, vomiting, or diarrhea lasting less than 72 hours, and either resolves 
spontaneously or responds to conventional medical intervention including adequate 
anti-emetics or other supportive care 
• Grade 3 or grade 4 elevation of amylase or lipase not associated with clinical or 
radiographic evidence of pancreatitis 
• Grade 3 fever not associated with hemodynamic compromise (eg, hypotension, 
clinical or laboratory evidence of impaired end-organ perfusion) 
• Grade 3 endocrinopathy that is well controlled by hormone replacement 
• Grade 3 infusion reaction that returns to Grade 1 in < 6 hours 
 
 
5. Any Grade ≥ 3 non-hematologic laboratory value if: 
a. Immune suppression other than corticosteroids is required to treat the subject, or 
b. The abnormality itself soley leads to hospitalization, or 
c. The abnormality persists for >1 week. For AST/ALT > 12x ULN, DLT is defined as 
not improving after >7 days or the value increases by more than 5X ULN over 72 hours; 


 
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e.g. if an AST of 300 rises to 500 in 72 hours, where AST 36 is ULN, a rise of 200 is 
greater than 5X ULN (180) and would be considered a DLT 
6. Any Grade ≥ 3 AST/ALT elevation combined with total bilirubin >2x ULN (for patients with 
Gilbert’s syndrome, use bilirubin > 2X baseline) or INR > 1.5 not on warfarin 
7. 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) 
8. Any death not clearly due to the underlying malignancy or extraneous causes (e.g. car accident) 
9. Recurrence of Grade 4 rash, or other Grade 3 immune-related AE (irAE), or Grade 4 infusion- 
related AE. Recurrent grade 3 infusion reactions should be discussed with the study PI. 
10. Any toxicity requiring  dose  reduction  of  APX005M  or  permanent discontinuation of 
any of the study drugs. 
 
irAE is defined as a clinically significant AE that is associated with study drug exposure, with the 
exception of AEs related to cytokine release, attributable to APX005M, and is consistent with   
an immune-mediated mechanism. 
 
 
Certain toxicities, even if already resolved, will make it unacceptable to advance to subsequent 
cohorts as planned, including but not limited to: 
 
• Grade 4 myocarditis; Grade 3 myocarditis will need to be discussed with the study PI 
• Grade 3 neurotoxicity with the exception of peripheral neuropathy 
• Grade 4 pneumonitis 
• Bone marrow aplasia 
 
 
3.1.2.2 Phase 1 Dose Escalation Extended Treatment Period 
 
Patients from the Phase 1 dose escalation combination cohorts are allowed to continue to receive 
APX005M in combination with nivolumab and/or cabiralizumab at the same dose levels until 
disease progression, unacceptable toxicity, or other reason for treatment discontinuation. 
 
If a complete response (CR) is achieved, patients will be allowed to continue on therapy until 
disease progression, unacceptable toxicity, or other reason for treatment discontinuation. 
 
3.1.2.3 Phase 1b Expansion Cohorts 
To further characterize safety and efficacy of APX005M in combination with nivolumab and 
cabiralizumab, Phase 1b will enroll patients of 3 advanced cancer types: melanoma, NSCLC, and 
RCC. Enrollment in Phase 1b will begin when an RP2D for APX005M has been identified based 
on overall safety, tolerability, PK, and PD (if available) data. 
 
During enrollment of any expansion cohort, if the observed number of responses makes it 
unlikely to achieve a target response rate for that indication, then further recruitment to that 
cohort may be suspended or terminated. 
 
3.1.3 End-of-Treatment Follow-up Period 


 
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All patients should return to the clinic 28 (±7) days and 100 (±7) days from their last dose of 
study drug to complete the End-of-Treatment Follow-up Period, irrespective of whether a patient 
is discontinued from the study drug at a planned visit or mid-cycle. AEs will be assessed until 
resolution, return to baseline, or are stabilized per treating Investigator’s assessment. Adverse 
event reporting will continue until 100 (±7) days after the last dose of study drug or until 
initiation of subsequent anti-cancer therapy. 
 
3.1.4 Long-Term Follow-up 
Patients should continue onto Long-Term Follow-up after completing the End-of-Treatment 
Follow-up Period. 
 
Patients will be followed every 12 weeks for survival, or more frequently as needed. Patients 
who discontinue treatment while showing clinical benefit (CR, partial response [PR], or stable 
disease [SD]) should have tumor assessments during these visits for duration of response. 
 
Long-term Follow-up for survival may be conducted by telephone, rather than by an in-person 
visit, once tumor progression is determined or use of subsequent anti-cancer therapy has been 
initiated. During the Long-Term Follow-up Period, if the patient undergoes local therapy (e.g., 
resection, radiation) or new systemic therapy is initiated, this should be documented. 
 
3.1.5 Study Duration 
Patients who receive study drug(s) may continue as long as they experience clinical benefit in the 
opinion of the Investigator or until unacceptable toxicity or symptomatic deterioration attributed 
to disease progression as determined by the Investigator after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status, or withdrawal of consent. The 
maximum time allowed time on study treatment will be up to 2 years unless the study is 
terminated sooner by the Sponsor. 
 
3.1.6 Stopping Rules 
 
3.1.6.1 Stopping Rules for All Cohorts 
Management of drug-related toxicities and laboratory abnormalities will follow the guidelines 
outlined in Section 4.8 and Section 4.9. 
 
The Sponsor will discuss such cases with the Industry Collaborators as appropriate to determine 
further enrollment. IRBs may be notified by the Sponsor of all cases and decisions regarding 
continued enrollment, according to applicable regulatory requirements or institution procedures. 


 
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3.1.6.2 Treatment Beyond Progression 
Accumulating clinical evidence indicates that the emergence of objective responses to agents that 
activate anti-tumor immune responses may follow delayed kinetics of weeks or months, and can 
be preceded by initial apparent progression of disease with the appearance of new lesions or 
some enlarging of lesions while certain index lesions are regressing (“mixed response”). 
Therefore, it is reasonable to allow patients who experience apparent progression to continue to 
receive treatment until progression is confirmed at the next imaging assessment. These 
considerations should be balanced by clinical judgment as to whether the patient is clinically 
deteriorating and unlikely to receive any benefit from continued treatment. 
 
Such deterioration will be assessed to have occurred after a clinical event that, in the 
Investigator’s opinion, is attributable to disease progression and is unlikely to reverse with 
continued study treatment and therefore indicates that the patient is not benefiting from study 
treatment and cannot be managed by the addition of supportive care. The decision to continue 
treatment should be discussed with the PI. 
3.2 
Study Population 
3.2.1 Planned Number of Patients 
 
In the Phase 1 dose escalation portion of the trial, we will enroll at least 3 patients per cohort. 
There are a total of 6 cohorts.  In the Phase 1b portion, a Simon two stage design will be used. 
At least 13 patients per each disease cohort (advanced melanoma, NSCLC, and RCC) will be 
enrolled in the first phase and in the second phase, an additional 21 patients per disease cohort, 
for a maximum of 34 patients per disease cohort, are expected to be enrolled, for a total of 102 
subjects. 
 
3.2.2 Inclusion Criteria for All Cohorts 
1. Biopsy proven metastatic melanoma, NSCLC or RCC whose disease has progressed on 
anti-PD(L)-1 therapy without any intervening therapy. Progression will be determined by the 
investigator based on clinical and/or radiographic features.  Additional requirements as 
below: 
 
Melanoma: 
• Unresectable stage III or stage IV melanoma, irrespective of BRAF status, 
with histologic or cytologic confirmation 
 
RCC:  
• Histologic or cytologically documented, locally advanced unresectable or 
metastatic RCC irrespective of histologic subtype 
 
NSCLC: 
• Histologic or cytologically documented, locally advanced or metastatic (i.e. 
Stage IIIB not eligible for definitive chemoradiotherapy, stage IV, or 
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• Patients known to harbor an ALK rearrangement or EGFR mutation known to 
be sensitive to FDA-approved tyrosine kinase inhibitors (TKI), are only 
eligible after experiencing disease progression (during or after treatment) or 
intolerance to an FDA approved ALK TKI or EGFR TKI, respectively. 
• Patients with TKI-treated EGFR mutant NSLC harboring the secondary 
EGFR T790M tumor must have received prior osimertinib. 
• Patients with crizotinib-treated ALK rearranged NSCLC must have received a 
next generation ALK inhibitor. 
 
2. At least 1 site of disease must be accessible to provide repeat biopsies for tumor tissue. 
This site may be a target lesion as long as it will not be made unmeasurable by the biopsy 
procedure. Subjects may forgo the pretreatment biopsy if 1) an entire archival FFPE tumor 
block is available that was taken after the last systemic therapy was administered or 2) if 
the Investigator deems that the subject does not have tumor in a site that is amenable to 
biopsy. 
 
3. Age ≥18, able to understand and sign the informed consent form 
 
4. ECOG performance status < 2 
 
5. Any number of previous treatments. Other prior systemic therapies must have been 
administered at least 4 weeks before administration of the study drugs; the exception to 
this is molecular targeted therapies which must have been administered at least 2 weeks 
prior to the start of the study drugs or after 5 half-lives have occurred, whichever is shorter. 
 
6. Life expectancy of at least 6 months 
 
7. A history of previously treated brain metastases is allowed, provided that they are stable 
for at least 4 weeks. 
 
8. Willingness to undergo mandatory tumor biopsy prior to initiation of therapy and before 
the fifth cycle. 
 
9. Willingness to provide an archival specimen block, if available, for research. 
 
10. Patients must have normal organ and marrow function as defined below: 
 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
≤1.5 X upper limit of normal (ULN) OR 
≥50 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 


 
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creatinine or CrCl) 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
11. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 24 hours prior to receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
12. Female subjects of childbearing potential should be willing to use a highly effective contraception 
(hormonal or IUD) or be surgically sterile, or abstain from heterosexual activity for a period of at 
least 5 months after the last dose of study drug. Subjects of childbearing potential are those who 
have not been surgically sterilized or have not been free from menses for > 1 year. 
 
13. Male subjects should agree to use an adequate method of contraception starting with the first dose 
of study therapy through at least 7 months after the last dose of study drug. 
 
14. Patients must have at least one measurable lesion at baseline by computed tomography 
(CT) or magnetic resonance imaging (MRI) as per RECIST v1.1 criteria. 
 
a.   Tumor sites situated in a previously irradiated area, or in an area subjected to other 
loco-reginal therapy, are not considered measurable unless there has been demonstrated 
progression in the lesion. 
15. Prior focal radiotherapy must be completed before first dose of study drug administration, 
although palliative radiation may be allowed on treatment (see permitted concomitant 
therapies below). Radiation to pulmonary or intestinal sites must be completed at least 4 
weeks prior to study Day 1. There is no time restriction prior to study Day 1 for patients 
who have received radiation to bone, soft tissue sites or other sites. No 
radiopharmaceuticals (strontium, samarium) within 8 weeks before first dose of study drug 
administration. 
 
16. Major surgery must be completed at least 4 weeks before first dose of study drug 
administration. Surgery requiring local/epidural anesthesia must be completed at least 72 
hours before first dose of study drug administration and patients should have recovered. 
Surgical wounds must be healed. 
 
3.2.3 Exclusion Criteria for All Cohorts 
Patients who meet ANY of the following criteria will be excluded from study entry. 


 
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1. Untreated brain metastases. 
 
2. A patient who has had prior immune therapy or chemotherapy within 4 weeks prior to study 
Day 1, or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent will be excluded. Patients who have had prior molecular 
targeted therapy using small molecule inhibitors must have received their last dose no less 
than 2 weeks prior to or no less than five half-lives from study Day 1. 
a. Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy. 
b. Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the inclusion 
requirements for laboratory parameters. 
 
3. Has had prior treatment with any other CSF1R inhibitor or CD40 agonist. 
 
4. Use of corticosteroids to control immune related adverse events at enrollment will not be 
allowed, and patients who previously required corticosteroids for symptom control must be 
off steroids for at least 2 weeks.  Low-dose steroid use (≤10 mg of prednisone or equivalent) 
as corticosteroid replacement therapy for primary or secondary adrenal insufficiency is 
allowed. 
 
5.   Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to prior treatments 
with the exception of clinically insignificant adverse events such as alopecia, clinically 
insignificant laboratory abnormalities, clinically insignificant rash and Grade 2 neuropathy.  
 
6. History of grade 3-4 neurologic or cardiac toxicity or life-threatening liver toxicity poorly 
responsive to steroids with prior anti-PD-1/anti-PDL1 monotherapy. 
 
7. Presence of leptomeningeal disease. 
 
8. Has active autoimmune disease unrelated to immune checkpoint inhibitors that has required 
systemic treatment in the past year (i.e. with use of disease modifying agents, corticosteroids 
or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
 
9. Pregnancy or breast feeding.  Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her treating physician immediately. 
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with nivolumab, cabiralizumab or APX005M, 
breastfeeding must be discontinued if the mother is enrolled on this trial. 
 
10. Patients may not be receiving any other investigational agents and may not have participated 
in a study of an investigational agent or using an investigational device within 4 weeks of the 
first dose of treatment. 
 
11. Patients with either a concurrent medical condition (including medical illness, such as active 
infection requiring treatment with intravenous antibiotics or the presence of laboratory 


 
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abnormalities) or history of a prior condition that places the patient at unacceptable risk if 
he/she were treated with the study drug or a medical condition that confounds the ability to 
interpret data from the study. 
 
12. Concurrent, active malignancies in addition to those being studied (other than cutaneous 
squamous cell carcinoma or basal cell carcinoma) 
 
13. Active (non-infectious) pneumonitis. 
 
14. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C 
(HCV) acute or chronic infection. 
 
15. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
 
16. History of myocardial infarction or unstable angina within 3 months prior to Cycle 1, Day 1 
 
17. Prisoners, or subjects who are under compulsory detention 
 
18. Current or history of clinically significant muscle disorders (e.g., myositis), recent 
unresolved muscle injury, or any condition known to elevate serum CK levels 
 
19. History of anti-drug antibodies, severe allergic, anaphylactic, or other infusion-related 
reaction to a previous biologic agent 
 
20. Concomitant use of statins on study. However, a patient using statins for over 3 months prior 
to study drug administration and in stable status without CK rise may be permitted to enroll 
 
21. Open wounds and active skin infections 
 
22. Uveal melanoma in the Phase Ib dose expansion trial 
 
 
3.2.4 Women of Childbearing Potential 
Women of childbearing potential (WOCBP) include any females who have experienced 
menarche and who have not undergone surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy), and who are not post-menopausal. Post-menopause is 
defined as: 
• Amenorrhea ≥12 consecutive months without another cause, and a documented serum 
follicle stimulating hormone (FSH) level >35 mIU/mL, or 
• Women with irregular menstrual periods and a documented serum FSH level 
>35 mIU/mL (Note: FSH level testing is not required for women ≥62 years old with 
amenorrhea of ≥1 year), or 
• Women on hormone replacement therapy (HRT). 
 
Women who are using oral or other hormonal contraceptives, such as vaginal products, skin 
patches, or implanted or injectable products, or mechanical products, such as an intrauterine 


 
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device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or who are 
practicing abstinence or who have a sterile (e.g., vasectomy) partner should be considered to be 
of childbearing potential [79, 80]. 
 
3.3 
Concomitant Medications 
All medications taken within 28 days before the administration of the first dose of any study drug 
and all concomitant therapy administered during the study until 100 (±7) days after last dose of 
any study drug (or until initiation of subsequent anti-cancer therapy) will be collected. All 
subsequent anti-cancer therapy will be collected in the Long-Term Follow-up Period. 
 
Information on all prior treatments indicated for advanced cancer, including chemotherapy, 
biochemotherapy, immunotherapy, radiation, surgery, biologic, and experimental therapy will be 
collected. 
 
No concomitant medication information will be collected following patient discontinuation from 
the study except for concomitant medication use associated with study drug-related AEs or AEs 
that lead to discontinuation from the study. 
 
3.3.1 Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE or specified in the eligibility section): 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids 
• Vaccines except as noted in Section 3.3.2 
• Statins for treatment of hypercholesterolemia. Statins will be allowed only if the patient is 
on a stable dose for over 3 months prior to the study and has a stable status without any 
CK elevations 
• Other therapies including biologic, immunotherapy, extensive non-palliative radiation 
therapy, standard treatments, or investigational agents or devices 
 
3.3.2 Permitted Therapy 
Patients are permitted to use of topical, ocular, intra-articular, intranasal, and inhaled 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses >10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions 
(e.g., delayed-type hypersensitivity reaction caused by a contact allergen) and also for the 
treatment of tumor-related AE is permitted. 
 
Concomitant palliative and supportive care for disease-related symptoms (including 
bisphosphonates and RANK-L inhibitors) is allowed. Transfusions are permitted as needed. 


 
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The inactivated seasonal influenza vaccine can be given to patients while on therapy without 
restriction. Influenza vaccines containing live virus or other clinically indicated vaccinations for 
infectious diseases (i.e., pneumovax, varicella, etc.) must be discussed with the Investigators and 
Industry Collaborators.  In general, live vaccines are prohibited within 30 days prior to start of 
study drugs and within the first 12 cycles on study. 
 
Palliative radiation or metastasectomy is allowed; these lesions will are not subsequently be 
included for tumor measurements. 
 
Concomitant use of statins will be allowed only if the patient is on a stable dose for over 
3 months prior to the study and is in stable status without any CK elevations. 
 
3.4 
Long-Term Follow-up 
Patients who discontinue treatment while still receiving clinical benefit (i.e., CR, PR or SD) 
should get follow-up tumor scans every 12 (±2) weeks until disease progression or use of 
subsequent anti-cancer therapy to determine the duration of response, unless consent is 
withdrawn. 
 
Long-Term Follow-up for survival may be conducted by telephone, rather than by an in-person 
visit, once tumor progression is determined or use of subsequent anti-cancer therapy has been 
initiated. 


 
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4. 
Study Drugs 
In this study, APX005M, cabiralizumab and nivolumab, are considered Investigational 
Medicinal Products (IMP). 
 
4.1 
Investigational Products 
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already having a marketing authorization but 
used or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. In 
this protocol, the investigational products are APX005M, cabiralizumab and nivolumab. 
 
Please refer to the Pharmacy Manual and/or Investigator’s brochures for more specific 
information on each drug product. 
 
Table 4 
Study treatments 
Product 
Description / 
Class and Dosage 
Form 
Potency/Route of 
Administration 
Blinded or 
Open Label 
Packaging / 
Appearance 
Storage 
Conditions 
(Per Label) 
Nivolumab 
(BMS-936558-01) 
Solution for 
Injection 
100 mg 
(10 mg/mL) 
Open label 
Vial 
Refer to the label 
on container 
and/or pharmacy 
manual 
Nivolumab 
(BMS-936558-01) 
Solution for 
Injection 
40 mg 
(10 mg/mL) 
Open label 
Vial 
Refer to the label 
on container 
and/or pharmacy 
manual 
Cabiralizumab 
(BMS-986227) 
Solution for 
Injection 
140 mg 
(20 mg/mL) 
Open label 
Vial 
Refer to the label 
on container 
and/or pharmacy 
manual 
APX005M 
Solution for 
Injection 
200 mg 
(10 mg/mL) 
Open label 
Vial 
Refer to the label 
on container 
and/or pharmacy 
manual 
 
 
4.2 
Handling and Dispensing 
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the Investigator to ensure that investigational product is only dispensed to 
Patients. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
 
 


 
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The applicable site personnel should ensure that the study drugs are stored in accordance with 
the environmental conditions (temperature, light, and humidity) determined by the Sponsor. If 
concerns regarding the quality or appearance of the study drugs arise, do not dispense the study 
drugs and contact the Sponsor or designee immediately. 
 
Study drug documentation including all processes required to ensure drug is accurately 
administered must be maintained. This includes documentation of drug storage and 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (e.g. required diluents, administration sets). 
 
Please refer to the current version of the Investigator Brochures and/or pharmacy manual for 
complete preparation, storage, and handling information. 
 
4.2.1 Cabiralizumab 
The investigational supply of cabiralizumab will be provided to the study centers by Bristol- 
Myers Squibb and will be administered to patients in the clinical study by a trained healthcare 
professional. 
Cabiralizumab drug product is supplied for IV administration as a sterile, aqueous, colorless to 
pale yellow liquid, clear to slightly opalescent pyrogen-free solution in 7 mL glass vials 
stoppered with coated stoppers, and equipped with aluminum seals. Light (few) particulates 
(consistent in appearance to proteinaceous particles) may be present. Each vial contains a 
minimum of 7 mL of a 20 mg/mL solution of cabiralizumab (approximately 140 mg per vial). 
Storage Conditions: 2–8°C (36–46°F). The vials will be provided in a carton. Both vials and 
cartons will be labeled per local regulations. 
Refer to Cabiralizumab Investigator’s Brochure for more specific information on the drug 
product. 
 
4.2.2 Nivolumab 
The investigational supply of nivolumab will be provided to the study centers by the Bristol- 
Myers Squibb. 
 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is a clear to opalescent, colorless to pale 
yellow liquid, which may contain light (few) particulates. The drug product is a sterile, non- 
pyrogenic, single-use, isotonic aqueous solution formulated at 10 mg/mL in sodium citrate, 
sodium chloride, mannitol, diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 
(Tween 80), pH 6.0 and includes an overfill to account for vial, needle, and syringe holdup. It is 
supplied in 10-cc Type I flint glass vials, stoppered with butyl rubber stoppers and sealed with 
aluminum seals. 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding (polyethersulfone membrane) in-line filter at the protocol 
specified doses and infusion times. It is not to be administered as an IV push or bolus injection. 
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. 


 
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During drug product preparation and handling, vigorous mixing or shaking is to be avoided. 
 
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. Nivolumab infusions are compatible with 
polyvinyl chloride (PVC) or polyolefin containers and infusion sets, and glass bottles. 
 
Vials of nivolumab injection must be stored at 2 degrees C to 8 degrees C (36°F to 46°F) and 
protected from light and freezing. The administration of nivolumab 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 (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. 
Refer to the Nivolumab Investigator’s Brochure for for more specific information on the drug 
product. 
 
4.2.3 APX005M 
The investigational supply of APX005M will be provided to the study centers by Apexigen. 
 
APX005M is supplied in 20 mL Type 1 clear glass vials for IV administration. Each vial contains 10 
mg APX005M/mL in a sterile, clear to slightly 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 (WFI). The 20 mL vials are intended for single use. 
 
APX005M is intended for IV infusion. For use, APX005M is diluted in normal saline and infused via 
IV infusion or syringe pump. 
 
Refer to the APX005M Investigator’s Brochure for more specific information on the drug 
product. 
 
4.3 
Method of Assigning Patient Identification 
Patients must be able to provide written informed consent and meet all eligibility criteria. No 
waivers of inclusion or exclusion criteria will be granted by Sponsor or its designee for any 
patient enrolled in the study. Before enrolling a patient, all eligibility criteria must be satisfied. 
 
See Section 4.4.1 and Figure 6 for dosing schema.  Patients who qualify for Phase 1 dose 
esclation of the study will be enrolled as follows: 
• Cohort 1 will be enrolled first and these patients will be followed one 14-day cycle. 
• Once the DLT follow-up period of 28 days is cleared for Cohort 1, simultaneous 
enrollment to Cohort 2 and Cohort 3 will occur. Patients in these cohorts will be treated 
for a total of one 14-day cycle. 
• Simultaneous enrollment into Cohort 4 and Cohort 5 will proceed once the 14-day DLT 


 
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period for dose escalation is cleared in the preceeding Cohorts 2 and 3. 
• Once the DLT period of 28 days for dose escalation is cleared Cohorts 4 and 5, 
enrollment to the final Cohort 6 will occur. 
• The MTD will be calculated for patients who have received at least 2 cycles (at least 28 
days) of study drug. 
• Dose escalation into sequential dose levels of APX005M in combination with 
cabiralizumab and nivolumab may proceed until DLTs are observed either in the 
cabiralizumab/APX005M doublet therapy cohorts 1, 3, and 5 or in the 
nivolumab/cabiralizumab/APX005M triplet therapy cohorts after discussion and 
agreement between the PIs and Industry Collaborators. 
 
In Phase 1b, a maximum of 34 patients will be enrolled per disease-specific cohort (advanced 
melanoma, NSCLC, or RCC). Enrollment will be open for all cohorts in parallel and will 
continue until the enrollment target is reached. Once a disease cohort is filled, further enrollment 
will be restricted to the cohort(s) that have not been filled. A total of approximately 102 patients 
will be enrolled in the Phase 1b arm of the study. 
 
4.4 
Study Drug Dosing and Dose Modification 
 
4.4.1 Dosing 
 
Dosing calculations should be based on the body weight assessed at Cycle 1 Day 1 prior to the 
first dose of study drug administration. It is not necessary to recalculate subsequent doses if the 
patient’s weight is within 10% of the weight used to calculate the previous dose. All doses 
should be rounded to the nearest milligram. 
 
Patients should be carefully monitored for infusion reactions during study drug administration. If 
an acute infusion reaction is noted, patients should be managed according to the guidelines in 
Section 4.8 and Section 4.9.  Patients must remain near the vicinity of a hospital with rapid 
access to an intensive care unit setting during the initial 48 hour period after treatment for the 
first two treatment cycles. 
 
All vials are for single use only. Further instructions on study drug preparation and 
administration are provided in the Pharmacy Manual. 
 
Please refer to the study schema for dosing as follows: 
 
• Phase 1 Dose Escalation (Dosing on Day 1 of each 14-day cycle): 
 
o Cohort 1:  Cabiralizumab 4 mg/kg + APX005M 0.03 mg/kg 
 
o Cohort 2:  Nivolumab 240 mg + Cabiralizumab 4 mg/kg + APX005M 0.03 mg/kg 
 
o Cohort 3:  Cabiralizumab 4 mg/kg + APX005M 0.1 mg/kg 


 
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o Cohort 4:  Nivolumab 240 mg + Cabiralizumab 4 mg/kg + APX005M 0.1 mg/kg 
 
o Cohort 5:  Cabiralizumab 4 mg/kg + APX005M 0.3 mg/kg 
 
o Cohort 6:  Nivolumab 240 mg + Cabiralizumab 4 mg/kg + APX005M 0.3 mg/kg 
• Phase 1b (Dosing on Day 1 of each 14-day cycle): 
 
o ALL patients:  Nivolumab 240 mg + Cabiralizumab 4 mg/kg + APX005M at the 
RP2D 
 
4.4.1.1 Nivolumab Dosing 
The following patients on the trial will receive nivolumab as follows: 
 
• Phase 1: 
o Cohorts 1, 3, and 5: will NOT receive nivolumab 
o Cohorts 2, 4, and 6: nivolumab 240 mg IV 
 
• Phase 1b: 
o All patients will receive nivolumab 240 mg IV as the first drug in sequence 
Nivolumab will be dosed as a 30-minute IV infusion on Day 1 of each 14-day treatment cycle as 
above. 
 
Routine premedication administered 30 minutes prior to nivolumab should include: 
 
• H1 antagonist (e.g. Benadryl 25 mg PO) 
• Oral or IV H2 antagonist (e.g., ranitidine 150−300 mg, cimetidine 300−800 mg, 
nizatidine 150−300 mg, and famotidine 20−40 mg) 
• Oral nonsteroidal anti-inflammatory drug (may comprise ibuprofen 400 mg or 
equivalent) 
• Acetaminophen 650 mg 
If a grade 1-2 infusion reaction is observed during the proposed infusion rate of nivolumab 240 
mg over 30 minutes, the infusion rate will be extended to 60 minutes.  Nivolumab should be 
held for a grade 3 infusion reaction and retreatment should be discussed with study PI.  
Nivolumab should be discontinued for a grade 4 infusion reaction. 
 
There will be no dose escalations or reductions of nivolumab allowed. Refer to the Pharmacy 
Manual for nivolumab preparation instructions. 
 
4.4.1.2 Cabiralizumab Dosing 
All patients in all cohorts of the trial will receive cabiralizumab. 
 
Cabiralizumab will be administered as a fixed dose of 4 mg/kg given over 30 minutes by IV 
infusion.  In phase 1 dose escalation cohorts 1, 3, and 5, cabiralizumab will be given first 


 
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followed by APX005M.  In this case, premedications outlined in Section 4.4.1.1 should be given 
30 minutes prior to cabiralizumab on Day 1 of each 14-day treatment cycle. 
 
In phase 1 dose escalation Cohorts 2, 4, and 6, and in all patients on the phase 1b portion of the 
trial, cabiralizumab will be administered 30 minutes after the end of the nivolumab infusion, on 
Day 1 of each 14-day treatment cycle. 
 
If any Grade 3 or higher infusion reaction is observed during the proposed infusion rate of 
cabiralizumab 4 mg/kg over 30 minutes, cabiralizumab should be discontinued permanently. For 
further management of infusion reactions, please see Section 4.8 and Section 4.9. 
 
A research pharmacist (or other responsible personnel) will prepare the solution for 
administration. After calculating the number of vials, based on the patient’s weight, the study 
drug product will be diluted with 0.9% Sodium Chloride Injection, USP. Prepared cabiralizumab 
should be administered within 6 hours after preparation (ambient temperature). The IV 
administration setup for cabiralizumab infusion must contain a 0.2 or 0.22 µm in-line filter or a 
0.2 or 0.22 µm syringe filter. Cabiralizumab will be administered under medical supervision as a 
30 minute (± 5 minutes) IV infusion via a peripheral vein or central venous catheter. No 
incompatibilities between cabiralizumab infusion and polyvinyl chloride (PVC), 
ethylene/propylene IV components, or glass bottles have been observed. 
 
4.4.1.3 APX005M Dosing 
All patients in all cohorts of the trial will receive APX005M as follows: 
 
• Phase 1: 
o Cohorts 1 and 2:  APX005M 0.03 mg/kg 
o Cohorts 3 and 4:  APX005M 0.1 mg/kg 
o Cohorts 5 and 6:  APX005M 0.3 mg/kg 
 
• Phase 1b: 
o At the determined RP2D 
 
APX005M is administered on Day 1 of each 14-day treatment cycle approximately 30 minutes 
following cabiralizumab using a 60 minute IV infusion. A window between -5 minutes and +10 
minutes is permitted (i.e., infusion time is 55 minutes to 70 minutes). 
 
Premedication should have already been administered 30 minutes prior to first dose of study 
drug, as described in Section 4.4.1.1.  When the time between premedication and scheduled 
APX005M administration exceeds 4 hours, patients may receive an additional course of 
premedication prior to APX005M administration. 
 
The APX005M infusion can be interrupted in the case of a grade 1-2 infusion reaction (see 
Section 4.8 and Section 4.9). Once symptoms resolve, infusion should be restarted at 50% of the 
initial infusion rate (e.g., from 50 mL/hr to 25 mL/hr).  For a grade 3 infusion reaction, APX005M 
should be held and the investigator should dose reduce with the next cycle.  Grade 4 infusion 


 
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reactions require discontinuation of APX005M. 
 
The Pharmacy Manual contains specific instructions for the preparation of the APX005M 
infusion and administration of infusion solution. 
 
4.5 
Blinding/Unblinding 
This is an open-label study and there will be no blinding or unblinding of patients during this 
study. 
 
4.6 
Dose Modifications, Delays or Discontinuation 
Doses of study drugs may be interrupted, delayed, or discontinued depending on how the patient 
tolerates the treatment.  Dose reductions for nivolumab and cabiralizumab are not permitted. 
Dose reduction for APX005M is permitted as per Section 4.8 and Section 4.9. 
 
If there is an infusion reaction or other unforeseen delay that makes dosing of APX005M 
impractical on the same day as nivolumab and cabiralizumab, the patient may be infused with 
APX005M the following day at the discretion of the Investigator. 
 
Administration of nivolumab, cabiralizumab and/or APX005M combination therapy should be 
skipped for the following reasons: 
• The treating physician determines that the patient would benefit from a break in 
treatment due to non-life threatening grade 1-2 toxicities such as fatigue, 
arthralgias or edema. 
• Any drug-related laboratory abnormalities would not require a dose delay unless 
clinically indicated or specified in the protocol or abnormal laboratory management 
guidelines (see Section 4.8 and Section 4.9). Please discuss with the PI as needed. 
• For dose delays or modifications for all other AEs please refer to the AE management 
guidelines in Section 4.8 and Section 4.9. 
 
If the causality of the AE requiring a dose delay is confirmed to be due to one of three study 
drugs, then the non-offending drug may be continued per protocol taking into account the safety 
and clinical benefit to the patient. 
 
4.7 
Criteria to Resume Treatment with APX005M, Cabiralizumab and Nivolumab 
Patients may resume treatment with APX005M, cabiralizumab and/or nivolumab when the drug- 
related AE resolves as noted in Section 4.8 and Section 4.9. 
 
A new treatment cycle should be initiated only if all toxicities are ≤ Grade 1 except: 
• Grade 2 neuropathy lasting shorter than 28 days (hold nivolumab only) 
• Grade 2 alopecia 
• Grade 2 rash or other skin toxicity 
• Grade 2 hypophysitis/endocrinopathies  
• Grade 2 fatigue 
• Grade 2-3 neutropenia/lymphopenia 
• CK increase up to 15x ULN 


 
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• 
AST/ALT ≤ 12x ULN for ≤ 7 days with bilirubin <2x ULN 
 
If a subject fails to meet these retreatment criteria then the treatment cycle should be skipped. 
The PI can be contacted at any time if further clarification is needed. 
 
4.8 
Management of Adverse Events and Supportive Care Guidelines 
Immuno-oncology agents are associated with AEs that can differ in severity and duration 
compared to AEs caused by other therapeutic classes. APX005M, cabiralizumab and nivolumab 
are considered immuno-oncology agents in this protocol. Early recognition and management of 
AEs associated with immuno-oncology agents may mitigate severe toxicity. Subjects should 
receive appropriate supportive care measures as deemed necessary by the treating Investigator. 
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined below. These treatment guidelines are intended to be applied when the 
Investigator determines the events to be related to the APX005M + cabiralizumab ± nivolumab 
combination and should not substitute for investigational product dose delays and/or 
modifications. Additional guidance for management of AEs with potential immunologic etiology 
is provided in the APX005M, cabiralizumab and nivolumab Investigator’s Brochures. 
 
If after evaluation the event is determined by the Investigator not to be related to investigational 
products, the Investigator does not need to follow the treatment guidance outlined in this section. 
 
For each disorder, attempts should be made to rule out other causes such as metastatic disease, or 
bacterial/viral infection, which might require additional supportive care. 
 
Steroid tapering may be necessary for prolonged exposures to corticosteroids, or if symptoms 
worsen when the corticosteroid dose is decreased. 
 
Diarrhea/Colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).  All subjects who experience diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI 
consultation and endoscopy to confirm or rule out colitis. 
• Grade 1-2: for subjects developing Grade 1–2 diarrhea loperamide (2 mg every 2 hours) 
is strongly recommended at the first onset of symptoms. For subjects with persistent 
diarrhea despite the use of loperamide (>7 days or recurrent) or Grade 2 colitis, the use of 
oral corticosteroids (0.5–1 mg/kg/day methylprednisolone or oral equivalent) is 
recommended. Other antidiarrheal agents (e.g. octreotide) may be used if necessary. 
When symptoms improve to Grade 1, steroids may be tapered as deemed appropriate by 
the investigator. If steroids are administered for over weeks, consider prophylactic 
antibiotics for opportunistic infections. If symptoms worsen or persist >5 days despite 
steroids treatment, treat as grade 3-4. 
• Grade 3-4: treat with corticosteroids (1–2 mg/kg/day methylprednisolone or IV 
equivalent) followed by oral corticosteroids until symptoms improve to Grade 1 or less. 
Add prophylactic antibiotics for opportunistic infections and consider lower endoscopy. 


 
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If persist or recurs continuously after improvement, consider infliximab 5mg/kg (unless 
sepsis or perforation is detected). 
 
Creatinine Elevation 
• Grade 2-3: treat with corticosteroids (0.5–1 mg/kg/day methylprednisolone or oral 
equivalent) until symptoms improve to Grade 1 or less. Consider renal biopsy with 
nephrology consult.  If persist > 14 days treat as grade 4. 
• Grade 4: treat with corticosteroids (1–2 mg/kg/day methylprednisolone or IV equivalent) 
followed by oral corticosteroids until symptoms improve to Grade 1 or less. Consider 
renal biopsy and consult nephrologist. Add prophylactic antibiotics for opportunistic 
infections. If worsen consider clinical referrals as needed. 
 
Pneumonitis 
• Grade 2: Treat with IV or oral corticosteroids until symptoms improve to Grade 1 or 
less. Consider prophylactic antibiotics for opportunistic infection. Consider 
bronchoscopy, lung biopsy and hospitalization. If does not improve after 2 weeks treat as 
grade 3-4. 
• Grade 3-4: Consider pulmonary or infectious disease consults. Hospitalize and treat 
immediately with IV corticosteroids (2–4 mg/kg/day methylprednisolone or IV 
equivalent). Add prophylactic antibiotics for opportunistic infections. Consider 
bronchoscopy and lung biopsy. If does not improve after 48h or worsens, add additional 
anti-inflammatory measures (e.g. cyclosporine, IVIG, mycophenolate mofetil) 
 
Liver Function Tests 
• Grade 3 transaminitis: Monitor liver function tests more frequently until returned to 
Grade 2 or less.  Start oral or IV corticosteroids if transaminitis > 5 to ≤ 12x ULN persists 
for > 7 days.  Continue steroids until returns to Grade 1 or less.  If the first transaminase 
value is 12X ULN or greater, start steroids immediately. 
 
• Grade 4 ALT and/or AST elevations, or grade 4 bilirubin increase: Treat with IV 
corticosteroids for 24-48 hours followed by oral corticosteroids until improvement to 
Grade 1 or less. If worsening in 3-5 days, administer additional immunosuppressive 
measures (e.g. mycophenolate mofetil), as needed. Consider adding prophylactic 
antibiotics for opportunistic infections. Consult gastroenterologist. 
 
• Grade ≥2 transaminitis (>3x ULN) and total bilirubin >2x ULN: Treat with IV 
corticosteroids (1–2 mg/kg/day methylprednisolone or IV equivalent) followed by oral 
corticosteroids. Consider adding prophylactic antibiotics for opportunistic infections. 
Consult gastroenterologist.  Continue steroids until symptoms improve to Grade 1 or less. 
If worsening in 3-5 days, add mycophenolate mofetil 1g BID. If no improvement 
consider additional immunosuppressive measures per local guidelines. 
 
Endocrinopathy 
• Asymptomatic TSH elevation: monitor fT4 if TSH is <0.5 x LLN, > 2 x ULN or 
consistently out of range in two subsequent measurements. 


 
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Symptomatic endocrinopathy: evaluate endocrine function. For abnormal laboratory 
results initiate hormone repletion. 
• Suspicion of adrenal crisis: rule out sepsis, administer IV fluids, treat as for 
symptomatic endocrinopathy.  Otherwise, administer stress dose of IV steroids with 
mineralocorticoid activity. 
 
Skin Adverse Events. 
• Grade 1-2: symptomatic treatment (e.g. antihistamines, topical steroids). If unresponsive, 
consider steroid burst. If worsens treat as grade 3-4. 
• Grade 3-4: Consider skin biopsy. Treat with steroids as deemed appropriate by the 
treating physician (1–2 mg/kg/day methylprednisolone or IV equivalent). 
 
Infusion Reaction/Cytokine Release Syndrome 
Precautions should be observed during the administration of APX005M, nivolumab and 
cabiralizumab. 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. 
 
Subjects should be instructed that symptoms associated with cytokine release syndrome/infusion 
reaction can occur within 48 hours following the administration of the investigational products, 
and if such symptoms develop while they are at home, they should contact the Investigator 
and/or seek emergency medical care if appropriate. 
 
• Grade 1: decrease infusion rate as per protocol 
• Grade 2: Stop infusion and treat symptoms following guidelines in Table 4. 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 4.  If subjects 
resume study treatment after previously having a grade 3 infusion-related reaction and/or 
cytokine release syndrome, a 48-hour inpatient observation period is mandatory after the 
infusion to perform frequent vital sign checks.  If grade > 3 infusion-related 
reaction/cytokine release syndrome does not recur upon rechallenge, further cycles may 
be administered in the outpatient setting. 
 
Table 4: Guidelines for Management of Cytokine Release/Infusion Reaction Symptoms 
 
Suspected Cytokine Release/Infusion-related 
Toxicity 
Recommended Treatment 
• Mild toxicity requiring symptomatic treatment only 
(e.g., fever, nausea, fatigue, headache, myalgia, 
malaise) 
• Vigilant supportive care 
• Maintain adequate hydration 
• Antipyretics, non-steroidal anti- 
inflammatory drugs, 
antihistamines, anti-emetics, 
analgesics as needed 
• In case of mild symptoms 
persisting for > 24 hours assess 
for infections; empiric treatment 


 
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of concurrent bacterial 
infections 
• Symptoms or clinical findings requiring and 
responding to moderate intervention, such as: 
o O2 requirement < 40% 
o Hypotension responsive to fluids ± low dose of 
one vasopressor (e.g., < 50 mg/min 
phenylephrine) 
o CTCAE v5.0 Grade 2 organ toxicity 
• All of the above 
• Monitor cardiac and other organ 
functions closely 
• Corticosteroids if not resolving 
with measures above 
• 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 
• CTCAE v5.0 Grade ≥3 organ toxicity 
• All of the above 
• Monitor cardiac and other organ 
functions closely 
• Corticosteroids if not resolving 
with measures above 
• Tocilizumab if not responsive to 
steroids and other measures 
 
Neurological Toxicity 
• Grade 2: symptomatic treatment per local guidelines.  Consider steroids (0.5–1 
mg/kg/day methylprednisolone or PO equivalent). If worsen treat as grade 3-4. 
• Grade 3-4 or grade 2 for >28 days: obtain neurological consult and treat symptoms per 
local guidelines. Administer corticosteroids (1–2 mg/kg/day methylprednisolone or IV 
equivalent). Add prophylactic antibiotics for opportunistic infections. Continue steroids 
until symptoms improve to Grade 2 or less.  If symptoms worsen or for atypical 
presentation consider IVIG, high doses steroids (e.g. 1g methylprednisolone) or other 
immunosuppressive measures per local guidelines. 
 
Periorbital Edema: 
• Grade 1: Monitor edema  
• Grade 2-4: Consider IV or oral corticosteroids until symptoms improve to Grade 1 or 
less. Consider adding eye drops, or analgesics as needed. Seek ophthalmologic consult if 
needed. 
Uveitis: 
• Grade 1: Watch for worsening of symptoms including visual disturbances, light 
sensitivity, decrease vision, monitor weekly. 
• Grade 2-4: Treat with IV or oral corticosteroids until symptoms improve to Grade 1 or 
less. Consider additional immunosuppressive agents if not responsive (such as 
infliximab). Consider adding prophylactic antibiotics for opportunistic infections and 
seek ophthalmologic consult. 
CK Increase: 


 
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• CK > 10x ULN: Consider measuring CK isoenzymes as clinically indicated. If CK 
isoenzymes are abnormal consider measuring troponin levels and other assessments 
(including uromyoglobin) as clinically indicated. If CK isoenzymes are normal monitor 
CK level as clinically indicated. 
• CK > 15x ULN: If clinically indicated, measure CK isoenzymes and test more 
frequently until returned to Grade 2. If CK isoenzyme panel is normal continue 
monitoring the subject. If CK isoenzyme panel is abnormal then consider measuring 
troponins. 
 
4.9 
Criteria for Holding, Discontinuing, or Modifying Study Drug 
Management of suspected adverse drug reactions may require temporary treatment hold (until re- 
treatment criteria are met), reducing the dose of APX005M, or discontinuation of some or all 
investigational products as per Table 5. If a subject experiences several toxicities, the 
recommended dose modification should be based on the highest grade toxicity. 
 
Up to two dose reductions are permitted for APX005M. There are no dose reductions for 
cabiralizumab or nivolumab. 
 
 
Table 5: Criteria for Holding, Discontinuing, or Modifying Study Drug 
 
 
Toxicity 
Grade 
APX005M 
Cabiralizumab 
Nivolumab 
Gastrointestinal AEs 
Diarrhea/colitis 
2-3 
1st occurrence:  
Hold 
 
2nd occurrence: 
dose reduction¥ 
Hold 
If not improving 
in 28 days with 
oral steroids: 
Discontinue 
Hold 
If not improving 
in 28 days with 
oral steroids: 
Discontinue 
4 
Discontinue 
Discontinue 
Discontinue 
Vomiting 
2-4 
Hold 
Hold 
Hold 
Endocrine AEs 
Hypophysitis/ 
Endocrinopathies 
2-4 
Hold only if 
clinically 
unstable 
Hold only if 
clinically 
unstable 
Hold only if 
clinically unstable 


 
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Toxicity 
Grade 
APX005M 
Cabiralizumab 
Nivolumab 
Hyperthyroidism 
2-4 
Hold only if 
clinically 
unstable 
Hold only if 
clinically 
unstable 
Hold only if 
clinically 
unstable 
Hepatic AEs 
Increased 
AST/ALT 
3 
(> 5 to ≤ 
12x ULN) 
and 
bilirubin 
<2x ULN 
Continue 
Continue 
Continue 
3 (> 12x 
ULN) for 
>14 days and 
not 
decreasing on 
steroids 
and 
bilirubin 
<2x ULN 
Hold 
Hold 
Hold 
2-3 and total 
bilirubin 
>2x ULN or 
3x baseline 
for patients 
with 
Gilbert’s 
syndrome 
and no 
cholestasis 
or INR >1.5 
not on 
warfarin 
Discontinue 
Discontinue 
Discontinue 
4 
Discontinue 
Discontinue 
Discontinue 
Increased 
bilirubin 
2 
Hold 
Hold 
Hold 
3 
Hold 
 
If >48 hours 
with no 
cholestasis or 
> 5 days with 
cholestasis: 
Discontinue 
Hold 
 
If >48 hours 
with no 
cholestasis or > 
5 days with 
cholestasis: 
Discontinue 
Hold 
 
If >48 hours 
with no 
cholestasis or > 
5 days with 
cholestasis: 
Discontinue 
4 
Discontinue 
Discontinue 
Discontinue 
 


 
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Toxicity 
Grade 
APX005M 
Cabiralizumab 
Nivolumab 
Skin AEs 
Rash or other skin 
toxicity 
3 
Hold 
 
If not improving 
in 28 days: 
Discontinue 
Hold 
 
If not improving 
in 28 days: 
Discontinue 
Hold 
 
If not improving 
in 28 days: 
Discontinue 
4 
Hold 
 
If not improving 
in 28 days: 
Discontinue 
Hold 
 
If not improving 
in 28 days: 
Discontinue 
Discontinue 
Neurological AEs 
Neurological 
Toxicity 
2 
Continue 
Continue 
Hold 
3 
Hold 
Hold 
1st occurrence: 
Hold 
 
2nd occurrence: 
Discontinue 
4 
Hold 
Hold 
Discontinue 
Infusion Reaction/ Cytokine Release Syndrome 
Nivolumab 
infusion reaction 
1-2 
Administer 
additional 
premedication. 
Increase infusion 
time to 90 min 
Administer 
additional 
premedication. 
Increase infusion 
time to 60 min 
Administer 
additional 
premedication 
and increase the 
infusion time to 
60 min 
3 
Hold  
Hold 
Hold.  Re-
challenge with 
nivolumab must be 
discussed with 
study PI 
4 
Discontinue 
Discontinue 
Discontinue 
Cabiralizumab 
infusion reaction 
1-2 
Administer 
additional 
premedication. 
Increase infusion 
time to 90 min 
Administer 
additional 
premedication. 
Increase infusion 
time to 60 min 
Already given 
3 
Hold 
Discontinue 
Already given 
4 
Discontinue 
Discontinue 
Discontinue 


 
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APX005M infusion 
reaction/ 
1-2 
Administer 
additional 
premedication.  
Increase 
infusion time to 
90 min* 
Already given 
Already given 
3 
Hold and dose 
reduce¥ for 
next cycle 
Already given 
Already given 
cytokine release 
syndrome 
4 
Discontinue 
Discontinue 
Discontinue 
Pulmonary AEs 
Pneumonitis 
2-3 
1st occurrence: 
Hold 
 
2nd occurrence or 
if not improving 
in 14 days: 
Discontinue 
1st occurrence: 
Hold 
 
2nd occurrence or 
if not improving 
in 14 days: 
Discontinue 
1st occurrence: 
Hold 
 
2nd occurrence or if 
not improving in 
14 days: 
Discontinue 
4 
Discontinue 
Discontinue 
Discontinue 
Renal AEs 
Creatinine 
Elevation 
2-3 
Hold 
If not improving 
in 21 days: 
Discontinue 
Hold 
If not improving 
in 21 days: 
Discontinue 
Hold 
If not improving in 
21 days: 
Discontinue 
4 
Discontinue 
Discontinue 
Discontinue 
Systemic AEs 
Fatigue 
3 
Hold.  
Consider dose 
reduction for next 
cycle 
Hold 
Hold 
 
 
 


 
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Toxicity 
Grade 
APX005M 
Cabiralizumab 
Nivolumab 
Hematologic AEs 
Neutropenia 
4 
Hold 
Hold 
Hold 
Febrile 
Neutropenia 
3-4 
Hold 
Hold 
Hold 
Thrombocytopenia 
2-3 
Hold 
Continue 
Continue 
3 with 
significant 
bleeding or 
transfusion or 
4 
Hold.  
Dose reduction¥ 
Hold 
Hold 
Ocular AEs 
Periorbital edema 
2-3 
Continue 
Hold at 
discretion of 
treating 
investigator 
Continue 
4 
Continue 
Discontinue 
Continue 
Uveitis 
2 
Hold 
 
If not improving 
in 28 days:  
Discontinue 
Hold 
 
If not improving 
in 28 days:  
Discontinue 
Hold 
 
If not improving in 
28 days:  
Discontinue 
3-4 
Discontinue 
Discontinue 
Discontinue 
Laboratory AEs 
CK increase without 
clinical or 
laboratory evidence 
of myocarditis or 
myositis 
4 (> 15 to < 
20x ULN) 
Continue 
Hold until returns 
to < 15x ULN 
Continue 
4 (>20x ULN) Resume once < 
10x ULN 
Discontinue 
Resume once < 
10x ULN 
Toxicity All Other Drug-
Related 
3 or Severe 
Hold 
Hold 
Hold 
4 
Discontinue 
Discontinue 
Discontinue 
 
 
 
 
4.10 
Dose Reduction 
Dose reduction for nivolumab and cabiralizumab are not permitted. Dose reduction for 
APX005M is permitted as below and as per Section 4.8 and Section 4.9. 
 
¥APX005M Dose Reductions 


 
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Dose Level 
(mg/kg) 
DL1 
(0.03) 
DL2 
(0.1) 
DL3 
(0.3) 
First Dose Reduction 
0.01 
0.06 
0.2 
Second Dose Reduction 
Not applicable 
0.03 
0.1 


 
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4.11 
Treatment Discontinuation Criteria 
Subjects must discontinue receiving investigational products for any of the following reasons: 
• Withdrawal of informed consent (patient’s decision to withdraw for any reason) 
• Toxicity requiring discontinuation of all investigational products as outlined in the dose 
modification guidelines 
• Any clinically significant AE, abnormal laboratory test results, or intercurrent illness 
which, in the opinion of the Investigator, indicates that continued participation in the 
study is not in the best interest of the patient 
• Failure to recover from a disease or treatment-related AE to baseline or ≤ Grade 1 within 
12 weeks of last dose of investigational product (except Grade 2 alopecia and Grade 2 
fatigue), unless the subject is benefiting from therapy and after discussion with and 
approval by the PI 
• Failure to recover within 4 weeks of last dose of investigational product if AE is related 
to infusion reaction/cytokine release 
• Inability to reduce corticosteroid to 10 mg or less of prednisone or equivalent per day 
within 12 weeks of last dose of investigational product 
• Patients who are required to have prohibited concomitant medications 
• Pregnancy 
• Termination of the study by the Sponsor 
• Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of a psychiatric or physical (e.g., infectious disease) illness 
• Documented disease progression or clinical deterioration while receiving active study 
therapy 
• Requirement for alternative therapy 
• Non-compliance with study procedures, including use of prohibited medications 
• Subject is lost to follow-up 
• Death 
For comprehensive discontinuation rules, refer to the Table 5 in Section 4.4. The PI can be 
contacted at any time if further clarification is needed. 
 
Other treatment discontinuation not specifically listed in Table 5 (Section 4.4) may include: 
 
• Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
– Dosing delays to manage drug-related adverse events are allowed for up to 12 weeks 
between doses. Prior to re-initiating treatment in a patient with a dosing delay lasting 


 
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> 6 weeks from the previous dose, the PI must be consulted. Tumor assessments 
should continue as per-protocol even if dosing is delayed. Periodic study visits to 
assess safety and laboratory studies should also continue per protocol, or more 
frequently if clinically indicated during such dosing delays or per the Investigator’s 
discretion. 
– Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug- 
related reasons may be allowed if approved by the PI.  Prior to re-initiating treatment 
in a patient with a dosing delay lasting > 6 weeks, the PI must be consulted. Tumor 
assessments should continue per protocol every 8 weeks for the first 4 months and 
every 12 weeks (±7 days) thereafter, even if dosing is delayed. Periodic study visits to 
assess safety and laboratory studies should also continue per-protocol or more 
frequently if clinically indicated during such dosing delays or per the Investigator’s 
discretion. 
• Any AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
Investigator, presents a substantial clinical risk to the patient with continued APX005M, 
cabiralizumab and/or nivolumab dosing. 
All patients who discontinue study treatment should comply with protocol specified follow- 
up procedures as outlined in Section 5. The only exception to this requirement is when a 
patient withdraws consent for all study procedures or loses the ability to consent freely (i.e., 
is imprisoned or involuntarily incarcerated for the treatment of a psychiatric or physical 
illness). 
If a patient was discontinued, the reason for discontinuation must be entered on the 
appropriate CRF. The date and reason for cessation of nivolumab, cabiralizumab, and 
APX005M will be documented, and the Investigator must make every effort to perform the 
End-of-Treatment Visits. Adverse event reporting will continue until 100 (±7) days after the 
last dose of study drug or until initiation of subsequent anti-cancer therapy. Patients with 
ongoing SAEs will be followed until resolution or stabilization. 
 
4.12 
Infusion Delays and Missed Doses with Nivolumab, Cabiralizumab and APX005M 
In case an infusion cannot be administered at a scheduled visit, it must be administered as soon 
as possible. If the delay is more than two days, the infusion at the originally scheduled visit will 
be considered a missed dose and the procedures at the next visit should be performed.  There 
must be at least 12 days between study drug administration. 
 
4.13 
Treatment Beyond Progression 
Accumulating evidence indicates a minority of patients treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease [60]. 
 
Patients treated with nivolumab, cabiralizumab and APX005M combination therapy will be 
permitted to continue treatment beyond initial RECIST v1.1 defined progressive disease, 
assessed by the Investigator, as long as the following criteria are met: 


 
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• Patients who will be treated beyond disease progression must review and sign an ICF 
before continuing on study drug 
• The patient demonstrates investigator-assessed clinical benefit, and do not have rapid 
disease progression 
• Tolerance of study drugs 
• No decline in current ECOG performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases) 
• Absence of signs, symptoms, and worsening laboratory values that would indicate rapid 
disease progression 
 
A radiographic assessment/scan should be performed approximately 8 weeks (±7 days) after 
initial Investigator-assessed progression to determine whether there has been a decrease in the 
tumor size or continued progressive disease. The assessment of clinical benefit should be 
balanced by clinical judgment as to whether the patient is clinically deteriorating and unlikely to 
receive any benefit from continued treatment with investigational products. 
 
If the Investigator feels that any patient receiving nivolumab, cabiralizumab and APX005M will 
obtain clinical benefit by continuing treatment, the patient may remain on the trial and continue 
to receive monitoring according to the time and event schedules per protocol. 
 
For the patients who continue nivolumab, cabiralizumab and APX005M study therapy beyond 
progression, further progression is defined as an additional 10% increase in tumor burden from 
time of initial progression. This includes an increase in the sum of diameters of all target lesions 
and/or the diameters of new measurable lesions compared to the time of initial progression. 
APX005M, cabiralizumab and nivolumab treatment should be discontinued permanently upon 
documentation of further progression. 
 
4.14 
Treatment Compliance 
Study drug will be administered by qualified trained site personnel in the clinical facility. The 
Investigator or their designated study personnel will maintain a log (Drug Accountability Log) of 
all study drugs received dispensed and destroyed. The Investigator and the study personnel will 
ensure that each patient receives the calculated dose of the study drug based on body weight. 
 
Drug supplies will be inventoried and accounted for throughout the study. The Drug 
Accountability Log will be reviewed by the PI during site visits and at the completion of the 
study. Any discrepancy should be brought to the attention of the Sponsor. Records of study 
medication administration (date, start and stop time, and dose administered relative to time of 
preparation) will be recorded on the patient’s CRF. 


 
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4.15 
Destruction of Study Drug 
Any unused study drugs can only be destroyed on site after being inspected and reconciled by the 
responsible site monitor unless study drug vials must be immediately destroyed as required for 
safety, or to meet local regulations (e.g., cytotoxics or biologics). 
 
• On-site destruction is allowed provided the following minimal standards are met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s Standard Operating Procedures (SOPs) and a copy provided to the 
Sponsor upon request. 
• Records are maintained that allow for traceability of each vial, including the date 
disposed of, quantity disposed, and identification of the person disposing of the 
containers. The method of disposal (i.e., incinerator, licensed sanitary landfill, or licensed 
waste disposal vendor) must also be documented. 
• Accountability and disposal records are complete, up-to-date, and available for the PI to 
review throughout the clinical trial period. 
 
If conditions for destruction cannot be met, the responsible PI will make arrangements for return 
of study drug (Section 4.16). 
 
It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures and provided that appropriate records of disposal are 
kept. 
 
4.16 
Return of Study Drug 
If study drug will not be destroyed on site upon completion or termination of the study, all 
unused and/or partially used study drug that was supplied must be returned. The return of study 
drug will be arranged by the responsible PI. 


 
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5. 
Study Assessments and Procedures 
5.1 
Schedule of Assessments 
 
The schedule of assessment tables are attached to the protocol as Appendix A, Appendix B, and 
Appendix C. 
 
5.2 
Study Procedures by Visit 
 
5.2.1 Phase 1 Dose Escalation 
 
5.2.1.1 Screening Period (Day –28 to Day 0) 
 
Patients who have fully consented to participation in the study will undergo screening 
assessments within 28 days (4 weeks) prior to administration of the first infusion of APX005M, 
cabiralizumab, and/or nivolumab (unless otherwise stated). To determine if the patient meets all 
inclusion criteria and does not violate any exclusion criteria, the following procedures will be 
performed (Appendix A). 
 
• Written, signed informed consent must be collected prior to any study-specific 
procedures 
• Collection of a formalin fixed, paraffin-embedded (FFPE) tissue block and/or a fresh 
tumor biopsy from an accessible site will be mandatory, unless the Investigator deems 
that the subject does not have tumor in a site amenable to biopsy. Tumor biopsy 
collection will be performed at least 24 hours prior to dosing (as in Appendix D). 
• Complete medical and disease history 
• Demographic and baseline characteristics 
• Complete physical examination including height and weight 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature in resting position 
after 5 minutes rest) 
• Photo of periorbital region 
• ECOG performance status evaluation 
• Screening labs (as described in Appendix A) 
• Clinical safety labs (as described in Appendix A) 
• 12-lead ECG (required at screening, and if clinically indicated during the study) 
• Radiological imaging: After determining progression on an anti-PD-1/PD-L1 agent, body 
imaging of disease sites with PET CT, CT scans, and/or MRI is to be performed within 
28 days prior to Cycle 1 Day 1. MRI brain is also to be performed within 28 days prior 
to C1D1.  If the Investigator deems that MRI of the brain cannot be performed, CT Head 
with and without intravenous contrast is acceptable.  If the imaging is performed as part 
of the patient’s standard of care is within 28 days of Cycle 1 Day 1, it does not need to be 


 
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repeated if the documentation of results is provided and is adequate for RECIST v1.1. 
• Serum pregnancy test (β-hCG) for women of childbearing potential within 7 days of 
Cycle 1 Day 1 
• SAE reporting, if applicable 
• Document prior and concomitant medications 
 
5.2.1.2 Cycle 1, Day 1 
The following procedures will be performed: 
• Prior to study drug infusion infusion (within ≤72 hours unless otherwise stated): 
– Verification of eligibility 
– Update medical and disease history to capture any changes from screening 
– Physical examination including weight 
– Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
– ECOG performance status evaluation 
– Clinical safety labs (as described in Appendix A; results must be reviewed before 
dosing) 
– Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of 
dosing 
– Blood collection for: 
 Biomarker blood sample collection (analyses described in Appendix D) 
 Serum PK (for APX005M only) 
– pre-infusion (APX005M) 
– end of infusion (APX005M) 
– if possible, 4 hours (±30 minutes) from start of infusion (APX005M) 
 Pre-treatment serum anti-drug antibody (ADA) levels (for APX005M only), 
Cycle 1 Day 1 and Day 1 of every 3rd cycle (Cycles 3, 6, 9, 12, etc.) 
– AE reporting, if applicable 
– Review of concomitant medications 
• Study drug administration 
– Pre- and post-study each drug administration: 
 Vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting 
position after 5 minutes rest) 
 Additional post-dose vital signs (heart rate, blood pressure, respiratory rate, and 
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post-APX005M infusion 
– 4 hour post-dose vital sign criteria for discharge include: 
 Systolic BP no more than 30 mmHg below baseline 
 Oxygen saturation > 90% 
 Heart rate no more than 30 beats per minute above baseline, unless 
febrile 
 If febrile, subjects can be discharged home as long as their 
temperature is less than 101 degrees Fahrenheit 
 Patients must remain near the vicinity of a hospital with rapid access to an 
intensive care unit setting during the initial 48 hour period after treatment. 
 
5.2.1.3 Cycle 1, Day 2 
Patients will return to the study center on Day 2 for 24-hour (± 6 hours) post-dose assessments. 
No treatment will be administered during this visit, but the following assessments will be 
completed: 
• Physical examination (focused, symptom-based exam) 
• Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
• Clinical safety labs (as described in Appendix A) 
• Blood collection for: 
– Biomarker blood sample collection (analyses described in Appendix D) 
– Serum PK at 24 hours (+ 6 hours) from the start of infusion (APX005M) 
• AE reporting, if applicable 
• Review of concomitant medications 
 
5.2.1.4 Cycle 1, Day 3 
Patients will return to the study center on Day 3 for 48-hour (± 6 hours) post-dose assessments. 
No treatment will be administered during this visit, but the following assessments will be 
completed: 
• Physical examination (focused, symptom-based exam) 
• Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
• Blood collection for: 
– 
Biomarker blood sample collection (analyses described in Appendix D) 
– Serum PK at 48 hours (+ 6 hours) from the start of infusion (APX005M) 


 
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• AE reporting, if applicable 
• Review of concomitant medications 
 
5.2.1.5 Cycle 1, Day 8 
Patients will return to the study center on Day 8 for post-dose assessments. No treatment will be 
administered during this visit, but the following assessments will be completed: 
• Physical Exam (focused, symptom-based exam) 
• Vital Signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
• Clinical Safety Labs (as described in Appendix A) 
• Blood collection for: 
– Biomarker blood sample collection (as described in Appendix D) 
– Serum PK at 168 hours (+ 6 hours) from the start of infusion (APX005M) 
• AE reporting, if applicable 
• Review of concomitant medications 
 
5.2.1.6 Cycle 2, Day 1 
 
The following procedures will be performed: 
 
• Prior to study drug infusion infusion (within ≤72 hours unless otherwise stated): 
– Physical examination including weight 
– Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
– ECOG performance status evaluation 
– Clinical safety labs (as described in Appendix A; results must be reviewed before 
dosing) 
– Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of 
dosing 
– Blood collection for: 
 Biomarker blood sample collection (analyses described in Appendix D) 
 Serum PK (for APX005M only) 
– pre-infusion (APX005M) 
– end of infusion (APX005M) 
– if possible, 4 hours (±30 minutes) from the start of infusion (APX005M) 
– AE reporting, if applicable 


 
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– Review of concomitant medications 
• Study drug administration 
– Pre- and post-study each drug administration: 
 Vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting 
position after 5 minutes rest) 
 Additional post-dose vital signs (heart rate, blood pressure, respiratory rate, and 
temperature in resting position after 5 minutes rest) at 4 hours (+ 30 minutes) 
post-APX005M infusion 
– 4 hour post-dose vital sign criteria for discharge include: 
 Systolic BP no more than 30 mmHg below baseline 
 Oxygen saturation > 90% 
 Heart rate no more than 30 beats per minute above baseline, unless 
febrile 
 If febrile, subjects can be discharged home as long as their 
temperature is less than 101 degrees Fahrenheit 
 Patients must remain near the vicinity of a hospital with rapid access to an 
intensive care unit setting during the initial 48 hour period after treatment. 
 
 
5.2.1.7 Cycle 2, Day 2 
Patients will return to the study center on Day 2 for 24-hour (± 6 hours) post-dose assessments. 
No treatment will be administered during this visit, but the following assessments will be 
completed: 
• Physical examination (focused, symptom-based exam) 
• Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
• Clinical safety labs (as described in Appendix A) 
• Blood collection for: 
– Biomarker blood sample collection (analyses described in Appendix D) 
– Serum PK at 24 hours (+ 6 hours) from start of infusion (APX005M) 
• AE reporting, if applicable 
• Review of concomitant medications 


 
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5.2.1.8 Cycle 2, Day 3 
Patients will return to the study center on Day 3 for 48-hour (± 6 hours) post-dose assessments. 
No treatment will be administered during this visit, but the following assessments will be 
completed: 
• Physical examination (focused, symptom-based exam) 
• Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
• Blood collection for: 
– Biomarker blood sample collection (analyses described in Appendix D) 
– Serum PK at 48 hours (+ 6 hours) from the start of infusion (APX005M) 
• AE reporting, if applicable 
• Review of concomitant medications 
 
5.2.1.9 Cycle 2, Day 8 
Patients will return to the study center on Day 8 for post-dose assessments. No treatment will be 
administered during this visit, but the following assessments will be completed: 
• Physical Exam (focused, symptom-based exam) 
• Vital Signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
• Clinical Safety Labs (as described in Appendix A) 
• Blood collection for: 
– Biomarker blood sample collection (as described in Appendix D) 
– Serum PK at 168 hours (+ 6 hours) from start of infusion (APX005M) 
• AE reporting, if applicable 
• Review of concomitant medications 
 
5.2.1.10 Subsequent Cycles, Day 1 
 
A ± 2 day window is allowed for Day 1 in subsequent cycles post Cycle 2, Day 1. 
 
Dosing will be discontinued if the patient experiences either disease progression or unacceptable 
toxicity. 
 
At each infusion visit, patients are to remain at the study site after each administration of 
APX005M until completion of all post-dose assessments for safety monitoring. The following 
assessments will be performed at each visit unless otherwise noted (Appendix A). 
 
Prior to study drug infusion (within ≤72 hours unless otherwise stated): 


 
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– Physical examination including weight 
– Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
– ECOG performance status evaluation 
– Clinical safety labs (as described in Appendix A; results must be reviewed before 
dosing) 
– Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of 
dosing 
– Blood collection for: 
 Biomarker blood sample collection (analyses described in Appendix D) 
 Serum PK (for APX005M only) on Day 1 of every 3rd cycle (Cycles 3, 6, 9, 12, 
etc.) during dose escalation 
– pre-infusion (APX005M) 
– end of infusion (APX005M) 
 Pre-treatment serum anti-drug antibody (ADA) levels (for APX005M only) on 
Day 1 of every 3rd cycle (Cycles 3, 6, 9, 12, etc.) during dose escalation 
– Body and brain imaging will be performed every 8 weeks (±7 days) from the first dose 
for the first 4 months for patients who remain on treatment and every 12 weeks (±7 
days) thereafter and 28 days (± 7 days) after the last dose of study treatment. See 
Appendix A for further details. 
– Biopsy at primary tumor or metastatic site will be collected within 7 days prior to 
Cycle 5 Day 1 and at least 24 hours prior to dosing 
– AE reporting, if applicable 
– Review of concomitant medications 
• Study drug administration 
Pre- and post-study each drug administration:  Vital signs:  Patients can be discharged 
from clinic if: oxygen saturation > 90%, SBP no more than 30 mmHg below baseline, 
heart rate no more than 30 beats per minute above baseline, unless febrile.  If febrile, 
subjects can be discharged home as long as their temperature is less than 101 degrees 
Fahrenheit. 
 
5.2.1.11 End-of-Treatment Follow-up Period 
Patients will return to the study center twice, approximately 28 (± 7) days, followed by a 
subsequent visit 100 (±7) days after their last infusion of study drug, to complete the End-of- 
Treatment Follow-up Period. 
 
The following assessments will be performed: 


 
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• Physical examination including weight 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature in resting position 
after 5 minutes rest) 
• ECOG performance status evaluation 
• Clinical safety labs (as described in Appendix A) 
• 12-lead ECG (28 [±7] days, post last infusion of study drug visit only). 
• Radiological imaging: CT or MRI scan does not need to be repeated if performed within 
8 weeks prior to the End-of-Treatment Visits or if tumor progression was previously 
determined. 
• Urine pregnancy test (β-hCG) for women of childbearing potential 
• Tumor biopsy when feasible for patients who progressed, (28 [±7] days, post last infusion 
of study drug visit only) (for analyses described in Appendix D) 
• Biomarker blood sample collection 
• Serum anti-drug antibody (ADA) levels (for APX005M only) 
• AE reporting, if applicable, until 100 (±7) days after the last dose of study drug or until 
initiation of subsequent anti-cancer therapy. Patients with ongoing SAEs will be followed 
until resolution or stabilization. 
• Review of concomitant medications 
 
.2.2 
Phase 1b 
 
.2.2.1 
Screening Period (Day -28 to Day 0) 
 
Patients who have fully consented to participation in the study will undergo screening 
assessments within 28 days (4 weeks) prior to administration of the first infusion of nivolumab, 
cabiralizumab, and APX005M (unless otherwise stated). To determine if the patient meets all 
inclusion criteria and does not violate any exclusion criteria, the following procedures will be 
performed (Appendix B). 
 
• Written, signed informed consent must be collected prior to any study-specific 
procedures 
• Collection of a formalin fixed, paraffin-embedded (FFPE) tissue block and/or a fresh 
tumor biopsy from an accessible site will be mandatory, unless the Investigator deems 
that the subject does not have tumor in a site amenable to biopsy. Tumor biopsy 
collection will be performed at least 24 hours prior to dosing (as in Appendix D). 
• Complete medical and disease history 
• Demographic and baseline characteristics 
• Complete physical examination including height and weight 


 
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• Vital signs (blood pressure, pulse, respiratory rate, and temperature in resting position 
after 5 minutes rest) 
• Photo of periorbital region 
• ECOG performance status evaluation 
• Screening labs (as described in Appendix B) 
• Clinical safety labs (as described in Appendix B) 
• 12-lead ECG (required at screening, and if clinically indicated during the study) 
• Radiological imaging: After determining progression on an anti-PD-1/PD-L1 agent, body 
imaging of disease sites with PET CT, CT scans, or MRI is to be performed within 
28 days prior to Cycle 1 Day 1. MRI brain is also to be performed within 28 days prior 
to C1D1.  If MRI brain cannot be performed for reasons deemed by the Investigator, CT 
Head with and without contrast should be performed.  If the imaging is performed as part 
of the patient’s standard of care within 28 days of Cycle 1 Day 1, it does not need to be 
repeated if the documentation of results is provided and is adequate for RECIST v1.1. 
• Serum pregnancy test (β-hCG) for women of childbearing potential within 7 days of 
Cycle 1 Day 1 
• SAE reporting, if applicable 
• Document prior and concomitant medications 
 
.2.2.2 
Cycle 1, Day 1 
The following procedures will be performed: 
• Prior to study drug infusion (within ≤72 hours unless otherwise stated): 
– Verification of eligibility 
– Update medical and disease history to capture any changes from screening 
– Physical examination including weight 
– Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
– ECOG performance status evaluation 
– Clinical safety labs (as described in Appendix B); results must be reviewed before 
dosing) 
– Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of 
dosing 
– Blood collection for: 
 Biomarker blood sample collection (analyses described in Appendix D) 
 Pre-treatment serum anti-drug antibody (ADA) levels (for APX005M only) pre- 
treatment and post-infusion and on Day 1 of every 3rd cycle thereafter (Cycles 3, 


 
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6, 9, 12, etc.) 
 Serum PK (for APX005M only) and on Day 1 of every 3rd cycle thereafter 
(Cycles 3, 6, 9, 12, etc.) 
– pre-infusion (APX005M) 
– end of infusion (APX005M) 
– AE reporting, if applicable 
– Review of concomitant medications 
• Study drug administration 
– Pre- and post-study each drug administration: 
 Vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting 
position after 5 minutes rest) 
 Additional post-dose vital signs (heart rate, blood pressure, respiratory rate, and 
temperature in resting position after 5 minutes rest) at 4 hours (+ 30 minutes) after 
the start of the APX005M infusion 
– 4 hour post-dose vital sign criteria for discharge include: 
 Systolic BP no more than 30 mmHg below baseline 
 Oxygen saturation > 90% 
 Heart rate no more than 30 beats per minute above baseline, unless 
febrile 
 If febrile, subjects can be discharged home as long as their 
temperature is less than 101 degrees Fahrenheit 
 Patients must remain near the vicinity of a hospital with rapid access to an 
intensive care unit setting during the initial 48 hour period after treatment. 
 
 
.2.2.3 
Cycle 1, Day 2 
Patients will return to the study center on Day 2 for 24-hour (± 6 hours) post-dose assessments. 
No treatment will be administered during this visit, but the following assessments will be 
completed: 
• Physical examination 
• Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
• Clinical Safety Labs 
• AE reporting, if applicable 
• Review of concomitant medications 
 
• Blood collection for: 
  Biomarker blood sample collection (analyses described in Appendix D) 


 
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.2.2.4 
Cycle 2, Day 1 
 
The following procedures will be performed (a ± 2 day window is allowed for Day 1 in 
subsequent cycles post Cycle 1, Day 1): 
 
• Prior to study drug infusion infusion (within ≤72 hours unless otherwise stated): 
– Physical examination including weight 
– Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
– ECOG performance status evaluation 
– Clinical safety labs (as described in Appendix B; results must be reviewed before 
dosing) 
– Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of 
dosing 
– Blood collection for: 
 Biomarker blood sample collection (analyses described in Appendix D) 
– AE reporting, if applicable 
– Review of concomitant medications 
• Study drug administration 
– Pre- and post-study each drug administration: 
 Vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting 
position after 5 minutes rest) 
 Additional post-dose vital signs (heart rate, blood pressure, respiratory rate, and 
temperature in resting position after 5 minutes rest) at 4 hours (+ 30 minutes) after 
the start of the APX005M infusion 
– 4 hour post-dose vital sign criteria for discharge include: 
 Systolic BP no more than 30 mmHg below baseline 
 Oxygen saturation > 90% 
 Heart rate no more than 30 beats per minute above baseline, unless 
febrile 
 If febrile, subjects can be discharged home as long as their 
temperature is less than 101 degrees Fahrenheit 
 Patients must remain near the vicinity of a hospital with rapid access to an 
intensive care unit setting during the initial 48 hour period after treatment. 


 
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.2.2.5 
Cycle 2, Day 2 
Patients will return to the study center on Day 2 for 24-hour (± 6 hours) post-dose assessments. 
No treatment will be administered during this visit, but the following assessments will be 
completed: 
• Physical examination 
• Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
• Clinical safety labs (as described in Appendix B) 
• AE reporting, if applicable 
• Review of concomitant medications 
• Blood collection for: 
  Biomarker blood sample collection (analyses described in Appendix D) 
•  
 
.2.2.6 
Phase 1b, Subsequent Cycles, Day 1 
 
At each infusion visit, patients are to remain at the study site after each administration of 
APX005M until completion of all post-dose assessments for safety monitoring. The following 
assessments will be performed at each visit unless otherwise noted (Appendix B) (a ± 2 day 
window is allowed for Day 1 in subsequent cycles post Cycle 1, Day 1): 
 
• Prior to study drug infusion infusion (within ≤72 hours unless otherwise stated): 
– Physical examination including weight 
– Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position 
after 5 minutes rest) 
– ECOG performance status evaluation 
– Clinical safety labs (as described in Appendix A; results must be reviewed before 
dosing) 
– Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of 
dosing 
– Blood collection for: 
 Biomarker blood sample collection (analyses described in Appendix D) 
 Pre-treatment serum anti-drug antibody (ADA) levels (for APX005M only) on 
Day 1 of every 3rd cycle (Cycles 3, 6, 9, 12, etc.) 
 Serum PK (for APX005M only) on Day 1 of every 3rd cycle (Cycles 1, 3, 6, 9, 12, 
etc.) 
– 15 (±5) minutes pre-infusion (APX005M) 
– 15 (±5) minutes post-infusion (APX005M) 


 
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– Body and brain imaging will be performed every 8 weeks (±7 days) from the first dose 
for the first 4 months for patients who remain on treatment and every 12 weeks (±7 
days) thereafter and 28 days (± 7 days) after the last dose of study treatment. See 
Appendix B for further details. 
– Biopsy at primary tumor or metastatic site will be collected within 7 days prior to 
Cycle 5 Day 1 and at least 24 hours prior to dosing 
– AE reporting, if applicable 
– Review of concomitant medications 
• Study drug administration 
Pre- and post-study each drug administration:  Vital signs:  Patients can be discharged 
from clinic if: oxygen saturation > 90%, SBP no more than 30 mmHg below baseline, 
heart rate no more than 30 beats per minute above baseline, unless febrile.  If febrile, 
subjects can be discharged home as long as their temperature is less than 101 degrees 
Fahrenheit. 
 
.2.2.7 
End of Treatment Follow-up Period 
See Section 5.2.1.11 
 
5.2.3 Long-Term Follow-up for All Patients 
Patients should continue onto Long-Term Follow-up after completing the End-of-Treatment 
Follow-up Period. 
 
Patients will be followed every 12 (±2) weeks for survival. Patients who discontinue treatment 
while showing clinical benefit (complete response [CR], partial response [PR], or stable disease 
[SD]) should have tumor assessments during these visits for duration of response. 
 
Long-Term Follow-up for survival may be conducted by telephone, rather than by an in-person 
visit, once tumor progression is determined or use of subsequent anti-cancer therapy has been 
initiated. 
 
During the Long-Term Follow-up Period, if the patient undergoes local therapy (e.g., resection, 
radiation) or new systemic therapy is initiated, this should be documented. Patients should be 
followed until death, loss to follow-up, withdrawal of consent, or study termination by the 
Sponsor. 
 
5.3 
Study Assessments 
 
5.3.1 Safety Assessments 
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status (Appendix ), 
ECG, blood pressure, heart rate, temperature, and oxygen saturation by pulse oximetry at rest 
(also monitor amount of supplemental oxygen, if applicable) within 28 days prior to first dose. 


 
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Safety assessments including serum hematology, chemistry, ECOG, weight and other 
assessments including ECG (if clinically indicated) will be done as part of standard care during 
each visit prior to dosing as noted in Appendix A, Appendix B, and Appendix C. Serum 
chemistry labs will be checked at screening and any abnormalities outside of the normal range 
will be followed closely with evaluation of symptoms and follow-up laboratory data. Patients 
will also be monitored for any infusion-related AEs during dosing and followed up accordingly 
based on protocol guidelines. Pre-medications including steroids, antihistamines or other 
treatments will be given prior to future dosing if a patient develops infusion reactions per 
protocol guidelines. 
 
Any patient who has received study drug will be evaluated for safety. Toxicity assessments will 
be continuous during the treatment phase and End-of-Treatment Follow-up Period clinic visits. 
Once patients reach the Long-Term Follow-up Period (and tumor progression has been 
determined or use of subsequent anti-cancer therapy has been initiated), documented telephone 
calls or email correspondence to assess the patient’s status are acceptable. 
 
AEs and laboratory values will be graded according to the NCI CTCAE v5.0. 
 
Oxygen saturation by pulse oximetry at rest (also the amount of supplemental oxygen, if 
applicable) should be assessed at each on-study visit prior to dosing. If a patient shows changes 
on pulse oximetry or other pulmonary-related signs (hypoxia, fever) or symptoms (e.g. dyspnea, 
cough, fever) consistent with possible pulmonary AEs, the patient should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management guidelines in Section 4.8 and Section 4.9. 
 
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious AE or SAE page. 
 
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (e.g., suspected 
drug-induced liver enzyme evaluations) will be monitored during the follow-up phase via 
on-site/local labs until all study drug-related toxicities resolve, return to baseline, or are deemed 
stable. 
 
Additional testing or assessments may be performed as clinically necessary or as required by 
institutional or local regulations. 
 
5.3.2 Efficacy Assessments 
 
5.3.2.1 Primary Efficacy Parameters 
The primary efficacy parameter is the objective response rate (ORR; number of patients with 
confirmed response of CR or PR, divided by the total number of treated patients who are 


 
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evaluable for a response). Tumor response status will be assessed using RECIST v1.1 by 
investigator review. 
 
Board-certified radiologists will determine radiographic response and/or progression following 
enrollment in according to RECIST v1.1. 
 
5.3.2.1.1  Tumor Assessment 
Tumor assessments will be performed at Screening (within 28 days prior to first dose), then 
every 8 weeks (± 7 days) for a total of 2 sets of imaging studies, followed by every 12 weeks (+ 
7 days) thereafter. Imaging will include an initial MRI of the brain with and without contrast as 
well as body imaging with either PET CT, CT scans, or MRI.  If an MRI of the brain is 
contraindicated, a head CT with and without contrast should be performed.  Brain imaging can 
be performed every 6 months unless clinically indicated in shorter intervals, such as in patients 
with metastatic melanoma.  All patients should have tumor response parameters assessed at the 
End-of-Treatment visit unless a tumor assessment has been performed within 8 weeks prior to an 
End-of-Treatment Visit or if tumor progression was previously determined. Patients who enter 
Long-Term Follow-up while showing clinical benefit should have tumor assessments every 12 
weeks (±7 days) for duration of response. The same measuring modality should be preferably 
used by the site to maintain consistency across the study. 
 
Response will be evaluated using RECIST v1.1. 
 
5.3.2.2 Additional Efficacy Parameters 
Additional efficacy parameters may include the following: Overall Survival (OS, 1-year OS, and 
median OS), progression-free survival (PFS), and duration of response (DOR) for those patients 
with confirmed responses, based on RECIST v 1.1. 
 
CT or MRI will be performed at screening, during treatment, and at the End-of-Treatment Visit 
per protocol. Measurements of change in tumor burden must be reviewed and documented after 
each measurement. 
 
5.3.2.3 Tumor Biopsy for Fresh Tumor Tissue Collection 
Biopsy at the primary tumor site or metastatic site will be collected prior to Cycle 1 Day 1 and 
on-treatment (within 7 days prior to Cycle 5, Day 1, and at least 24 hours prior to dosing) for all 
patients. Patients may also have on-treatment biopsy upon documented tumor response and post- 
treatment biopsy upon documented tumor progression, as deemed safe and accessible by the 
Investigator (Appendix E). If available, tumor tissue obtained from post-treatment procedures 
such as surgery may also be collected. 
 
Biopsied lesions may become inflamed, bleed, or change dimensions, which could result in 
inaccurate tumor measurements. Therefore, it is recommended not to use the biopsied lesion as a 
target lesion when assessing the response by RECIST v 1.1 criteria when possible. 


 
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5.3.3 Pharmacokinetic Assessments 
Blood samples for the PK evaluation of APX005M will be collected from all patients in the 
Phase 1 dose escalation component, as described in Section 5 and in Appendix A and Appendix 
D. 
 
Blood samples will be collected and processed for serum according to the instructions provided 
in the Laboratory Manual. 
 
5.3.4 Biomarker Assessments 
A variety of factors that could potentially predict clinical response to the combination of 
APX005M, cabiralizumab and nivolumab will be investigated in peripheral blood and in tumor 
specimens collected from patients prior to and during treatment. Data from these investigations 
will be evaluated for associations with response and/or safety (AE) data. In addition, analyses of 
markers between the treatment arms will provide the necessary data to identify and validate 
biomarkers with predictive vs prognostic value. Complete instructions on the collection, 
processing, handling and shipment of all samples described herein will be provided in a 
Laboratory Manual. 
 
5.3.4.1 Tumor Tissue Specimens 
Mandatory tumor tissue specimens in the form of a paraffin embedded block, and/or fresh frozen 
tissue, will be submitted. These biopsy samples should be excisional, incisional or core needle as 
fine needle aspirates or other cytology specimens are insufficient for downstream biomarker 
analyses. Patients undergoing core needle biopsy will be required to provide a minimum of two 
cores. Tissue samples are being collected to evaluate the PD effect of study drugs on the tumor 
microenvironment. These samples may also undergo RNA sequencing to determine the effect of 
study drugs on gene expression, single cell RNA-seq, CyTOF and quantitative 
immunofluorescence.  These analyses may help predict future response to treatment. A summary 
of analyses to be performed are described in Appendix D. 
 
Tumor biopsy specimens will be obtained before treatment and on-treatment to examine immune 
infiltrates and expression of selected tumor markers. Tumor biopsies may be obtained upon 
documentation of tumors that have responded and/or progressed on or after treatment to 
understand mechanisms of resistance. 
 
Samples may be assessed for the expression of immune or disease related genes and/or proteins, 
as well as for the presence of immune cell populations using a variety of methodologies 
including but not limited to immunofluorescence,  CyTOF, bulk RNA-seq, and single cell RNA 
Seq. 
 
Blood samples for exploratory serum biomarker analyses will be drawn at the time points 
indicated in the Schedule of Assessments (Appendix A, Appendix B, and Appendix C). Blood 
samples will be processed to collect serum and PBMCs. and stored frozen prior to analysis. In 
addition to the PK analyses mentioned above, serum samples will be analyzed to determine the 


 
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PD effect of study drugs on cytokines, CSF1R ligand, and CD40 ligand concentrations. Whole 
blood will be collected, spun and stored to profile PBMCs by methods such as CyTOF or single 
cell RNA-seq. Samples may be also assessed by multiplex ELISA, seromics, and/or other 
relevant multiplex-based protein assay methods. Serum marker analyses may also help establish 
a biomarker signature that may predict benefit or correlate with efficacy that can be used to 
inform this and future studies. Timings of sample collection are listed in Appendix C and 
analyses to be performed are described in Appendix D. 
 
5.3.4.2 Flow Cytometry 
Pre-treatment and on-treatment whole blood and PBMC samples will be analyzed by flow 
cytometry to study the effects of APX005M, cabiralizumab and nivolumab on various peripheral 
blood immune cell subsets. Timing of sample collection is listed in Appendix C and analyses to 
be performed are described in Appendix D. 


 
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APPROVED BY THE YALE UNIVERSITY IRB 5/2/2018 VALID THROUGH 2/22/2019 
 
 
 
6. 
Adverse Events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation, patient-administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug. 
 
The causal relationship to study drug is determined by an investigator and should be used to 
assess all AEs. The causal relationship can be one of the following: 
• Definitely related 
• Possibly related 
• Unlikely related 
• Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
 
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a patient. (In order to prevent reporting bias, patients should not be questioned 
regarding the specific occurrence of one or more AEs.) 
 
6.1 
Collection of Adverse Events 
Any new symptoms, injury or worsening of symptoms that occur following signing of the 
informed consent form (ICF) but prior to first infusion (Cycle 1 Day 1) will be considered 
pretreatment events and reported on the Medical History page of the electronic case report form 
(eCRF), unless they directly correlate to a study-related procedure. Adverse event reporting will 
continue until 100 (±7) days after the last dose of study drug or until initiation of subsequent 
anti-cancer therapy. 
 
6.2 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death. Death may occur as a result of the underlying disease process. All 
events other than progression of underlying disease that result in death during the 
reporting period up to 100 (±7) days after the last dose of study drugs or until initiation 
of subsequent anti-cancer therapy, whichever comes first, must be treated as an SAE and 
reported as such. 
• Is life-threatening (defined as an event in which the patient was at risk of death at the 
time of the event) 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 


 
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• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event (defined as a medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the patient or may require intervention [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.]). Potential DILI is also considered an important medical event. (See Section 6.7 
for the definition of potential DILIs.) 
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE. 
 
Although pregnancy and potential drug-induced liver injury (DILI), are not always serious by 
regulatory definition, these events must be handled as SAEs and reported within the SAEs 
timeline (See Section 6.2.1 for reporting pregnancies). 
 
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).  
 
Note: The following hospitalizations are not considered SAEs in this clinical study: 
• Visit to the emergency room or other hospital department <24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event) 
• Elective surgery, planned prior to signing consent 
• Admissions as per protocol for a planned medical/surgical procedure 
• Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 
• Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases. 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
• Admission for administration of anti-cancer therapy in the absence of any other SAEs 
• Hospitalization for an event solely related to disease progression or for an elective or 
planned procedure to treat a pre-existing condition 
• Admission to hospice or care facility to support activities of daily living 
 
6.2.1 Serious Adverse Event Reporting 
 
The Investigator should report any SAE that occurs after the first study drug dose and until 
100 (±7) days after the last dose of study drug or until initiation of subsequent anti-cancer 
therapy, whichever comes first. Protocol-specified procedure related SAE will be collected 
following signing of ICF. 


 
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An SAE report should be completed for any event where doubt exists regarding its seriousness. 
 
If the Investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
 
• SAEs, related or unrelated to study drug, and pregnancies must be reported to the PI 
within 24 hours of becoming aware of the event. SAEs must be recorded on the SAE 
Report Form, and pregnancies must be recorded on a Pregnancy Surveillance Form 
(paper forms). SAE and pregnancy data reporting must be done on the paper 
SAE/Pregnancy Surveillance Forms provided by the Industry Collaborators. They are to 
be transmitted via email or fax to the Yale DSMC. If related to study drugs, SAEs will be 
reported to the HIC within 48 hours. 
 
Yale Safety Reporting: 
 
The PIs and IND holders will monitor the clinical trial for safety.  The PI will assess all 
expedited adverse events and will periodically review all adverse events observed on the trial. 
Yale Cancer Center standard operating procedures (SOPs) for assessment and reporting of 
adverse events are followed which are in compliance with 21 CFR 312.32 and 312.22. 
The clinical trial data consisting of all required observations, AEs, and laboratory data are 
entered into a computerized database in a timely manner. The accuracy and completeness of the 
database, timely submission of SAEs and compliance with the protocol, is assured by periodic 
auditing conducted by the Yale Cancer Center Office of Protocol Review and Monitoring, which 
reports to the Yale Data Safety & Monitoring Committee (DSMC). Safety data will be 
submitted to the DSMC at least once yearly or more often as required by the DSMP. The DSMC 
will conduct an internal audit of the study every 6-12 months, per institutional requirements. On 
a regular interval basis, status reports of all laboratory parameters, AEs and SAEs are reviewed 
by the PI to view composite data across subjects.  Regular meetings are held to discuss ongoing 
patient treatment and adverse events. 
 
Expedited SAE reports submitted by the Investigator to FDA are also copied to the HIC and 
other relevant institutional safety committees within the timeframes required by Yale. These will 
also be copied to BMS and Apexigen.  The Principal Investigator will distribute manufacturer- 
provided safety reports and updated Toxicity Lists to the institution’s HIC and all relevant 
personnel involved in the conduct of the study. The Toxicity List, in addition to the 
Investigator’s Brochure, will be used as a reference for reporting any new SAE. 
Possible actions taken by the PI or the Yale DSMC if a new unexpected toxicity is identified 
from the above safety review, or if the periodic review of all adverse events and laboratory data 
indicates a pattern of incidence or severity of toxicity that raises a safety concern, can be to: 
1. Revise consent form 
2. Amend the protocol 
3. Suspend the protocol 
 
All AEs found to be expected or non-serious, will be included in the Annual Report. 


 
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SAE reporting to BMS and Apexigen: 
• All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 100 (+7) days of discontinuation of dosing or until 
initiation of subsequent anti-cancer therapy, whichever comes first, must be reported to 
BMS Worldwide Safety and to Apexigen Safety, whether related or not related to study 
drug. If applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (eg, a follow-up skin biopsy). 
• Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, are collected, including those thought to be associated 
with protocol-specified procedures. The investigator should report any SAE occurring after 
these aforementioned time periods, which is believed to be related to study drug or 
protocol-specified procedure. 
• An SAE report should be completed for any event where doubt exists regarding its 
seriousness; 
• If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
 
A Medwatch SAE form will be used to report SAEs to BMS and Apexigen. 
 
• Worldwide.Safety@bms.com 
• drugsafety@apexigen.com 
• For studies with long-term follow-up periods in which safety data are being reported, include 
the timing of SAE collection 
• The Sponsor will reconcile the clinical database AE cases (case level only) transmitted to 
BMS Global Pharmacovigilance (Worldwide.Safety@bms.com) and to Apexigen Safety 
(drugsafety@apexigen.com) 
o The Investigator will request from BMS GPV&E, aepbusinessprocess@bms.com the 
SAE reconciliation report and include the BMS protocol number every 3 months and 
prior to data base lock or final data summary. 
o The Investigator will request from Apexigen Safety, drugsafety@apexigen.com a 
CA025-007 specific listing of SAEs and include the Apexigen protocol number on an 
ever 3-month basis and prior to data base lock or final data summary 
o GPV&E and Apexigen Safety will send the investigator the report to verify and confirm 
all SAEs have been transmitted to BMS GPV&E and Apexigen Safety. 
o The data elements listed on the GPV&E reconciliation report will be used for case 
identification purposes. If the Investigator determines a case was not transmitted to 
BMS GPV&E and Apexigen Safety, the case should be sent immediately to BMS 
(Worldwide.Safety@bms.com) and Apexigen (drugsafety@apexigen.com).  
• In addition to the Sponsor Investigator’s responsibility to report events to their local health 
authority (HA), suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS and by Apexigen to the relevant competent health authorities in all 
concerned countries according to local regulations (either as expedited and/or in aggregate 
reports).  
• In accordance with local regulations, BMS and Apexigen will notify sponsor investigators of 


 
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all reported SAEs that are suspected (related to the investigational product) and unexpected 
(i.e., not previously described in the IB). An event meeting these criteria is termed a 
Suspected Unexpected Serious Adverse Reaction (SUSAR). Sponsor investigator 
notification of these events will be in the form of either a SUSAR Report or a Semi-Annual 
SUSAR Report. 
o Other important findings which may be reported by BMS or by Apexigen as an 
Expedited Safety Report (ESR) include: increased frequency of a clinically significant 
expected SAE, an SAE considered associated with study procedures that could modify 
the conduct of the study, lack of efficacy that poses significant hazard to study subjects, 
clinically significant safety finding from a nonclinical (eg, animal) study, important 
safety recommendations from a study data monitoring committee, or sponsor decision 
to end or temporarily halt a clinical study for safety reasons. 
o Upon receiving an ESR from BMS or Apexigen, the investigator must review and retain 
the ESR with the IB. Where required by local regulations or when there is a central 
IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
and Apexigen within 24 hours \ 1 Business Day of becoming aware of the event. SAEs must be 
recorded on either CIOMS, MedWatch, or approved site SAE form. 
 
Pregnancies must be reported and submitted to BMS and to Apexigen. Investigator will perform 
due diligence follow-up using the BMS Pregnancy Form which the investigator must complete.  
 
BMS SAE Email Address:  Worldwide.Safety@BMS.com 
Apexigen SAE Email Address: drugsafety@apexigen.com 
 
BMS SAE Facsimile Number: +1 609-818-3804 
Apexigen SAE Facsimilie Number (required for SAE and pregnancy reporting):  
+1 510-295- 6449 
- 
If only limited information is initially available, follow-up reports are required  
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to 
BMS and Apexigen  using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following: 
 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
 
Not related: There is not a reasonable causal relationship between study drug administration and 


 
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the AE. 
 
The term “reasonable causal relationship” means there is evidence to suggest a causal relationship. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
 
Non-Serious Adverse Event 
 
• Non-serious Adverse Events (AE) are to be provided to BMS and to Apexigen in aggregate 
via interim or final study reports as specified in the agreement or, if a regulatory requirement 
[e.g., IND US trial] as part of an annual reporting requirement. 
• Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the subjects. 
 
 
Non-serious Adverse Event Collection and Reporting 
 
The collection of non-serious AE information should begin at initiation of study drug. All non-
serious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 (+7) days following the last 
dose of study treatment or until initiation of subsequent anti-cancer therapy, whichever comes first.  
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
 
Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted any laboratory abnormality that required the subject to receive specific corrective 
therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value). 


 
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Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant). 
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either 
the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE 
reporting procedures. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the CIOMS, 
MedWatch, BMS Pregnancy Surveillance Form, or approved site SAE form.  A BMS Pregnancy 
Surveillance Form may be provided upon request. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must sign an informed consent form for disclosure of this 
information. 
 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious AE, 
as appropriate, and reported accordingly. 


 
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Adverse Events that are routinely collected according to GCP shall be submitted to BMS every three 
(3) months by the last working day of the third month.   
The Adverse Event information required to be sent to BMS is noted in the ‘Bristol-Myers Squibb 
Early Asset Investigator Sponsored Research (ISR) Import Plan’ which describes the method of 
collection 
and 
submission 
to 
BMS 
via 
the 
mailbox: 
 
 
MG-RD-GPVE-
PHARMACOVIGILANCE@bms.com  
 
When the file is submitted to BMS, it must be noted whether the file contains: 
 
All Non Serious Adverse Events (only adverse events not previously submitted to BMS within 
the 3 months) 
 
 
6.3 
Non-Serious Adverse Events 
A non-serious adverse event is any AE not classified as serious. 
 
6.3.1 Non-serious Adverse Event Reporting 
 
Non-serious AEs should also be followed to resolution or stabilization, or reported as SAEs if 
they become serious (see Section 6.2.1). Follow-up is also required for non-serious AEs that 
cause interruption or discontinuation of study drug and for those present at the end-of-study 
treatment, as appropriate. All identified non-serious AEs must be recorded and described on the 
appropriate AE page of the CRF. 
 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported during the course of the study. 
 
6.4 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the appropriate CRF 
page or SAE Report Form as appropriate: 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory test result abnormality that required the patient to have study drug 
discontinued or interrupted 
• Any laboratory test result abnormality that required the patient to receive specific 
corrective therapy. 


 
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It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting Investigator (e.g., anemia versus low hemoglobin value). 
 
6.5 
Pregnancy 
 
If, following initiation of the investigational product, it is discovered that a study patient is 
pregnant or may have been pregnant at the time of investigational product exposure, including 
during at least 5 half-lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner. 
 
The Investigator must immediately notify the Industry Collaborators of this event and complete 
and forward a Pregnancy Form to the Sponsor (or designee) within 24 hours and in accordance 
with SAE reporting procedures described in Section 6.2.1. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information, must be reported on the Pregnancy 
Surveillance Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form. 
 
6.6 
Overdose 
 
Any dose of study drug in excess of 50% of the dose level specified in the protocol is considered 
to be an overdose. Signs and symptoms of an overdose that meet any SAE criterion must be 
reported as an SAE in the appropriate time frame and documented as clinical sequelae to an 
overdose. There is no known antidote for a drug overdose to either cabiralizumab or nivolumab. 
In the event of an overdose, patients should be closely monitored and given appropriate 
supportive treatment. 
 
6.7 
Potential Drug Induced Liver Injury 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences 
of potential DILIs, meeting the defined criteria, must be reported as SAEs. 
 
Potential drug induced liver injury is defined as: 
 
1. 
ALT or AST elevation >3x ULN 
and 
2. 
Total bilirubin >2x ULN (> 2x baseline in patients with Gilbert’s syndrome) without initial 
findings of cholestasis (elevated serum alkaline phosphatase) or INR > 1.5 xULN (in the 
absence of anticoagulation) 
and 
3. 
No other immediately apparent possible causes of aminotransferase elevation and 


 
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hyperbilirubinemia including, but not limited to viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drugs known to be hepatotoxic. 


 
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7. 
Statistical Considerations 
7.1 
Sample Size Determination 
 
The primary endpoint of safety and MTD of APX005M in combination with cabiralizumab and 
nivolumab will be determined by a 3+3 dose escalation design as described above.  In this first 
phase, patients will be enrolled regardless of disease (melanoma, NSCLC, and RCC). The 
maximum tolerated dose (MTD) will be estimated independently of cohort. Upon completion of 
this determination, we will proceed to three parallel two-stage designs, separately for each of the 
three disease cohorts using the MTD. Patients exposed to the MTD in the dose escalation phase 
will be carried over to the appropriate two-stage design. 
 
Simon’s two-stage design will be used in the phase 1b portion of the trial which will include 3 
separate and parallel disease-specific cohorts (melanoma, NSCLC, and RCC). For each of the 
three tumor types, an immune therapy regimen which is modestly active in patients whose 
disease had progressed on PD-1/PD-L1 inhibitors would have a response rate (RR) of 10%. The 
null hypothesis that the true response rate is 10% will be tested against a one-sided alternative. 
A regimen worthy of further investigation in any of the three tumor types will have a RR of 25%. 
In the first stage, 13 patients of each cancer will be accrued.  If there are 1 or fewer responses in 
these 13 patients, that cohort will be stopped. Otherwise, 21 additional patients of the same 
disease cohort will be accrued for a maximum total of 34 patients per disease cohort. Each of the 
three null hypotheses will be rejected if 6 or more responses are observed in 34 patients for each 
cohort.  This design yields a type I error rate of 0.1 and a power of 80% when the true response 
rate is 25% in each of the three cohorts. There will not be a correction for multiplicity across the 
three separate cohorts. 
 
7.2 
Demographics and Baseline Characteristics 
Demographic data, medical history, other baseline characteristics, concomitant disease, and 
concomitant medication will be summarized by cohort and overall. To determine whether the 
criteria for study conduct are met, corresponding tables and listings will be provided. These will 
include an assessment of protocol deviations, study drug accountability, and other data that may 
impact the general conduct of the study. 
 
7.3 
Efficacy Analyses 
For each disease type, response to treatment will be summarized for all treated patients for ORR, 
defined as the ratio of the number of patients that achieve an objective response (a BOR of CR or 
PR) to total number of patients who are evaluable for a response, which may include patients 
who die or for which clinical progression has occurred even if a post-treatment scan has not been 
performed. Exact confidence interval will be constructed for the response rate. Overall Survival, 
survival at 1 year, and median survival will be estimated by the Kaplan-Meier method. The 
corresponding confidence interval will also be presented. 


 
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7.4 
Safety Analyses 
Safety analyses will be performed for all treated patients. Incidence of AEs, clinical laboratory 
information, vital signs, ECOG performance status, weight, and ECGs will be tabulated and 
summarized. 
 
Incidence of AEs will be summarized overall and with separate summaries for SAEs, AEs 
leading to discontinuation, AEs leading to death, and NCI-CTCAE v5.0 Grade 3 or higher AEs. 
 
Weight and vital signs will be summarized descriptively (n, mean, standard deviation, median, 
minimum, and maximum). ECOG performance status will be summarized categorically and 
descriptively. 
 
Shift tables displaying patient counts and percentages classified by baseline grade and maximum 
grade on treatment will be provided for laboratory data by cohort and overall. A marked 
laboratory change is defined as a shift from a baseline Grade 0 to Grade 3 (non-hematologic) or 
Grade 4 (hematologic) on treatment, or a shift from a baseline Grade 1 to Grade 4 on treatment. 
The number and percentage of patients with marked laboratory changes will be tabulated by 
cohort and overall. 
 
7.5 
Pharmacokinetic Analyses 
Individual and mean serum concentration of APX005M versus time data will be plotted by dose 
level. Summary statistics will be tabulated for the serum concentration-time data and estimated 
PK parameters of APX005M, as appropriate.  For APX005M, PK parameters including Cmax, 
AUC, Cmin, CL, and Vss will be estimated. 
 
7.6 
Biomarker Analyses 
To assess the PD effects of APX005M, cabiralizumab and nivolumab on various exploratory 
biomarkers (such as soluble factors, peripheral blood immune cell subsets, and other markers as 
assessed) summary statistics for these markers and their changes (or percent changes) from 
baseline will be tabulated by visit and dose. In addition, the time course of exploratory biomarker 
outcomes will be investigated graphically by summary plots or individual patient plots over time. 
Patterns of change in these biomarker values over time and how the patterns differed among dose 
levels may be additionally investigated using appropriate modeling, for example, by linear mixed 
effects models. 
 
Possible associations of biomarker measures with clinical efficacy measures including OS will 
be investigated based on data availability. Methods such as, but not limited to, logistic regression 
may be used to further investigate such associations. 
 
If at the time of database lock for the primary and secondary endpoints, biomarker data related to 
the exploratory objectives are not available, these biomarker results may not be included in the 
clinical study report (CSR) but reported separately. 


 
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Selected serum markers: Analyses are descriptive in nature and intended to examine the 
distribution of expression and assess potential associations between expression and efficacy 
measures. If there is an indication of a meaningful association, future work will evaluate 
expression as a predictive biomarker, including selection of an optimal expression cut-off to 
classify patients as positive or negative.  See Appendix D. 


 
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8. 
Ethical Considerations 
8.1 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by GCP guidelines of the ICH and the Declaration of Helsinki [81]. The study 
also will be carried out in compliance with local legal requirements. 
 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the Informed Consent Form (ICF) will receive Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study. 
 
All potential serious breaches must be reported to the Sponsor immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
patients of the study or the scientific value of the study. 
 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
 
8.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the Investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, ICF, patient recruitment materials (e.g., advertisements), and 
any other written information to be provided to patients. The Investigator or Sponsor should also 
provide the IRB/IEC with a copy of the IB or product labeling information to be provided to 
patients and any updates. 
 
The Investigator should provide the IRB/IEC with reports, updates and other information (e.g., 
expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
 
8.3 
Informed Consent 
All information about the clinical study, including patient information and the ICF, is prepared 
and used for the protection of the human rights of the patient according to ICH GCP guidelines 
and the Declaration of Helsinki [81]. 
 
The ICF, prepared by the Investigator with the assistance of the Sponsor, must be approved 
along with the study protocol by the IEC/IRB and be acceptable to the Sponsor. Before each 
patient is enrolled on the study, written informed consent will be obtained according to the 
regulatory and legal requirements. A copy of the signed ICF will be retained by the patient and 
the original will be filed in the Investigator’s site file, unless otherwise agreed. The Investigator 


 
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will not undertake any investigation specifically required only for the clinical study until valid 
consent has been obtained. The terms of the consent and when it was obtained must be 
documented in the source documents and in the CRF. 
 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IRB/IEC, 
and signed by all patients subsequently enrolled in the study as well as those currently enrolled in 
the study. 
 
All signed and dated ICFs must remain in each patient’s study file and must be available for 
verification by PIs at any time. 
 
The rights, safety, and well-being of the patients are the most important considerations and 
should prevail over interests of science and society. 


 
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9. 
Study Management 
9.1 
Compliance 
 
9.1.1 Compliance with the Protocol and Protocol Revisions 
The study shall be conducted as described in this approved protocol. All revisions will be 
approved by the sponsor. Investigators should not implement any deviation or change to the 
protocol without prior review and documented approval of the HIC of an amendment, except 
where necessary to eliminate an immediate hazard(s) to Patients. 
 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard prior to 
obtaining HIC approval, as soon as possible the deviation or change will be submitted to: 
• HIC for review and approval 
• BMS and Apexigen 
 
If an amendment substantially alters the study design or increases the potential risk to the patient: 
(1) the consent form must be revised and submitted to the HIC for review and approval; (2) the 
revised form must be used to obtain consent from patients currently enrolled in the study if they 
are affected by the amendment; and (3) the new form must be used to obtain consent from new 
patients prior to enrollment. 
 
9.1.2 Yale Safety Reporting and Monitoring (DSMP) 
The PI and IND holders will monitor the clinical trial for safety. The PI will assess all expedited 
adverse events and will periodically review all adverse events observed on the trial. Yale Cancer 
Center standard operating procedures (SOPs) for assessment and reporting of adverse events are 
followed which are in compliance with 21 CFR 312.32 and 312.22. 
 
The clinical trial data consisting of all required observations, AEs, and laboratory data are 
entered into a computerized database in a timely manner. The accuracy and completeness of the 
database, timely submission of SAEs and compliance with the protocol, is assured by periodic 
auditing conducted by the Yale Cancer Center Office of Protocol Review and Monitoring, which 
reports to the Yale Data Safety & Monitoring Committee (DSMC). Safety data will be 
submitted to the DSMC at least once yearly or more often as required by the DSMP. The DSMC 
will conduct an internal audit of the study every 6-12 months, per institutional requirements. On 
a regular interval basis, status reports of all laboratory parameters, AEs and SAEs are reviewed 
by the PI to view composite data across subjects.  Regular meetings are held to discuss ongoing 
patient treatment and adverse events. 
 
Expedited SAE reports submitted by the Investigator to FDA are also copied to the HIC and 
other relevant institutional safety committees within the timeframes required by Yale. These will 
also be copied to BMS and Apexigen.  The Principal Investigator will distribute manufacturer- 
provided safety reports and updated Toxicity Lists to the institution’s HIC and all relevant 


 
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personnel involved in the conduct of the study. The Toxicity List, in addition to the 
Investigator’s Brochure, will be used as a reference for reporting any new SAE. 
 
Possible actions taken by the PI or the Yale DSMC if a new unexpected toxicity is identified 
from the above safety review, or if the periodic review of all adverse events and laboratory data 
indicates a pattern of incidence or severity of toxicity that raises a safety concern, can be to: 
1. Revise consent form 
2. Amend the protocol 
3. Suspend the protocol 
 
All AEs found to be expected or non-serious, will be included in the Annual Report. AEs 
considered to be serious will be communicated to the industry collaborators Bristol-Myers 
Squibb and Apexigen within 24 hours. 
During the study, the DSMC will perform routine monitoring visits to review protocol 
compliance, compare CRFs and individual patients’ medical records, assess drug accountability, 
and ensure that the study is being conducted according to pertinent regulatory requirements. CRF 
entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. 
 
Yale University will take particular care in ensuring that original imaging source data (images, 
echo images, etc.) are maintained and accessible for monitoring, and that these original source 
data are then archived on a long-term basis in compliance with ICH GCP (Section 9.1). These 
images must be stored in a secure location until the Sponsor (or designee) authorizes their 
destruction, and must be retrievable by study patient number in the event of an audit. 
 
9.1.2.1 Source Documentation 
All data obtained during this study should be entered into the CRFs promptly. All source 
documents from which CRF entries are derived should be placed in the patient’s medical 
records. CRF fields for which source documents will typically be needed include laboratory 
assessments, physical exam reports, nursing notes, ECG recordings, hospital records, and CT or 
MRI reports. 
 
The CRFs for each patient will be checked against source documents at the study site by the Site 
Monitor. 
 
Instances of missing or uninterpretable data will be discussed with the Investigator for resolution. 
 
9.1.3 Investigational Site Training 
The Sponsor or designee will provide quality investigational staff training prior to study 
initiation. Training topics will include but are not limited to: GCP, AE reporting, study details 
and procedure, CRFs, study documentation, informed consent, and enrollment of WOCBP. 


 
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9.2 
Records 
 
9.2.1 Records Retention 
The study site will maintain a study file, which should contain, at minimum, the Investigator’s 
Brochures, the protocol and any amendments, the protocol for tissue sampling, drug 
accountability records, correspondence with the IEC/IRB and the Sponsor (or designee), and 
other study-related documents. 
 
The Sponsor agrees to keep records and those documents that include but are not limited to the 
identification of all participating patients, medical records, study-specific source documents, 
source worksheets, all original signed and dated ICFs, copies of all eCRFs, query responses, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities 
and FivePrime or its designees. 
 
The Sponsor shall retain records required to be maintained for a period of 5 years following the 
date a marketing application in an ICH region is approved for the drug for the indication for 
which it is being investigated or, if no application is to be filed or if the application is not 
approved for such indication, until at least 5 years after the investigation is discontinued. 
However, these documents should be retained for a longer period if required by the applicable 
regulations or if needed by the Sponsor. In addition, the Investigator must make provision for the 
patients’ medical records to be kept for the same period of time. 
 
No data should be destroyed without the agreement of the Sponsor. Should the Investigator wish 
to assign the study records to another party or move them to another location, the Sponsor must 
be notified in writing of the new responsible person and/or the new location. 
 
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site. 
 
9.2.2 Study Drug Records 
It is the responsibility of the Investigator to ensure that a current disposition record of each study 
drug is maintained at each study site where study drugs are inventoried and dispensed. Records 
or logs must comply with applicable regulations and guidelines and should include: 
• Amount received and placed in storage area 
• Amount currently in storage area 
• Label identification number or batch number 
• Amount dispensed to and returned by each patient, including unique patient identifiers 
• Non-study disposition (e.g., lost, wasted) 
• Amount destroyed at study site, if applicable 
• Amount returned to designated parties 


 
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• Dates and initials of person responsible for Investigational Product 
dispensing/accountability as per the Delegation of Authority Form. 
 
9.2.2.1 Case Report Forms 
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the electronic CRF (eCRF) must be consistent with the source documents or the 
discrepancies must be explained. 
 
eCRFs will be prepared for all data collection fields except for fields specific to SAEs and 
pregnancy, which will be reported on the paper SAE form and Pregnancy Surveillance form, 
respectively. Spaces may be left blank only in those circumstances permitted by study-specific 
CRF completion guidelines. 
 
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The Investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
 
The completed CRF, including any paper SAE/pregnancy report forms, must be promptly 
reviewed, signed, and dated by the Investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. For eCRFs, review and 
approval/signature is completed electronically using the Yale electronic data capture tool. 
 
The PI must retain a copy of the CRFs including records of the changes and corrections. Each 
individual electronically signing eCRFs must meet the PI’s training requirements and must only 
access the PI’s electronic data capture tool using the unique user account provided by the PI. 
User accounts are not to be shared or reassigned to other individuals. 


 
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[70] Rutebemberwa A, Ray S, Astemborksi J, Levine J, Liu L, Dowd K. High Programmed 
Death-1 Levels on Hepatitis C Virus-Specific T Cells During Acute Infection are Associated 
with Viral Persistance and Require Preservation of Cognate Antigen During Chronic Infection. J 
Immunol 2008;181:8215-25. 
[71] Wang C, Thudium KB, Han M, Wang X-T, Huang H, Feingersh D, et al. In Vitro 


 
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Characterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, and In Vivo Toxicology 
in Non-Human Primates. Cancer Immunol Res 2014;2:846-56. 
[72] Habicht A, Dada S, Jurewicz M, Fife B, Yagita H, Azuma M. A Link Between PDL1 and T 
Regulatory Cells in Fetomaternal Tolerance. J Immunol 2007;179:5211-9. 
[73] Barr TA, Heath AW. Functional activity of CD40 antibodies correlates to the position of 
binding relative to CD154. Immunology 2001;102:39-43. 
[74] Butowski N, Colman H, De Groot JF, Omuro AM, Nayak L, Wen PY, et al. Orally 
administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: 
an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro-oncology 
2016;18:557-64. 
[75] Cassier PA, Italiano A, Gomez-Roca CA, Le Tourneau C, Toulmonde M, Cannarile MA, et 
al. CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell 
tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. The Lancet 
Oncology 2015;16:949-56. 
[76] Genovese MC, Hsia E, Belkowski SM, Chien C, Masterson T, Thurmond RL, et al. Results 
from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients 
with Active Rheumatoid Arthritis Despite Disease-Modifying Antirheumatic Drug Therapy. The 
Journal of Rheumatology 2015;42:1752-60. 
[77] Sadis S, Mukherjee A, Olson S, Dokmanovich M, Maher R, Cai CH, et al. Safety, 
Pharmacokinetics, and Pharmacodynamics of PP-0360324, a Human Monoclonal Antibody to 
Monocyte/Macrophage Colony Stimulating Factor, in Healthy Volunteers. ACR/ARHP 
Scientific Meeting 2009. New London, CT Pfizer Global Research and Development; 2009.  
[78] Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, et al. Structure- 
Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. New England Journal of 
Medicine 2015;373:428-37. 
[79] Gabbay M, Thomas J, Gibbs A, Hold P. A Randomized Crossover Trial of the Impact of 
Additional Spermicide on Condom Failure Rates. Sexually Transmitted Diseases 2008;35:862-8. 
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Involving Human Subjects. In: 64th WMA General Assembly, editor.: World Medical Associan, 
Inc.; 2013. p. 8. 


 
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11. 
Appendices 
Appendix A:   Schedule of Assessments – Phase 1 Dose Escalation: Cabiralizumab and 
APX005M (Cohorts 1, 3, and 5) and Nivolumab, Cabiralizumab, and 
APX005M (Cohorts 2, 4, and 6) ......................................................................... 122 
Appendix B: Schedule of Assessments – Phase 1b: Nivolumab + Cabiralizumab + 
APX005M ........................................................................................................... 126 
Appendix C: Schedule of PK and PD Blood Sample Collection .............................................. 130 
Appendix D:   PD Analyses ........................................................................................................ 132 
Appendix E: Biopsy Requirements .......................................................................................... 134 
Appendix F: ECOG Performance Status .................................................................................. 135 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix A:  Schedule of Assessments – Phase 1 Dose Escalation: Cabiralizumab and APX005M (Cohorts 1, 3, and 5) and Nivolumab, 
Cabiralizumab, and APX005M (Cohorts 2, 4, and 6) 
 
Procedurea 
Screening 
Cycle 1 
Cycle 2 
Cycle xs 
End-of-Treatment 
Follow-up Period 
Long-Term 
Follow-up 
Periodu 
Day –28 to 
Day 0 
Day 1b 
Day 2 
Day 3 
Day 8 
Day 1b 
Day 2 
Day 3 
Day 8 
Day 1b 
28 (±7) days and 100 (±7) 
days post-last dose 
Informed Consent 
x 
Review/Confirm 
Eligibility Criteria 
x 
x 
Medical History / 
Demographics 
x 
x 
Physical Examinationc 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Height and Weightd 
x 
x 
x 
x 
x 
Vital Signse 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Photo of Periorbital 
Region 
x 
ECOG Performance 
Statusf 
x 
x 
x 
x 
x 
Screening Labsg 
x 
Clinical Safety Labsh 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-Lead ECGi 
x 
x 
CT or MRI Tumor 
Assessmentj,k 
x 
x 
x 
x 
Serum Pregnancy Testl 
x 
x 
x 
x 
Tumor Biopsym 
x 
x 
x 
PK Samplingn 
x 
x 
x 
x 
x 
X 
x 
PD/Biomarker blood 
Samplingo, p 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Anti-drug Antibodiesn 
x 
x 
x 
Study Drug(s)q,r 
x 
x 
x 
Adverse Eventss 
x ---------------------------------------------------------------------------------------------------------------------------------------------------- x 
Prior/Concomitant 
Medications 
x ---------------------------------------------------------------------------------------------------------------------------------------------------- x 


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Procedurea 
Screening 
Cycle 1 
Cycle 2 
Cycle xs 
End-of-Treatment 
Follow-up Period 
Long-Term 
Follow-up 
Periodu 
Day –28 to 
Day 0 
Day 1b 
Day 2 
Day 3 
Day 8 
Day 1b 
Day 2 
Day 3 
Day 8 
Day 1b 
28 (±7) days and 100 (±7) 
days post-last dose 
Long-Term Follow-up 
Contactt 
x 


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Notes for Phase 1 Dose Escalation Schedule of Assessments 
a. Unless specified, prior to infusion procedures are to be completed within 24 hours of scheduled time point and to be synchronized with administration of assigned study drug. Any clinical 
assessment, laboratory study, or additional non-specified tests may be obtained at any time, if clinically indicated. 
b. Each cycle will be 14 days long, with administration of cabiralizumab, APX005M, + nivolumab on Day 1; a ± 2 day window is allowed for Day 1starting with Cycle 3. 
c. 
Standard physical examination will be performed as determined by the Investigator, particularly to follow physical findings to resolution. Targeted physical exams should be conducted at any time 
to follow up on AE reports. A symptom-directed physical exam can be performed for days 2, 3, and 8 of Cycles 1 and 2. 
d. Height is only required to be recorded at screening. Weight is required to be recorded at Day 1 of each cycle. Dose will be adjusted only if weight change is >10% from first dose on Cycle 1 Day 1. 
e. Vital signs include pulse, respiratory rate, blood pressure, and temperature in the resting position (sitting or supine). Measure prior to dose and after completion of each IV infusion for all cycles. 
For Day 1 of Cycles 1 and 2 only, additionally measure vital signs 4 hours (+ 30 min) post-APX005M infusion. Pulse oximetry is performed at rest prior to dosing for day 1 of each cycle and 
otherwise as clinically indicated. At the Investigator’s discretion, vital sign monitoring may be extended beyond the time points specified. Additional measures should be performed as clinically 
indicated. 
f. 
Patient ECOG Status assessments are to be performed within 72 hours prior to dosing (Day 1 of each cycle). 
g. Screening labs include serology for Hepatitis B (HBsAg) and Hepatitis C (HCV antibody). 
h. Clinical Safety Labs: 
Hematology including CBC with differential, platelets, hemoglobin, hematocrit, RBC, and RBC indices 
Chemistry includes CK (creatine kinase), AST (aspartate transaminase), ALT (alanine transaminase), alkaline phosphatase, bicarbonate, bilirubin, (direct and total), BUN (blood urea nitrogen), 
calcium, chloride, creatinine, glucose, LDH (lactate dehydrogenase), phosphorus, potassium, sodium, and, if applicable, serum pregnancy. Albumin, amylase, lipase, thyroid panel includes TSH, 
 
Free T4, PT/INR, and PTT (aPTT) perform at Screening and as indicated. If CK elevation is clinically significant,   obtain troponins (cardiac and skeletal), CK isoenzymes, aldolase, and ECG; 
repeat CK and these additional tests within 48 hours or other interval as clinically indicated, until resolved   or stable. If either AST or ALT is elevated, obtain total serum bilirubin, alkaline 
phosphatase; repeat within 48 hours or other interval, as clinically indicated, until resolved or stable. Additional tests may be obtained at any time, if clinically indicated. 
Urinalysis: Urine dipstick will only be done at screening, and when clinically indicated. 
i. 
Obtain ECG records at Screening and the Day 28 post last infusion End-of-Treatment Visit. Additional ECGs should be obtained at any time, if serum CK or cardiac troponin is elevated; if 
abnormal (excluding sinus tachycardia), ECGs should be obtained (if clinically indicated), until the abnormality is resolved or clinically stable. Additional ECGs may be obtained at any time, if 
clinically indicated. ECGs for each patient should be obtained from the same machine whenever possible. To minimize variability, it is important that patients be in a resting position for at least 
5 minutes prior to each ECG evaluation. Body position should be consistently maintained for each ECG evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, 
radio, conversation) should be avoided during the pre-ECG resting period and during ECG recording. 
j. 
PET CT, CT scans or MRI of the Tumor sites and MRI brain measured as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). If patient terminates prior to scheduled CT or MRI 
scans, patient should have scans done at End-of-Treatment Visits (does not need to be repeated if performed within 8 weeks prior to End-of-Treatment Visits or if tumor progression was previously 
determined). Patients who enter Long-Term Follow-up while showing clinical benefit should have tumor assessments q12w for duration of response. The same measuring modality should be used 
by the site to maintain consistency across the various time points. (Documentation of skin lesions by color photography, including a ruler to measure the size of the lesion, is suggested and should 
follow the CT or MRI schedule.) If there is a contraindication to brain MRI, CT head with and without contrast can be performed. 
k. Performed every 8 weeks (±7 days) from the first dose for the first 4 months for patients who remain on treatment and every 12 weeks (±7 days) thereafter and 28 days (± 7 days) after the last dose 
of study treatment. The exception is MRI of the brain, which can be performed every 6 months in patients with NSCLC and RCC, unless clinically indicated to be done in shorter intervals. CT or 
MRI scans do not need to be repeated if performed within 8 weeks prior to the End-of-Treatment Visits or if tumor progression was previously determined. 
l. 
All women of childbearing potential will have a serum pregnancy test at screening, and urine pregnancy test on Day 1 of each cycle and at the End-of-Treatment Visits. 
m. Biopsy at primary tumor or metastatic tumor site will be collected at screening [at least 24 hours prior to dosing] and prior to Cycle 5 Day 1 [within 7 days prior to Cycle 5 Day 1 and at least 24 
hours prior to dosing]. It is recommended that patients who have documented response receive another biopsy within 28 (±14) days post tumor assessment and/or patient who have progression 
receive another biopsy at the final End-of–Treatment visit. The post-response and post-progression biopsies are optional. Collect an FFPE tissue block or 10 slides of archival tumor sample at 
Screening. 
n. 
Serum PK for APX005M and ADA samples will be collected as indicated in Appendix C. 
o. 
Samples will be collected for PD and biomarker analyses for correlative studies. 
p. 
Biomarker blood sample collection will be collected on Day 1, 2, 3, and 8 of Cycles 1 and 2, and on Day 1 of every cycle thereafter. See Appendix C and D for further information. 
q.Nivolumab and cabiralizumab will both be administered by IV infusion over 30 minutes (± 5 minutes). APX005M will be administered by IV infusion over 60 minutes. Nivolumab will be given 


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first (in Cohorts 2, 4, and 6), with a 30- to 60-minute rest, followed by cabiralizumab as a 30-minute infusion. APX005M will be administered 30 minutes after cabiralizumab and will be given for 
a 60 minute infusion period. For Cohorts 1, 3, and 5, cabiralizumab will be given first, followed by APX005M with the same parameters as above. 
r. 
Cabiralizumab and APX005M will be administered every 2 weeks in 14-day cycles for cohorts 1, 3, and 5. Nivolumab, cabiralizumab, and APX005M will be administered every 2 weeks in 14-day 
cycles for cohorts 2, 4, and 6.  The dosing may continue until PD or unacceptable toxicity. 
s. 
These assessments are to be performed prior to each dose (with the exceptions noted in Appendix C) for those patients who continue treatment without signs of progressive disease or toxicity. 
t. 
Patients should be contacted every 12 (±2) weeks for survival status. Patients should have tumor scans every 8 weeks for the first 4 months on study drugs, followed by every12 (±2) weeks 
thereafter, if tumor progression was not previously determined and/or use of subsequent anti-cancer therapy has not been initiated. Any new anti-cancer therapy should be documented. 


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Appendix B:  Schedule of Assessments – Phase 1b: Nivolumab + Cabiralizumab + APX005M 
 
Procedurea 
Screening 
Cycle 1 
Cycle 2 
Cycle xs 
End-of-Treatment 
Follow-up Period 
Long-Term 
Follow-up 
Periodt 
Day –28 to 
Day 0 
Day 1b 
Day 2 
Day 1b 
Day 2 
Day 1b 
28 (±7) days and 100 
(±7) days post-last 
dose 
Week 0 
Week 1 
Week 3 
Week > 5 
Informed Consent 
x 
Review/Confirm Eligibility 
Criteria 
x 
x 
Medical History / 
Demographics 
x 
x 
Physical Examinationc 
x 
x 
x 
x 
X 
x 
x 
Height and Weightd 
x 
x 
x 
x 
x 
Vital Signse 
x 
x 
x 
x 
X 
x 
x 
Photo of Periorbital Region 
x 
ECOG Performance Statusf 
x 
x 
x 
x 
x 
Screening Labsg 
x 
Clinical Safety Labsh 
x 
x 
x 
x 
X 
x 
x 
12-Lead ECGi 
x 
x 
CT or MRI Tumor 
Assessmentj,k 
x 
x 
x 
x 
Serum Pregnancy Testl 
x 
x 
x 
x 
x 
Tumor Biopsym 
x 
x 
x 
PK Samplingn 
x 
x 
x 
Anti-drug Antibodiesn 
x 
x 
x 
PD/Biomarker blood sample 
collectiono 
x 
x 
x 
x 
x 
x 
Study Drugsp,q 
x 
x 
x 
Adverse Eventsr 
x ----------------------------------------------------------------------------------------- x 


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Procedurea 
Screening 
Cycle 1 
Cycle 2 
Cycle xs 
End-of-Treatment 
Follow-up Period 
Long-Term 
Follow-up 
Periodt 
Day –28 to 
Day 0 
Day 1b 
Day 2 
Day 1b 
Day 2 
Day 1b 
28 (±7) days and 100 
(±7) days post-last 
dose 
Week 0 
Week 1 
Week 3 
Week > 5 
Prior/Concomitant Medications 
x ----------------------------------------------------------------------------------------- x 
Long-Term Follow-up 
Contactss 
x 
Notes for Phase 1b Schedule of Assessments 
a. 
Unless specified, prior to infusion procedure are to be completed within 72 hours of scheduled time point and to be synchronized with study drug administration day. Any clinical assessment, 
laboratory study, or additional non-specified tests may be obtained at any time, if clinically indicated. 
b. 
Each cycle will be 14 days long, with administration of nivolumab + cabiralizumab + APX005M on Day 1. The first day of treatment in Cycle 1 is defined as Day 1; a ± 2 day window is allowed 
for Day 1 in subsequent cycles. 
c. 
Standard physical examination will be performed, particularly to follow physical findings to resolution. Targeted physical exams should be conducted at any time to follow up on AE reports. 
d. 
Height is only required to be recorded at screening. Weight is required to be recorded at Day 1 of each cycle. Dose will be adjusted only if weight change is >10% from first dose. 
e. 
Vital signs include pulse, respiratory rate, blood pressure, and temperature in the resting position (sitting or supine). Measure prior to dose and after completion of each IV infusion. Pulse oximetry 
is performed at rest prior to dosing for day 1 of each cycle and otherwise as clinically indicated. At the Investigator’s discretion, vital sign monitoring may be extended beyond the time points 
specified. Additional measures should be performed as clinically indicated. 
f. 
Patient ECOG Status assessments are to be performed within 96 hours prior to dosing (Day 1 of each cycle). 
g. 
Screening labs include serology for Hepatitis B (HBsAg), Hepatitis C (HCV antibody) 
h. 
Clinical Safety Labs: 
Hematology including CBC with differential, platelets, hemoglobin, hematocrit, RBC, and RBC indices. 
Chemistry includes CK (creatine kinase), AST (aspartate transaminase), ALT (alanine transaminase), alkaline phosphatase bicarbonate, bilirubin, (direct and total), BUN (blood urea nitrogen), 
calcium, chloride, creatinine, glucose, LDH (lactate dehydrogenase), phosphorus, potassium, sodium, and, if applicable, serum pregnancy. Albumin, amylase, lipase, thyroid panel includes TSH, 
 
Free T4, PT/INR, and PTT (aPTT) perform at Screening and as indicated, If CK elevation is clinically significant, obtain troponins (cardiac and skeletal), CK isoenzymes, aldolase, 
and ECG; 
repeat CK and these additional tests within 48 hours or other interval as clinically indicated, until resolved or stable. If either AST or ALT is elevated, obtain total serum bilirubin, alkaline 
phosphatase; repeat within 48 hours or other interval, as clinically indicated, until resolved or stable. Additional tests may be obtained at any time, if clinically indicated. 
Urinalysis: Urine dipstick will only be done at screening, and when clinically indicated. 
i. 
Obtain ECG records at screening and the Day 28 post last infusion End-of-Treatment Visit. Additional ECGs should be obtained at any time, if serum CK or cardiac troponin is elevated; if 
abnormal (excluding sinus tachycardia), ECGs should be obtained (if clinically indicated), until the abnormality is resolved or clinically stable. ECGs for each patient should be obtained from the 
same machine whenever possible. To minimize variability, it is important that patients be in a resting position for at least 5 minutes prior to each ECG evaluation. Body position should be 
consistently maintained for each ECG evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG resting 
period and during ECG recording. Additional tests may be obtained at any time, if clinically indicated. 
j. 
PET CT, CT scans or MRI of the Tumor sites and MRI brain measured as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). If patient terminates prior to scheduled CT or MRI 
scans, patient should have scans done at End-of-Treatment Visits (does not need to be repeated if performed within 8 weeks prior to End-of-Treatment Visits or if tumor progression was previously 
determined). Patients who enter Long-Term Follow-up while showing clinical benefit should have tumor assessments q12w for duration of response. The same measuring modality should be used 
by the site to maintain consistency across the various time points. (Documentation of skin lesions by color photography, including a ruler to measure the size of the lesion, is suggested and should 


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31-Mar- 2020 
 
 
 
 
 
follow the CT or MRI schedule.) If there is a contraindication to brain MRI, CT head with and without contrast can be performed. 
k. 
Performed every 8 weeks (±7 days) from the first dose for the first 4 months for patients who remain on treatment and every 12 weeks (±7 days) thereafter and 28 days (± 7 days) after the last dose 
of study treatment. The exception is MRI of the brain, which can be performed every 6 months in patients with NSCLC and RCC, unless clinically indicated to be done in shorter intervals. CT or 
MRI scans do not need to be repeated if performed within 8 weeks prior to an End-of-Treatment Visit or if tumor progression was previously determined. 
l. 
All women of childbearing potential will have a serum pregnancy test at screening, and urine pregnancy tests will be done on Day 1 of every Cycle and at End-of-Treatment Visits. 
m. Biopsy at primary tumor or metastatic tumor site will be collected at screening [at least 24 hours prior to dosing] and prior to Cycle 5, Day 1 [within 7 days prior to Cycle 5 Day 1 and at least 24 
hours prior to dosing]. It is recommended that patients who have documented response receive another biopsy within 28 (±14) days post tumor assessment and/or patient who have progression 
receive another biopsy at the 28-days End-of–Treatment visit. The post-response and post-progression biopsies are optional. If available, collect an FFPE tissue block or 10 slides of archival tumor 
sample at Screening. 
n. 
Samples will be collected for PK analysis and anti-drug antibodies (ADA) as in Appendix C. 
o. 
Biomarker blood sample collection will be collected on Day 1 of each cycle and on C1D2 and C2D2. See Appendix C and D for further information. 
p. 
Nivolumab and cabiralizumab will both be administered by IV infusion over 30 minutes (± 5 minutes. Nivolumab will be given first, with a 30-to 60-minute rest, followed by cabiralizumab as a 
30-minute infusion. A 30-minute rest period will then occur, followed by APX005M as a 60-minute infusion. 
q. 
Nivolumab + cabiralizumab + APX005M study drug will be administered every 2 weeks in 14-day cycles and will continue until PD or unacceptable toxicity. 
r. 
These assessments are to be performed prior to each subsequent dose (with exceptions noted in Appendix C) for patients who continue treatment without signs of progressive disease or toxicity. 
s. 
Patients should be contacted every 12 (±2) weeks for survival status. Patients should have tumor scans 12 (±2) weeks, if tumor progression was not previously determined and/or use of subsequent 
anti-cancer therapy has not been initiated. Any new anti-cancer therapy should be documented. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix C:  Schedule of PK and tumor and Blood Biomarker Sample Collection 
 
Phase 1 dose escalation 
Study Cycle 
Study Day 
Time Point 
Type of Sample 
Screening 
Screening (Day –28) 
At least 24 hours prior 
to dosing 
Tumor Biopsy (or archival FFPE tumor block 
available) 
Cycles 1 and 2 only 
Day 1 
Prior to infusion 
PK for APX005M (serum) 
Biomarker blood sample collection 
Anti-drug antibody blood sample (Cycle 1 only) 
End of infusion 
PK for APX005M (serum) 
If possible, 4 (±30 min) 
hours from start of 
infusion 
PK for APX005M (serum) 
Day 2 
24 (±6) hours from 
start of infusion 
PK for APX005M (serum) 
Biomarker blood sample collection 
Day 3 
48 (±6) hours from 
start of infusion 
PK for APX005M (serum) 
Biomarker blood sample collection 
Day 8 
168 (±6) hours from 
start of infusion 
Biomarker blood sample collection 
Prior to Cycle 5 only 
Within 7 days prior to 
C5D1 and at least 24 
hours prior to dosing 
Prior to infusion 
Tumor Biopsy 
Subsequent Cycles on 
every cycle (Cycles 3, 4, 5, 
etc. 
Day 1 
Prior to infusion 
Biomarker blood sample collection 
Subsequent Cycles on 
every 3rd cycle (Cycles 3, 
6, 9, 12, etc.) 
Day 1 
Prior to infusion 
PK for APX005M (serum) 
Anti-drug antibody blood sample 
End of infusion 
PK for APX005M (serum) 
Phase 1b 
Screening 
Screening (Day –28) 
At least 24 hours prior 
to dosing 
Tumor Biopsy (or archival FFPE tumor block 
available) 
Cycles 1, 2, and each cycle 
therafter 
*Every 3rd cycle (Cycles 1, 
3, 6, 9 , 12, etc.) 
Day 1 
Prior to infusion 
Biomarker blood sample collection 
PK for APX005M (serum)* 
Anti-drug antibody blood sample* 
End of infusion 
PK for APX005M (serum)* 


 
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Day 2 of C1 and C2 
Prior to Infusion 
Biomarker blood sample collection 
Within 7 days prior to 
C5D1 and at least 24 
hours prior to dosing 
Prior to infusion 
Biopsy Tissue (prior to Cycle 5 only) 


 
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End-of-Treatment Follow- 
up Period (28 [±7] days 
and 100 [±7] days post-last 
dose) 
Treatment 
discontinuation/PD 
Post completion of 
treatment course 
Optional biopsy for patients who have documented 
response within 28 (+14) days post-tumor assessment 
Anti-drug antibody blood sample 
Biomarker blood sample collection 


 
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Appendix D:  PD Analyses 
 
Exploratory endpoints will include description of antitumor activity of APX005M administered 
in combination with nivolumab and cabiralizumab as measured in mandatory serial tumor biopsy 
and blood collection specimens.  Biopsies will be taken pre-treatment (at least 24 hours prior to 
dosing), before Cycle 5 Day 1 (within 7 days and at least 24 hours prior to dosing), and at time of 
disease progression, if this occurs.  PBMCs (for CyTOF and single cell RNA Seq) and plasma 
(for ELISA cytokine panel) samples will also be collected at the same time points. These 
samples will be used to study biomarkers to assess for prediction of response or resistance to 
therapy and to search for pharmacodynamic indicators of anti-tumor activity.  Tumor assessment 
will include the following: 
• Routine histologic examination 
• Quantitative immunofluorescence (QIF) 
• Flow cytometry by CyTOF 
• Single cell RNA-seq studies 
 
QIF utilizing formalin-fixed paraffin embedded (FFPE) tumors will be profiled for: 
 
Marker expression will be analyzed in responders versus non-responders.  Assays for the 
biomarkers listed in the table above have already been developed. 
 
Flow cytometry by CyTOF will be performed on tumor infiltrating immune cells and PBMCs to 
explore and potentially validate the markers outlined for QIF. We will profile shifts in TAM 
types from pre-treatment to post-treatment initiation and will also measure production of TNF-α, 
IFN-γ, IL-6, IL-12, p40, CCL3, CCL4, and CCL5. Cell sorting by FACS will be performed for 
CD3, CD4, and CD68.  We aim to determine the functional properties of the immune infiltrates 
in promoting or inhibiting tumor growth. 
Biomarkers of effect for cabiralizumab include: 
• Peripheral blood changes in CD14+/CD16hi non-classical monocytes 
Biomarkers of effect for APX005M include: 
• Peripheral blood analysis for antigen presenting cell activation using flow cytometry: Cell 
surface immune markers that will be examined include but are not limited to: CD19, 


 
CA025-007 Clinical Protocol 
 
 
 
 
 
CD123, CD11c, CD86, MHC class I and II, CD70, CD54. 
 
Please note that patients undergoing core biopsy will be required to provide two cores for these 
analysis – one snap frozen and one paraffin embedded. 
 
All samples will be banked at Yale in the Kluger laboratory. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix E:  Biopsy Requirements 
 
Biopsy at primary tumor or metastatic tumor site are mandatory and will be collected at: 
• At time of screening 
o At least 24 hours prior to dosing 
 
• Prior to Cycle 5 Day 1 
o Within 7 days prior to Cycle 5 Day 1 and at least 24 hours prior to dosing 
 
It is recommended that patients who have documented response receive another biopsy within 28 (±14) 
days post tumor assessment and/or patients who have progression receive another biopsy at the final 
End-of–Treatment visit. The post-response and post-progression biopsies are optional. 
 
If available, patients will be required to provide an archival FFPE tissue block as well at screening. 
Patients undergoing core biopsy for the study will be required to provide two cores for these analysis – 
one snap frozen and one paraffin embedded. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Version 8 
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Appendix F:  ECOG Performance Status 
 
 
  Grade   
  
Performance Status Criteria  
 
0 
Fully active, able to carry on all pre-disease activities without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light sedentary nature (light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ICF_001.pdf: 
ClinicalTrials.gov ID: NCT03502330 
Title: APX005M With Nivolumab and Cabiralizumab in Advanced Melanoma, Non-small Cell Lung Cancer 
or Renal Cell Carcinoma 
Document Type: ICF 
Date: 2/7/2020 


APPROVED BY THE YALE UNIVERSITY IRB 2/7/2020
Principal Investigator:
Harriet Kluger, MD
HIC #: 
2000021757
Funding Source:
Bristol Myers Squibb and Apexigen Inc.
Page 1 of 2
YCC v1.0 (12-Jan-2018)
Treatment Beyond Progression 
CONSENT FOR CONTINUED PARTICIPATION IN A RESEARCH PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL
Study Title: A Phase I/Ib Study of APX005M in Combination with Nivolumab and 
Cabiralizumab in Patients with Advanced Melanoma, Non-small Cell Lung Cancer or Renal Cell 
Carcinoma Whose Disease Has Progressed on Anti-PD-1/PD-L1 Therapy
Principal Investigator: Harriet Kluger, MD
Principal Investigator’s Phone Number: 203-200-6622
24-Hour Phone Number: 203-200-6622
Principal Investigator’s Mailing Address: PO BOX 20856, New Haven, CT 06520
Funding Source:  Bristol Myers Squibb and Apexigen, Inc.
Continuing Treatment Beyond Progression
Invitation to Participate and Description of Project
All parts of the informed consent that you have signed before for the main study remain valid, as 
does your consent to it, except any that are specifically revised by this document. 
Continuing Treatment beyond Disease Progression
With most anti-cancer drugs, an increase in the size or number of tumors detected with CT or 
MRI scans or a physical exam is a signal that your disease has progressed and that you should 
consider switching to another therapy.  However, an early increase in the size or number of 
tumors may not always be a sign of disease progression.  Because of this possibility, you will 
have the option of continuing to receive study drug even after a scan in the course of receiving 
study drug shows an increase in the size or number of your tumors.  A later scan will help to 
determine whether the increase was caused by real progression of your disease. Additional tests 
may help determine the cause for the increase in the size or number of your tumors and may be 
required to allow you to continue in the study.  
You may have other potentially beneficial approved treatments available to you.  These 
treatments may include those that may shrink tumors, delay progression of cancer, provide 
symptom relief, or prolong your life. The option to continue the study drugs in spite of an 
apparent increase in tumor size should be carefully discussed with your study doctor.  There are 
risks of continuing to treatment beyond an apparent increase in tumor size because of the 
possibility that it represents true progression of your disease.  In that case, you may be exposed 
to an ongoing risk of side effects caused by the study drugs and delay the initiation of other 
treatment options that may have demonstrated benefit in clinical trials.  In addition, your cancer 
may progress to the point that you are no longer able to receive other potentially effective 
therapies.  If you show true progression of your disease, you will be discontinued from the study 
and the study doctor will ask you to visit the office for follow up exams.
APPROVED BY THE YALE UNIVERSITY IRB 2/7/2020


APPROVED BY THE YALE UNIVERSITY IRB 2/7/2020
Principal Investigator:
Harriet Kluger, MD
HIC #: 
2000021757
Funding Source:
Bristol Myers Squibb and Apexigen Inc.
Page 2 of 2
YCC v1.0 (12-Jan-2018)
Treatment Beyond Progression 
Questions/Information
If you or your representative(s) have any questions regarding the information above, you should 
contact your study doctor at the telephone number on page one of this form.
Signature Acknowledgement of Treatment Continuation after Possible Disease Worsening
This signature page applies only to subjects after possible disease worsening has occurred 
for the first time while receiving treatment and only after the study doctor determines that 
continued treatment is possible. 
I understand that because of the nature of this experimental treatment, I may be able to continue 
treatment after apparent disease worsening.  My study doctor has explained that other approved 
therapies may be available to me, which may include those that may shrink tumors, delay 
progression of cancer, provide symptom relief, or prolong life.  I understand that continuing to 
take study treatment may delay the start of treatment with these other therapies.  
Study Participant (print name)
Signature
Date
Person obtaining consent (print 
name)
Signature
Date
Person obtaining consent (print 
name) – only if applicable, 
otherwise blank
Signature
Date
Interpreter/ Witness (print name) 
– only if applicable, otherwise blank
Signature
Date
 
If after you have signed this form you have any questions about your privacy rights, please contact the 
Yale Privacy Officer at (203) 432-5919.
If you have further questions about this project or if you have a research-related problem, you may 
contact the Principal Investigator, Dr. Harriet Kluger, at (203) 200-6622.  If you would like to talk with 
someone other than the researchers to discuss problems, concerns, and questions you may have 
concerning this research, or to discuss your rights as a research subject, you may contact the Yale Human 
Investigation Committee at (203) 785-4688. 
APPROVED BY THE YALE UNIVERSITY IRB 2/7/2020