A Randomized Phase 2 Trial of AM0010 in Combination With Pembrolizumab vs. Pembrolizumab Alone as First-Line (1L) Therapy in Patients With Stage IV / Metastatic Wild Type (WT) Non-Small Cell Lung Cancer and Tumors With High Expression of PD-L1 (> 50%)
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
Sponsor: Eli Lilly and Company

Protocol J1L-AM-JZGC, AM0010-201 
Study of Pegilodecakin (LY3500518) With Pembrolizumab Compared to Pembrolizumab Alone 
First-line Tx in Participants With Metastatic Non-Small Cell Lung Cancer (Cypress 1) 
 
 
NCT03382899 
 
Approval Date: 06-Nov-2018 
 
 
 

Clinical Protocol AM0010 – 201 (J1L-AM-JZGC)
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CLINICAL TRIAL PROTOCOL
Confidential Information
The information contained in this protocol is confidential and is intended for the use of clinical 
investigators.  It is the property of Eli Lilly and Company or its subsidiaries and should not be copied by 
or distributed to persons not involved in the clinical investigation of AM0010 (pegilodecakin; 
LY3500518), unless such persons are bound by a confidentiality agreement with Eli Lilly and Company 
or its subsidiaries. 
Note to Regulatory Authorities:  This document may contain protected personal data and/or 
commercially confidential information exempt from public disclosure.  Eli Lilly and Company requests 
consultation regarding release/redaction prior to any public release.  In the United States, this document 
is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise 
disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
PROTOCOL TITLE:
An Open-Label, Randomized Phase 2 Trial of AM0010 in 
Combination with Pembrolizumab vs Pembrolizumab Alone as 
First-Line Therapy in Patients with Stage IV/Metastatic 
Non-Small Cell Lung Cancer and Tumors with High Expression 
of PD-L1 (≥50%)
PROTOCOL NUMBER:
AM0010-201; J1L-AM-JZGC
TRIAL NAME:
CYPRESS-1
TRIAL DRUG:
AM0010 (pegilodecakin; LY3500518) 
PEGylated Recombinant Human Interleukin 10 (PEG-rHuIL-10)
IND NUMBER:
131683
SPONSOR:
Eli Lilly and Company (Lilly)
Indianapolis, Indiana USA 46285
ORIGINAL PROTOCOL:
AMENDMENT 1 
AMENDMENT 2
06 December 2017
02 July 2018
See approval date stamp at the end of this page
Approval Date: 06-Nov-2018 GMT

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PROTOCOL APPROVAL PAGE
PROTOCOL TITLE:
An Open-Label, Randomized Phase 2 Trial of AM0010 in 
Combination with Pembrolizumab vs Pembrolizumab Alone 
as First-Line Therapy in Patients with Stage IV/Metastatic 
Non-Small Cell Lung Cancer and Tumors with High 
Expression of PD-L1 (>50%)
PROTOCOL NUMBER:
AM0010-201; J1L-AM-JZGC
TRIAL NAME:
CYPRESS-1
TRIAL DRUG:
AM0010 (pegilodecakin; LY3500518) 
PEGylated Recombinant Human Interleukin 10
(PEG-rHuIL-10)
IND NUMBER:
131683
SPONSOR:
Eli Lilly and Company
Indianapolis, Indiana USA 46285
ORIGINAL PROTOCOL:
AMENDMENT 1
AMENDMENT 2
06 December 2017
02 July 2018
See approval date stamp on the first page of this document
Approval of protocol by sponsor: See electronic signature on the last page of this document

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PROTOCOL ACCEPTANCE PAGE
PROTOCOL TITLE:
An Open-Label, Randomized Phase 2 Trial of AM0010 in 
Combination with Pembrolizumab vs Pembrolizumab Alone as 
First-Line Therapy in Patients with Stage IV/Metastatic Non-Small 
Cell Lung Cancer and Tumors with High Expression of PD-L1 
(≥50%)
PROTOCOL NUMBER:
AM0010-201; J1L-AM-JZGC
TRIAL NAME:
CYPRESS-1
TRIAL DRUG:
AM0010 (pegilodecakin; LY3500518) 
PEGylated Recombinant Human Interleukin 10 (PEG-rHuIL-10)
IND NUMBER:
131683
SPONSOR:
Eli Lilly and Company
Indianapolis, Indiana USA 46285
ORIGINAL PROTOCOL:
AMENDMENT 1
AMENDMENT 2
06 December 2017
02 July 2018
See approval date stamp on the first page of this document
I have read the foregoing protocol and agree to conduct the trial as outlined.  In addition, I agree to 
conduct the trial in compliance with the principles of Good Clinical Practice (GCP), as described in 
the United States Code of Federal Regulation (CFR) 21 Parts 11, 50, 54, 56, and 312 and the 
appropriate International Council for Harmonisation guidance documents and with all applicable 
regulations and guidelines as stated in the protocol and other information supplied to me.
INVESTIGATOR:
Printed Name
Institution
Signature
Date

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SUMMARY OF CHANGES
Summary of Key Changes for Protocol AM0010-201 (J1L-AM-JZGC) Amendment 2
Section
Summary of Changes
Across the protocol
Sponsor name changed from ARMO Biosciences, Inc. to Eli 
Lilly and Company.
Synopsis; Sections 2.2, 2.3, 3.4
Duration of response was added as a secondary objective; 
disease control rate was moved from exploratory objective 
to secondary objective; characterization of 
pharmacokinetics in combination with pembrolizumab was 
added as an exploratory objective; corresponding changes 
were made to the endpoints description.
Synopsis; Sections 2.2, 3.0, 3.5, 7.1, 7.2, 7.10, 
8.1
Tumor and overall survival assessment frequencies were 
revised.
Synopsis; Section 3.0, 4.1
Removed reference to echinoderm microtubule-associated 
protein-like 4 (EML4), as EML4 is not the only fusion 
partner with anaplastic lymphoma kinase (ALK).
Synopsis; Sections 3.0, 5.1, 10.1
Reference to tumor mutational burden (TMB) measurement
was deleted. 
Synopsis; Sections 3.0, 6.3, 7.2, 7.8
An option of receiving AM0010 alone as maintenance 
treatment for patients on Arm 1 who experienced
pembrolizumab intolerance was deleted.
Synopsis; Section 3.0
Trial and treatment design schema were updated to reflect 
the changes in study design.
Synopsis; Section 4.1
Inclusion criterion about target population was updated to 
specify that the patients must not have had systemic 
treatment for incurable disease.  If patients had 
chemotherapy as part of curative intent radical radiotherapy 
or surgery they should have completed the last dose of 
chemotherapy 6 months prior to randomization.
Synopsis; Section 4.1, 4.2
Inclusion criterion “patients without known epidermal 
growth factor receptor (EGFR) or EML4-anaplastic 
lymphoma kinase (ALK) mutation” was moved to exclusion 
criteria and revised as “Patients with non-squamous NSCLC
with known EGFR mutation or ALK rearrangement.”
Synopsis; Section 4.1
Inclusion criteria about laboratory values were revised to 
delete approval of a patient with isolated increase by the 
Medical Monitor; exclusion criterion about prothrombin 
time was revised and moved under inclusion criteria.
Synopsis; Section 4.2
Criterion that required exclusion of patients with no history 
of tobacco use was deleted.
Synopsis; Section 4.2
Exclusion criterion “Patients that have received 
pembrolizumab” was deleted.
Synopsis; Sections 6.1, 6.2, 7.2, 7.7, 11.1
Reference to product concentration was deleted and 
reference to product label for full storage instructions was 
added.
Synopsis
Reticulocyte count and lactate dehydrogenase investigations 
were added to the laboratory panel.

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Section
Summary of Changes
Synopsis; Sections 3.5, 7.2, 7.10, 8.1, 9.3, 10.5
Safety observation period was extended from 30 days to 90 
days, including follow-up visits 60 and 90 days after the last 
dose of study treatment (±7 days).
Synopsis; Sections 3.7
Study design was updated to allow continued access of the 
study treatment to the patients remaining on study after 
study completion and continuing to experience clinical 
benefit. 
Synopsis; Section 7.13, 7.14
Biomarker and immunogenicity sample collection 
requirement was updated to include collection on both the 
arms.
Synopsis; Section 10.3
Sample size justification was added.
Synopsis; Section 10.3
Schedule of analyses for key endpoints, including interim 
analysis, was added.
Synopsis
Clarified that all efficacy analyses will be based on the 
Intent-to-Treat population.
Synopsis; Sections 3.4, 6.4, 7.1, 8.1, 9.3, 10.5; 
and Appendix F
National Cancer Institute (NCI) - Common Terminology 
Criteria for Adverse Events (CTCAE) version was changed 
from 5.0 to 4.03.
Trial Glossary
Trial glossary was updated per changes made in the 
protocol.
Section 3.6
Study completion was defined.
Section 3.8
End of trial was defined.
Section 6.4
Terms Treatment Delay and Interruption were replaced by 
treatment Withhold; the section was updated to clarify the 
treatment withhold, discontinuation, and dose schedule 
reduction criteria.
Section 7.4; Appendix A
A requirement of mandatory tumor tissue sample for 
biomarker research was specified.
Section 7.12; Appendices A and B
Pharmacokinetic sample collection time points were 
revised; storage requirement for pharmacokinetic samples 
was added.
Section 7.13; Appendices A and B
Anti-drug antibody sample collection time points were 
revised; storage requirement for immunogenicity samples 
was added.
Section 7.14
Storage requirement for biomarker samples was added.
Section 9.0
Adverse event reporting requirement was updated to ensure 
accurate and effective reporting of safety information, 
including adverse events, serious adverse events, suspected 
unexpected serious adverse events, pregnancy, and 
complaint handling. 
Appendix A
Updated per changes made in the protocol, including 
addition of extended safety observation period and addition 
of sample collection time points for pharmacokinetics, 
immunogenicity, and biomarkers.
Appendix B
Added schedule of assessment table for continued-access 
period.

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Section
Summary of Changes
Appendix E
Added guidance on hepatic monitoring tests for treatment 
emergent abnormality.
Across the protocol
Other minor editorial changes were made to add clarity and 
to correct the inconsistencies.

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PROTOCOL SYNOPSIS
PROTOCOL TITLE:
An Open-Label Randomized Phase 2 Trial of AM0010 in Combination with 
Pembrolizumab vs Pembrolizumab Alone as First-Line (1L) Therapy in 
Patients with Stage IV/Metastatic Non-Small Cell Lung Cancer and Tumors 
with High Expression of PD-L1 (>50%)
PROTOCOL NUMBER:
AM0010-201; J1L-AM-JZGC
CLINICAL PHASE: 
2
INDICATION:
Wild type (without known specific driver mutations in epidermal growth factor 
receptor – EGFR or anaplastic lymphoma kinase [ALK]) non-small cell lung 
cancer (NSCLC).
NUMBER OF PATIENTS:
Approximately 100
INVESTIGATIONAL 
PRODUCT:
AM0010 (pegylated IL-10 [pegilodecakin]; LY3500518)
ACTIVE INGREDIENT:
PEG-rHuIL-10
OTHER DRUG:
Pembrolizumab
TRIAL LOCATION:
Multi-center, USA only
TRIAL DURATION:
Approximately 60 months
RESEARCH
HYPOTHESIS:
In newly diagnosed metastatic NSCLC patients whose tumors have high PD-L1 
expression, the administration of AM0010 in combination with pembrolizumab 
increases the objective response rate (ORR) when compared with the 
administration of pembrolizumab alone.
OBJECTIVES:
The trial objectives will be evaluated in adult patients with histologically or 
cytologically documented NSCLC that is metastatic or recurrent and whose 
tumor tissue PD-L1 expression ≥50%.  PD-L1 IHC 22C3 assay is mandatory.
To compare the efficacy of AM0010 in combination with pembrolizumab vs
pembrolizumab alone as measured by:
Primary
ORR
Secondary
progression-free survival (PFS)
overall survival (OS)
disease control rate (DCR) 
duration of response (DoR)
safety and tolerability profile
Exploratory
Characterize AM0010 pharmacokinetics in combination with 
pembrolizumab
To explore biomarkers including immune activation markers that may 
correlate with efficacy outcome measures
TRIAL DESIGN:
This is an open-label, randomized, multicenter Phase 2 trial in adult patients 
with treatment-naïve, Stage IV/metastatic NSCLC whose tumors are not known 
to have EGFR mutation or ALK rearrangement, and have high expression 
(≥50%) of PD-L1.  PD-L1 will be determined with an FDA-approved PD-L1 
IHC 22C3 assay.
Patients will be stratified according to tumor histology (squamous vs 
non-squamous).

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PROTOCOL SYNOPSIS
Patients will be randomized in a 1:1 ratio into 1 of 2 treatment arms.  
Arm 1: Patients will receive AM0010 as a subcutaneous (SQ) daily (QD) 
injection and pembrolizumab as intravenous (IV) infusion on Day 1 of a 21-
day cycle.
o
AM0010 Dose

≤80 kg body weight = 0.8 mg

>80 kg body weight = 1.6 mg
o
Pembrolizumab Dose

200 mg over approximately 30 minutes IV infusion
Arm 2: Patients will receive pembrolizumab as IV infusion on Day 1 of a 21-
day cycle.
o
Pembrolizumab Dose

200 mg over approximately 30 minutes IV infusion
Trial sites will provide best supportive care per institution’s standard of care,
including concomitant medications.
Arm 1 and 2 dosing (QD for AM0010 and Q3W for pembrolizumab) will 
continue in the absence of disease progression, unacceptable toxicity, or the 
patient withdraws consent, whichever is first. Patients will be treated with a 
maximum of 35 cycles of pembrolizumab every 3 weeks or 2 years, whichever 
is longer.
At the time of documented disease progression (per Investigator assessment) 
patients in Arm 1 will be discontinued from the treatment period of the trial and 
patients in Arm 2 may crossover to receive treatment with AM0010 with 
pembrolizumab.
All randomized patients will be followed for OS every 9 weeks (±7 days)
during the first year from the 90-day follow-up visit, every 12 weeks (±7 days) 
during the second year, and every 16 weeks (±7 days) thereafter. The survival 
follow-up will be done until death or the study completion, whichever is first,
whether or not trial drug was administered. For patients who were randomized, 
but withdraw consent, survival (date of death) will be obtained by use of 
publicly available information.
Tumor assessment will be performed for all randomized patients every 9 weeks 
(±7 days) during the study treatment and during the first year from 
discontinuation of the study treatment, every 12 weeks (±7 days) during the 
second year, and every 16 weeks (±7 days) thereafter. Tumor assessment will 
be repeated until disease progression, death, or receipt of new anti-cancer 
therapy, or until study completion, whichever is first, whether or not study 
treatment was administered.
All computed tomography (CT)/magnetic resonance imaging (MRI) scans for 
all randomized patients enrolled in the trial will be collected prospectively and 
submitted to a central imaging vendor for archiving.  These scans may be 
independently reviewed at a later time at the request of Eli Lilly and Company 
(Lilly).

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PROTOCOL SYNOPSIS
TRIAL and TREATMENT 
DESIGN SCHEMA:

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INCLUSION CRITERIA:
Patient will be eligible for trial participation as defined by the inclusion and 
exclusion criteria as follows:
Eligible patients must meet the following criteria to be enrolled in the trial: 
1. Signed Written Informed Consent (ICF). Patients must have signed and 
dated an IRB/IEC approved written ICF in accordance with regulatory and 
institutional guidelines. This must be obtained before the performance of 
any protocol-related procedures that are not part of normal patient care.
a. Patients must be willing and able to comply with scheduled visits, 
dosing schedule, laboratory tests, and other requirements of the trial.
2. Target Population
a. Patients must have histologically or cytologically confirmed NSCLC 
that is Stage IV/metastatic.
b. Patients must not have had systemic treatment for incurable disease.  If 
patients had chemotherapy as part of curative intent radical radiotherapy 
or surgery they should have completed the last dose of chemotherapy 6 
months prior to randomization.
c. Patients with tumor tissue high expression of PD-L1 as defined by 
Tumor Proportion Score (TPS) ≥50% and as determined by an
FDA-approved PD-L1 IHC 22C3 assay is mandatory.
d. Patients ≥18 years of age.
e. Patients with Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1.
f. Patients with measurable disease by CT or MRI per Response 
Evaluation Criteria in Solid Tumor (RECIST) v.1.1 criteria.
g. Patients with Radiographic Tumor Assessment performed within 
30 days prior to randomization.
i) Target lesions may be located in a previously irradiated field if there
is documented (radiographic) disease progression at that site.
h. Patients that have completed prior radiotherapy or radiosurgery at least 2 
weeks prior to randomization.
i) Patients with brain metastases are eligible if they are asymptomatic, 
or are treated and are neurologically stable for at least 2 weeks 
without the use of steroids or on stable or decreasing dose of ≤10 mg 
daily prednisone (or equivalent).
i. Patients with baseline laboratory values obtained 21 days prior to 
randomization meeting the following criteria:
i) WBCs≥2000/µL.
ii) Neutrophils ≥1500/µL.
iii) Platelets ≥100×103/µL.
iv) Hemoglobin ≥9.0 g/dL.
v) Creatinine of ≤1.5×ULN or calculated creatinine clearance 
>60 mL/minute per institutional standard. For patients with a body 
mass index (BMI) >30 kg/m2, lean body weight should be used 
instead of actual body weight.
vi) AST≤1.5×ULN (<5×ULN for patients with liver metastasis).
vii) ALT≤1.5×ULN (<5×ULN for patients with liver metastasis).  
viii) Total bilirubin ≤1.5×ULN (except patients with Gilbert Syndrome 
who must have total bilirubin <3.0 mg/dL).
ix) Alkaline phosphatase <2.5×ULN (<5×ULN for patients with liver 
metastasis).  
x) Prothrombin 
Time 
(PT) 
<1.5×ULN,
unless 
receiving 
anticoagulation therapy; activated Partial Thromboplastin Time 
(aPTT) <1.5×ULN, unless receiving anticoagulation therapy.
3. Reproductive Status

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a. Women of childbearing potential (WOCBP) must agree to use method(s) 
of contraception.
b. WOCBP must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of hCG) within 24 hours prior to 
the start of investigational product.
c. Male or non-pregnant, non-lactating female, ≥18 years of age:
If sexually active, the subject must agree to use contraception 
considered adequate and appropriate by the Investigator during the 
period of trial drug administration.  In addition, male and female 
patients must utilize contraception after the end of the treatment in 
the individual drugs product’s Prescribing Information provided in 
the trial manual and the Clinical Trial Facilitation Group, provided in
Appendix B
EXCLUSION CRITERIA:
Eligible patients must not have the following criteria (except where indicated) 
to be enrolled in the trial:
1. Medical History and Concurrent Diseases
a. Patients with carcinomatous meningitis.
b. Patients with active central nervous system (CNS) metastases.
i) Patients are eligible if CNS metastases are adequately treated and 
neurologically stable at baseline (except for residual signs or 
symptoms related to the CNS treatment) for at least 2 weeks prior to 
enrollment. In addition, patients must be either off corticosteroids or 
on a stable or decreasing dose of ≤10 mg daily prednisone (or 
equivalent) at the time of consent for the trial.
c. Patients with life expectancy of <3 months.
d. Patients with non-squamous NSCLC with known EGFR mutation or 
ALK rearrangement.
e. Patients currently using medicinal or recreational cannabis.
f. Patients with any serious or uncontrolled medical disorder or active 
infection with the hepatitis virus or the human immunodeficiency virus 
(HIV).
g. Patients with other active malignancies requiring concurrent intervention 
other than hormone antagonists.
h. Patients with previous malignancies (except non-melanoma skin cancers 
and the following in situ cancers: bladder, gastric, colon, 
cervical/dysplasia, endometrial, melanoma, or breast) are excluded,
unless a complete remission was achieved at least 2 years prior to trial 
entry AND no additional therapy other than hormone antagonists is 
required or anticipated to be required during the trial period.
i. Patients with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other 
immunosuppressive medications at the time of consent for the trial.  
Inhaled or topical steroids and adrenal replacement steroid doses >10 mg 
daily prednisone equivalent are permitted in the absence of active 
autoimmune disease.
j.
Patients with known prior history of hemophagocytic 
lymphohistiocytosis (HLH).
k. Patients with active known or suspected autoimmune disease that 
required systemic therapy within 2 years of treatment or a medical 
condition that required immunosuppression.  Patients with vitiligo, Type 
I diabetes mellitus, residual hypothyroidism requiring hormone 
replacement, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.
l. Patients with >Grade 1 (NCI-CTCAE v.4.03) toxicities attributed to 
prior anti-cancer therapy (other than alopecia and fatigue) prior to 
randomization.
m. Patients that have received therapy with anti-tumor vaccines or other 

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immuno-stimulatory antitumor agents.  Non-cancer vaccines 
(non-attenuated and non-live) are permitted.
n. Patients that have received therapy with anti-PD-1, anti-PD-L1, anti-PD-
L-2, anti-CD-137, and/or anti CTLA-4 antibodies (including ipilimumab 
or any other antibody or drug specifically targeting T cell co-stimulation 
or checkpoint pathways).
o. Patients with a history of symptomatic interstitial lung disease.
p. Patients not completely recovered from the effects of major surgery or 
significant traumatic injury at least 14 days before the first dose of trial 
treatment.
2. Physical and Laboratory Test Findings
a. Patients with active Hepatitis B or C infections.
b. Patients known to be HIV-positive.
3. Allergies and Adverse Drug Reaction
a. Patients with a history of severe hypersensitivity reactions to 
monoclonal antibodies.
b. Patients with a history of allergy or intolerance (unacceptable adverse 
event) to trial drug components, Polysorbate 80-containing infusions.
4. Sex and Reproductive Status
a. WOCBP who are pregnant or breastfeeding.
b. Women with a positive pregnancy test at enrollment or prior to 
administration of trial drug.
5. Prohibited Treatments and/or Restricted Therapies
a. Patients requiring ongoing or planned administration of anti-cancer 
therapies other than those specified in this trial.
b. Patients requiring the use of corticosteroids or other immunosuppressive 
medications (>10 mg daily prednisone equivalent for more than 14
sequential days).  Corticosteroids or other immunosuppressive 
medications for more than 14 sequential days require approval of the 
Medical Monitor.
c. Patients receiving any investigational agent within 28 days of first 
administration of trial treatment.
6. Other Exclusion Criteria
a. Patients with any other serious or uncontrolled medical disorder, active 
infection, physical exam finding, laboratory finding, altered mental 
status, or psychiatric condition that, in the opinion of the Investigator, 
would limit the individual’s ability to comply with the trial 
requirements, substantially increase risk to their well-being, or impact 
the interpretability of trial results.
Eligibility criteria for this trial have been carefully considered to ensure the 
safety of the trial patients and to ensure the integrity of the trial results. It is 
imperative that patients meet in full all eligibility criteria and requirements.
AM0010:
DRUG and
FORMULATION
AM0010 is provided as a sterile, single-use prefilled syringe, with a clear 
solution. AM0010 drug product is stored refrigerated. Refer to the product 
label for full storage instructions.
AM0010:
DOSE/ROUTE/REGIMEN
Patients in Arm 1 (including crossover patients) will self-administer AM0010 
as a QD SQ injection (abdomen, thigh, or back of upper arm) at 
weight-dependent dose.
≤80 kg body weight = 0.8 mg
>80 kg body weight = 1.6 mg
Doses will continue in the absence of disease progression, unacceptable 
toxicity, or subject’s withdrawal of consent.

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PEMBROLIZUMAB:
DRUG and
FORMULATION
Pembrolizumab is commercially available.  Trial sites will be responsible for 
procurement, storage, and destruction.
Pembrolizumab for injection (lyophilized powder): carton containing 1 50-mg 
single-dose vial (NDC 0006-3029-02).
Store vials refrigerated. Refer to the product label for full storage 
instructions.
Pembrolizumab injection (solution): carton containing one 100-mg/4-mL 
(25 mg/mL), single-dose vial (NDC 0006-3026-02)
Store vials refrigerated. Refer to the product label for full storage 
instructions..
PEMBROLIZUMAB:
DOSE/ROUTE/REGIMEN
Patients in trial Arm 1 or Arm 2 will be administered pembrolizumab as an IV 
infusion on Day 1 of a 21-day cycle.
Patients on Arm 1 (including crossover patients) will be administered 
pembrolizumab at a fixed dose of 200 mg over approximately 30 minutes of 
IV infusion
Patients on Arm 2 will be administered pembrolizumab at a fixed dose of 
200 mg over approximately 30 minutes of IV infusion
Treatment will continue every 3 weeks in the absence of disease progression, 
unacceptable toxicity, or subjects’ withdrawal of consent.
TRIAL PROCEDURES:
The trial consists of the following procedures:
Screening Period: The screening period must occur within 21 days prior to 
randomization (unless noted otherwise). Some screening assessment may be 
counted as Day 1 assessment (Baseline) if completed within 72 hours prior to 
dosing.
Baseline scans must include head, chest, abdomen, and pelvis.
Clinical evaluation: complete medical and cancer history, physical 
examination (Site/Organ System Status [includes: General appearance, skin, 
H/E/E/N/T – Thyroid, Pulmonary, Cardiovascular, Gastrointestinal, 
Musculoskeletal/Extremities, Genitourinary/Breast, Lymph Nodes, 
Neurological, and Psychiatric]), ECOG performance status, ECG, 
height (screening only), weight, vital signs, documentation of concomitant 
medications and obtaining pathology report of archival tissue.
Laboratory studies: hematology (WBC with differential, RBC count, 
hemoglobin, reticulocyte count, and platelet count); aPTT and 
International Normalized Ratio (INR) or PT; comprehensive chemistry 
panel (sodium, potassium, chloride, CO2, creatinine, calcium, BUN, 
albumin, AST, ALT, alkaline phosphatase, lactate dehydrogenase, and 
total bilirubin); Thyroid Function Test (TSH, free T3, and free T4);
urinalysis with microscopic examination; and serum or urine pregnancy 
test for women of childbearing potential.
Clinical staging: imaging for measurable disease by CT or MRI if allergic 
to contrast media must be performed within 30 days prior to randomization.  
Scan performed as part of standard practice may be used if conducted within 
30 days prior to randomization.
A fresh tissue biopsy is only required if no archival tissue is available within 
60 days of Informed Consent or unless approved by the Medical Monitor.
Biopsy of prior radiation-treated areas is not preferred.
Most recent PD-L1 expression status >50% to determine eligibility.  An
FDA-approved PD-L1 IHC 22C3 assay is mandatory.
Randomization:
Patients will be randomized within 21 days of their screening assessments.
Patients must begin treatment within 3 days after randomization.
Trial Treatment Period: Patients may participate in this trial until they 
experience drug intolerance, disease progression, or withdraw consent.

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Clinical evaluation: complete history, physical examination (Site/Organ 
System Status [includes: General appearance, skin, H/E/E/N/T – Thyroid, 
Pulmonary, Cardiovascular, Gastrointestinal, Musculoskeletal/Extremities, 
Genitourinary/Breast, Lymph Nodes, Neurological, and Psychiatric]), ECOG 
performance status, height, weight, vital signs, and documentation of 
concomitant medications.
Laboratory studies: hematology (WBC with differential, RBC count, 
reticulocyte count, and platelet count); aPTT and International Normalized 
Ratio (INR) or PT; comprehensive chemistry panel (sodium, potassium, 
chloride, CO2, creatinine, calcium, BUN, albumin, AST, ALT, alkaline 
phosphatase, lactate dehydrogenase, and total bilirubin); Thyroid Function 
Test (TSH, free T3, and free T4); urinalysis with microscopic examination; 
and serum or urine pregnancy test for women of child bearing potential.
Pharmacokinetic: sparse sampling in all patients in Arm 1 and crossover 
and exploratory molecular biomarker sample collection in all patients.
Tumor Assessment: CT or MRI (if allergic to contrast media) scans will be 
performed every 9 weeks (±7 days) during the study treatment and during 
the first year from discontinuation of the study treatment, every 12 weeks 
(±7 days) during the second year, and every 16 weeks (±7 days) thereafter, 
to evaluate response to treatment by RECIST v.1.1.
Tumor assessment will be repeated until disease progression, death, or 
receipt of new anti-cancer therapy, or until study completion, whichever is 
first, whether or not study treatment was administered
The same radiographic procedure to define measurable lesions must be used 
throughout the trial for each patient.
Patients will continue the assigned trial treatments until tumor progression 
by RECIST v.1.1 criteria (per Investigator’s assessment) by CT or MRI (if 
allergic to contrast media), withdrawal from the trial, or intolerance of 
therapy not manageable with dose modifications outlined in the 
protocol/package insert and/or supportive care.  Note: Patients with 
suspected radiographic pseudoprogression, in the absence of clinical 
deterioration, should remain on trial treatments and be rescanned at 4 weeks 
or later.  If progression is confirmed on follow-up scan, patients in Arm 1 
will be discontinued from the treatment and patients in Arm 2 may crossover 
to receive treatment with AM0010 with pembrolizumab if they fulfill 
eligibility requirements.  Refer to Section 7.6.
Patients who discontinue trial treatments with response of CR, PR, or SD
will undergo CT or MRI scan evaluations per protocol until time of PD or 
death, or until study completion or initiation of subsequent anti-cancer 
therapy, whichever is first.
Patients who demonstrate clinical progression will have a scan conducted at 
the time to document disease status by RECIST v.1.1.
The first scheduled tumor response assessment will be performed at 9 weeks 
(±7 days), and responders (CR or PR per RECIST v1.1) will have a 
confirmatory scan at ≥4 weeks after response has been established using the 
same technique as baseline scans.
To mitigate the chance of detecting false progression (ie, pseudoprogression) 
early in the course of treatment with AM0010 in combination with 
pembrolizumab or the pembrolizumab-alone arm, patients whose scans show 
radiographic progression in the absence of clinical deterioration including 
worsening performance status as assessed by the Investigator may remain on 
trial treatments and an additional scan should be obtained at ≥4 weeks (±7 
days) as outlined in Section 7.6.  If this subsequent scan shows disease 
progression, patients in Arm 1 will be discontinued from the treatment 
period of the trial; patients in Arm 2 may cross over to receive treatment 
with AM0010 in combination with pembrolizumab if they fulfil the 
necessary eligibility criteria.
All screening and on-trial CT/MRI scans for all patients randomized on the 

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trial will be collected prospectively and submitted to a central imaging 
vendor for archiving.  These scans may be independently reviewed at a later 
time at the request of Lilly.
End of Treatment Visit and Extended Safety Observation Period: All 
patients must have the end-of-treatment visit 28 days after the last dose of study 
treatment (±7 days) and extended safety observation period visits 60 and 90 
days after the last dose of study treatment (±7 days). The procedures should be 
conducted as described in the protocol and schedule of events (Appendix A).
Long-Term Follow-Up Period: All randomized patients will be followed for 
OS every 9 weeks (±7 days) during the first year from the 90-day follow-up 
visit, every 12 weeks (±7 days) during the second year, and every 16 weeks (±7 
days) thereafter. The survival follow-up will be conducted until death or study 
completion, whichever is first, whether or not trial treatment was administered.
For patients who were randomized, but withdrew consent, survival (date of 
death) will be obtained by use of publicly available information.
Tumor assessment will be performed for all randomized patients every 9 weeks 
(±7 days) during the study treatment and during the first year from 
discontinuation of the study treatment, every 12 weeks (±7 days) during the 
second year, and every 16 weeks (±7 days) thereafter. Tumor assessment will 
be repeated until disease progression, death, or receipt of new anti-cancer 
therapy, or until study completion, whichever is first, whether or not study 
treatment was administered.
Scans will include head and chest, abdomen, and pelvis (CAPs) and will be sent 
to the central imaging vendor for archiving and possible assessment at a later 
date.  If clinical progression is suspected, all relevant clinical documentation is 
to be submitted to the central imaging vendor for archiving.
All randomized patients will be followed after the end-of-treatment visit for 
treated patients or after randomization for patients not treated, until study 
completion or death, whichever is first. 
The Investigator (or designee) will acquire the following information from 
patients who were randomized: 

Tumor assessment will be performed for all randomized patients every 
9 weeks (±7 days) during the study treatment and during the first year from 
discontinuation of the study treatment, every 12 weeks (±7 days) during the 
second year, and every 16 weeks (±7 days) thereafter. Tumor assessment 
will be repeated until disease progression, death, or receipt of new anti-
cancer therapy, or until study completion, whichever is first, whether or not 
study treatment was administered.

Subsequent cancer treatments (all randomized patients).

Any serious adverse events (SAEs) considered to be related to trial 
treatment >90 days post last day of trial treatment, follow until resolution.

Date and cause of death (all randomized patients).
Continued access:  All patients remaining on AM0010 without disease 
progression following study completion (see Section 3.7) will be able to enter 
the continued-access period of the study, in which patients on study treatment 
who continue to experience clinical benefit may continue to receive study 
treatment until disease progression, death, unacceptable toxicity, or end of trial.  
SAFETY ASSESSMENTS:
Safety and tolerability will be monitored through continuous reporting of 
adverse events (AEs) and SAEs.  Safety will be assessed by physical exam, 
standard clinical and laboratory tests (hematology, chemistry, coagulation tests, 
thyroid function, and urinalysis), and incidence of patients experiencing dose 
modifications, withholds, and/or discontinuation of trial drugs with reasons for 
trial drug discontinuation (refer Section 6.4). All AEs will be assessed 
regarding the relationship to trial treatments and the toxicity grade will be 
defined by National Cancer Institute (NCI) - Common Terminology Criteria for 
Adverse Events (CTCAE) v.4.03.

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EFFICACY
ASSESSMENTS:
Tumors responses will be assessed by RECIST v.1.1 criteria using CT or MRI 
scan (in patients who are known to be allergic to contrast media).  Scans will be 
performed as described in Section 7.1 PFS and OS will be assessed from the 
date of randomization.
PHARMACOKINETICS:
Blood samples for pharmacokinetics (PK) with sparse sampling techniques will 
be obtained on all patients in Arm 1 (including crossover patients) to 
characterize PK of AM0010 in combination with pembrolizumab and to explore 
exposure-safety and exposure-efficacy relationships.  Data from these 
investigations may be evaluated for correlations with response, survival, and 
safety data.
BIOMARKERS:
Blood samples for biomarker analysis will be obtained on all patients in Arms 1 
and 2. A variety of factors that may impact the immunomodulatory properties 
and efficacy of AM0010 in combination with pembrolizumab will be 
investigated in peripheral blood.  Data from these investigations may be 
evaluated for correlations with response, survival, and safety data.
IMMUNOGENICITY:
(Anti-AM0010 Antibodies)
Blood samples for immunogenicity analysis will be obtained on all patients in 
Arms 1 and 2 according to the Schedule of Assessments. Samples will be 
evaluated for development of anti-drug antibodies (ADAs) by a validated 
immunoassay.
SAMPLE SIZE:
With 100 patients, this study has more than 80% power to detect a 25% 
improvement (ie, 45% vs 70%) in the ORR between AM0010 in combination 
with pembrolizumab and pembrolizumab alone at a 1-sided 5% type I error rate.
INTERIM ANALYSIS:
A planned interim analysis may be performed when the 50th randomized 
patient has been followed up for approximately 3 months. No statistical 
boundaries or alpha spending will be applied for this interim analysis as the 
primary purpose of this analysis is to assess safety and PK. At the time of 
interim data lock, all patients on study will continue on the study per protocol. 
See Table 6 for the schedule of analyses of key endpoints.
STATISTICAL 
METHODS:
EFFICACY ANALYSES
All efficacy analyses will be based on the Intent-to-Treat (ITT) population, 
which includes all randomized patients regardless of whether the patient 
receives any study drugs or has any efficacy assessments.
The primary efficacy endpoint is objective tumor response assessed according 
to RECIST v.1.1 criteria.  The ORR will be summarized and compared using a 
Cochran-Mantel-Haenszel 2-sided test at a type I error rate of 10% stratified by 
tumor histology (squamous vs non-squamous.)
Progression-free survival will be compared in the 2 randomized treatment arms 
using a 2-sided log-rank test, stratified by the tumor histology.  Progression-free 
survival time will be summarized using the Kaplan-Meier method to estimate 
the median PFS and 95% confidence interval (CI).  Overall survival will be 
summarized in the same manner as the PFS.
SAFETY ANALYSES
Safety Population includes all randomized patients who received any amount of 
study drug.  Trial treatment exposure will be summarized. Adverse events will 
be summarized in terms of treatment-emergent events defined to be any event 
that begin or worsen in grade after first dose through 30 days after the last dose 
of trial drugs.  Descriptive statistics of safety will be presented using NCI-
CTCAE version 4.03 by treatment arm. All treatment-emergent AEs, due to 
any cause, treatment-related AEs, AEs leading to discontinuation from the trial 
treatments, SAEs, and drug-related SAEs will be tabulated using worst grade 
per NCI-CTCAE v4.03 criteria by system organ class and preferred term.  On-
trial lab parameters including hematology and chemistry will be summarized 
using the worst grade per NCI-CTCAE v4.03 criteria.

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Table of Contents
CLINICAL TRIAL PROTOCOL ..........................................................................................1
CONFIDENTIAL INFORMATION......................................................................................1
PROTOCOL APPROVAL PAGE .........................................................................................2
PROTOCOL ACCEPTANCE PAGE ....................................................................................3
SUMMARY OF CHANGES.................................................................................................4
PROTOCOL SYNOPSIS ......................................................................................................7
TRIAL GLOSSARY ...........................................................................................................21
1.0
BACKGROUND AND RATIONALE........................................................................24
Non-Small Cell Lung Cancer ..........................................................................24
1.1
AM0010 Background......................................................................................25
1.2
1.2.1
AM0010 Mechanism of Action................................................................25
1.2.2
AM0010 Nonclinical Experience .............................................................26
1.2.2.1
AM0010 Toxicology................................................................26
1.2.2.2
AM0010 Pharmacology ...........................................................27
1.2.2.3
AM0010 Pharmacokinetics and Metabolism ............................28
1.2.3
AM0010 Clinical Experience...................................................................30
1.2.3.1
Clinical Trial AM0010-001......................................................30
1.2.3.2
Clinical Trial AM0010-301......................................................31
Trial Rationale and Design..............................................................................31
1.3
2.0
TRIAL OBJECTIVES................................................................................................34
Primary...........................................................................................................34
2.1
Secondary .......................................................................................................34
2.2
Exploratory.....................................................................................................34
2.3
3.0
TRIAL DESIGN.........................................................................................................35
Number of Trial Centers..................................................................................36
3.1
Number of Patients..........................................................................................36
3.2
Estimated Trial Duration.................................................................................36
3.3
Trial Endpoints ...............................................................................................36
3.4
3.4.1
Primary....................................................................................................36
3.4.2
Secondary................................................................................................36
3.4.3
Exploratory..............................................................................................37
End of Treatment/Follow-Up Period ...............................................................37
3.5
Study Completion Definition...........................................................................37
3.6
Continued-Access Period ................................................................................38
3.7
End of Trial Definition....................................................................................38
3.8
4.0
PATIENT ELIGIBILITY ...........................................................................................39
Inclusion Criteria ............................................................................................39
4.1
Exclusion Criteria ...........................................................................................40
4.2
5.0
PATIENT ENROLLMENT........................................................................................43
Treatment Arms ..............................................................................................43
5.1
6.0
TREATMENT PROCEDURES..................................................................................44
Investigational Product Dosage, Administration, and Schedule .......................44
6.1
Pembrolizumab Administration.......................................................................44
6.2

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Dosing Schedule .............................................................................................45
6.3
Treatment Withhold, Dose or Schedule Reduction, or Discontinuation for 
6.4
Toxicity ................................................................................................46
6.4.1
Treatment Withhold and Discontinuation.................................................46
6.4.1.1
AM0010 ..................................................................................46
6.4.1.2
Pembrolizumab........................................................................47
6.4.2
Toxicity ...................................................................................................53
6.4.3
Data Monitoring Committee (DMC) ........................................................53
Concomitant Medication .................................................................................53
6.5
Surgery During Trial Period............................................................................54
6.6
7.0
TRIAL ASSESSMENTS AND PROCEDURES.........................................................55
General Trial Procedures.................................................................................55
7.1
Overview ........................................................................................................56
7.2
Screening ........................................................................................................57
7.3
Clinical Visits .................................................................................................58
7.4
7.4.1
Clinic Evaluations....................................................................................58
Tumor Assessments ........................................................................................59
7.5
Pseudoprogression and Confirmation of Disease Progression..........................59
7.6
Trial Drug Administration...............................................................................60
7.7
Continued Treatment.......................................................................................61
7.8
7.8.1
Crossover.................................................................................................61
End of Treatment Visit....................................................................................61
7.9
Follow-Up Period............................................................................................62
7.10
Laboratory Assessments..................................................................................62
7.11
Pharmacokinetics ............................................................................................63
7.12
Immunogenicity (ADA [anti-drug antibodies])................................................63
7.13
Biomarkers......................................................................................................64
7.14
8.0
REMOVAL AND REPLACEMENT OF PATIENTS.................................................65
Removal of Patients ........................................................................................65
8.1
Replacement of Patients..................................................................................66
8.2
9.0
ADVERSE EVENT REPORTING.............................................................................67
Definitions ......................................................................................................67
9.1
9.1.1
Adverse Events........................................................................................67
9.1.2
Serious Adverse Events............................................................................68
Suspected Unexpected Serious Adverse Reactions ..........................................68
9.2
9.2.1
Pregnancy................................................................................................68
Reporting Procedures for All Adverse Events..................................................69
9.3
Serious Adverse Event Reporting Procedures..................................................71
9.4
Complaint Handling........................................................................................71
9.5
10.0 STATISTICAL CONSIDERATIONS ........................................................................72
Trial Design ....................................................................................................72
10.1
Trial Endpoints ...............................................................................................72
10.2
10.2.1 Primary Endpoint.....................................................................................72
10.2.2 Secondary Endpoints................................................................................72

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Sample Size Considerations ............................................................................73
10.3
Schedule of Analyses ......................................................................................73
10.4
Analysis Populations.......................................................................................73
10.5
Planned Method of Analysis............................................................................74
10.6
10.6.1 General Approach/Considerations............................................................74
10.6.2 Demographic and Baseline Characteristics...............................................74
10.6.3 Efficacy Analyses ....................................................................................74
10.6.3.1
Primary Efficacy Analyses.......................................................74
10.6.3.2
Secondary Efficacy Analyses ...................................................74
10.6.4 Safety Analyses .......................................................................................75
10.6.5 Extent of Exposure...................................................................................75
10.6.6 Adverse Events........................................................................................75
10.6.7 Clinical Laboratory Data..........................................................................76
10.6.8 ECOG Performance Status.......................................................................76
10.6.9 Vital Signs ...............................................................................................76
10.6.10
12-Lead ECG .......................................................................................76
10.6.11
Immunologic Biomarkers .....................................................................76
10.6.12
Pharmacokinetic Analyses....................................................................76
11.0 INVESTIGATIONAL PRODUCT .............................................................................78
AM0010..........................................................................................................78
11.1
Compliance in Investigational Product Administration....................................78
11.2
12.0 ETHICAL CONSIDERATIONS ................................................................................79
Local Regulations ...........................................................................................79
12.1
Informed Consent............................................................................................79
12.2
Institutional Review Board..............................................................................79
12.3
Documentation Requirements .........................................................................80
12.4
Patient Confidentiality.....................................................................................80
12.5
13.0 ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................81
Protocol Amendments and Trial Termination ..................................................81
13.1
Trial Documentation and Archive ...................................................................81
13.2
Trial Monitoring and Data Collection..............................................................82
13.3
Language ........................................................................................................83
13.4
Publication Policy ...........................................................................................83
13.5
14.0 REFERENCES...........................................................................................................84
15.0 APPENDICES............................................................................................................87
List of Tables
Table 1.
Clinical Pharmacokinetics of AM0010...............................................................29
Table 2.
Toxicity Management Guideline for AM0010....................................................46
Table 3.
Dose and Dose Schedule Reduction of AM0010 ................................................47
Table 4.
Dose Modification and Toxicity Management Guidelines for Immune-Related 
AEs Associated with Pembrolizumab ..................................................................................49
Table 5.
Pembrolizumab Infusion-Related Reaction Treatment Guidelines ......................52
Table 6.
Schedule of Analyses ........................................................................................73

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List of Figures
Figure 1.
Trial Design.......................................................................................................35
Figure 2.
Dosing Schedule ................................................................................................45
List of Appendices
Appendix A – Schedule of Assessments..............................................................................88
Appendix B – Continued-Access Period Assessments .........................................................89
Appendix C – Birth Control Methods that May Be Considered as Highly Effective.............90
Appendix D – RECIST v.1.1 Criteria ..................................................................................91
Appendix E - Hepatic Monitoring Tests for Treatment Emergent Abnormality....................98
Appendix F – NCI-CTCAE Version 4.03 ............................................................................99

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TRIAL GLOSSARY
Abbreviation/Acronym
Definition
ADA
anti-drug antibody
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALK
anaplastic lymphoma kinase mutation
ALT
alanine transaminase
AM0010
PEGylated recombinant Human IL-10
aPTT
activated partial thromboplastin time
AST
aspartate transaminase
AUC
area under the curve (pharmacological exposure)
BMI
body mass index
BUN
blood urea nitrogen
CAPs
chest, abdomen, and pelvis
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum drug concentration
CMH
Cochran-Mantel Haenszel
Cmin
minimal drug concentration/serum trough concentration
CNS
central nervous system
Continued-access period
The 
continued-access 
period 
begins 
after 
study 
completion and ends at the end of trial.
CPK
creatine phosphokinase
CR
complete response (no measurable residual tumor)
CRF
case report form
CRP
Clinical Research Physician
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
EC10
equivalent to 10% effective concentration
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EKG
electrocardiogram
End of trial
End of the trial is defined as the date of the last visit or 
last scheduled procedure for the last patient. The end of 
trial 
occurs 
after 
study 
completion 
after 
the 
continued-access period (if any).
FDA
US Food and Drug Administration
GCP
good clinical practice
G-CSF
granulocyte-colony-stimulating factor
GGT
gamma-glutamyl transferase
GLP
good laboratory practices
hCG
human chorionic gonadotropin
HCT
hematocrit
Hgb
hemoglobin
HIV
human immunodeficiency virus

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HNSTD
highest non-severely toxic dose
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IFNγ
Interferon gamma
IL-10
interleukin 10
IND
Investigational New Drug Application
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IV 
intravenous(ly)
LFT
liver function test
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NHP
non-human primate
NIMP
Non-investigational medicinal products
NOAEL
no observed adverse effect level
NSCLC
non-small cell lung carcinoma
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed death 1
PDAC
pancreatic ductal adenocarcinoma 
PE
physical examination
PEG-rHuIL-10
PEGylated recombinant human interleukin 10
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response
PT
prothrombin time 
qd
Latin: quaque die (once a day)
QT
QT interval
QTc
corrected QT interval
RCC
renal cell carcinoma
rHuIL-10
recombinant human interleukin 10
rMuIL-10
recombinant murine interleukin 10
SAE
serious adverse event
SD
stable disease
SQ
subcutaneous
Study completion
This study will be considered complete when the final 
analysis of the primary and secondary objectives is
complete.  This includes 3-year follow-up for OS after the 
last patient is randomized.
t½ 
half-life
TPS
tumor proportion score
TK
toxicokinetics
Tmax
time of maximum concentration observed

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TRAEs
treatment-related adverse events
ULN
upper limit of normal
vs
versus
WBC
white blood cell
WOCBP
women of childbearing potential 

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1.0
BACKGROUND AND RATIONALE
Non-Small Cell Lung Cancer
1.1
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality 
worldwide, accounting for approximately 18% of all cancer deaths (Jemal, Bray et al. 2011). 
Despite treatment with platinum and taxane-based chemotherapy, patients with metastatic 
NSCLC have a median survival of approximately 10 months, and a 5-year survival rate of 
approximately 15%. Despite the increased number of treatment options available for patients 
with both non-squamous and squamous histology NSCLC, there has been little overall 
survival (OS) improvement from several new agents, including pemetrexed, erlotinib, and 
bevacizumab, beyond very small subpopulations. Therapeutic options for mutation wild-type 
non-squamous and squamous NSCLC in the first-line setting are particularly limited. 
Docetaxel was approved as a second-line treatment for advanced NSCLC on the basis of 
longer survival than that with best supportive care (Fossella, DeVore et al. 2000); (Shepherd,
Dancey et al. 2000). Newer agents, such as pemetrexed and erlotinib, which have a better 
side-effect profile than docetaxel, have either been shown to be non-inferior to docetaxel or 
have failed to show superiority to docetaxel with respect to OS when they are used as 
second-line therapy (Hanna, Shepherd et al. 2004); (Garassino, Martelli et al. 2013).
Immunotherapeutic approaches for the treatment of malignancies recently have demonstrated 
clinical efficacy in several cancer types. The programmed death 1 (PD-1) receptor expressed 
on activated T cells is engaged by the tumor-expressed ligands of PD-L1 and PD-L2 which 
are expressed on the tumor cell itself or on the tumor infiltrating cells, as well as on T cells. 
PD-1 activation down-regulates T cell activation and promote tumor immune escape (ie, the 
mechanism by which tumor cells escape recognition and elimination by the immune system) 
(Pardoll 2012).
Pembrolizumab is a humanized monoclonal antibody against PD-1 that in a recent phase 3
trial in advanced NSCLC was tested against chemotherapy. The patient population was 
previously untreated, with PD-L1 expression on at least 50% of the tumor cells.  The median 
progression-free survival (PFS) was 10.3 months in the pembrolizumab group versus 6 
months in the chemotherapy group. The survival at 6 months was 80.2% in the 
pembrolizumab versus 72% in the chemotherapy group. The objective response rate (ORR)
was higher in the pembrolizumab group at 44.8% versus 27.8% in the chemotherapy group 
(Reck et al NEJM 375; 19 Nov 10, 2016). Recently, pembrolizumab in combination with 
platinum and pemetrexed received accelerated approval as first line of therapy for all non-
squamous NSCLC patients based on PFS. The ORR with the combination was 55% as 
compared to 29% with chemotherapy alone and the median PFS was 13 months versus 8.9 
months. The mOS was not established, but the OS was similar between both groups (Langer, 
Gadgeel et al. 2016). Due to insufficient data on the benefit of the combination, the most 
recent ASCO guidelines do not recommend the combination of immune checkpoint 
inhibitors with chemotherapy in first line treatment of NSCLC (Hanna, Johnson et al. 2017).

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Pembrolizumab is FDA approved as a single agent for the first-line treatment of patients with 
metastatic NSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS]
≥50%) as determined by an FDA-approved test, with no epidermal growth factor receptor
(EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Combining 
AM0010 with pembrolizumab may represent a promising therapeutic combination to address 
this unmet medical need in patients with advanced NSCLC.
AM0010 Background 
1.2
AM0010 is a PEGylated recombinant form of human IL-10 (PEG-rHuIL-10). AM0010 is 
produced by prokaryotic fermentation, refolding, purification of rHuIL-10, followed by 
PEGylation and final purification of AM0010. AM0010 and PEG-rMuIL-10 bind and 
activate the murine IL-10 receptor in a comparable molar concentration, as shown in cell-
based activity assays.
Preliminary evidence for the clinical activity of AM0010 was obtained in a first in human 
trial (Naing, Papadopoulos et al. 2016). Objective responses to AM0010 monotherapy were 
observed in 4 of 15 patients with renal cell cancer (RCC), one patient with ocular melanoma, 
and one patient with cutaneous T cell lymphoma. Combination of AM0010 with an anti-PD-
1 immune checkpoint inhibitor lead to objective responses in 4 of 8 patients with RCC and in 
2 of 5 patients with NSCLC. While a small number of patients were included in these
cohorts, the rate of objective responses and the sustained duration of the observed responses 
appeared increased over what would be expected from monotherapy of either agent. This 
may indicate that a combination of AM0010 with anti-PD-1 is clinically beneficial for 
patients with refractory or resistant metastatic NSCLC. An additional 30 patients with 
NSCLC which progressed on or after platinum containing regimen are enrolled for the 
treatment with AM0010 (1.6 or 2 mg SQ qd based on weight of <80 kg or ≥ 80 kg, 
respectively) and nivolumab (240 mg IV, q2w). Preliminary results indicate that at least 38% 
of evaluable patients have an objective response, including one patient with a complete 
response.
1.2.1
AM0010 Mechanism of Action
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.  Genetic 
mutations in tumor cells lead to the translation and presentation of mutant proteins on tumor 
and immune cells. Those are recognized by CD8+ T cells which in turn kill the tumor cells. 
As a consequence, tumors such as NSCLC and melanoma, which have a relatively high 
burden of somatic mutations, have a higher probability to respond to immune oncology drugs 
(Rizvi, Hellmann et al. 2015). Tumor progression may also be facilitated by the acquisition 
of traits that allow cancer cells to evade immunosurveillance and escape effective innate and 
adaptive immune response (Pardoll 2003); (Zitvogel, Tesniere et al. 2006); (Dunn, Bruce et
al. 2002). The role of immunosurveillance in NSCLC and other cancers is supported by 
many studies, demonstrating a correlation between tumor infiltrating CD8+ T cells in 

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surgically resected specimens and patient survival (Fridman, Pages et al. 2012). AM0010 
increases the infiltration of CD8+ T cells in preclinical models and in cancer patients. In 
addition, AM0010 induces a CD8+ T cell mediated immune activation in most treated 
patients, represented by elevation of activation markers on CD8+ T cells, elevation of CD8+ 
T cells stimulating cytokines in the serum, increase of the cytotoxic products of CD8+ T cells 
in the serum and the tumor and a de-novo expansion of CD8+ T cell clones in systemic 
circulation. Pembrolizumab releases the inhibition of CD8+ T cells by PD-1. This facilitates 
the stronger activation of CD8+ T cells recognizing foreign or novel mutated tumor antigens. 
Since the mechanisms of AM0010 and pembrolizumab are independent but activate the same 
target cell, it was postulated that the combination of AM0010 with an anti PD-1 immune 
checkpoint inhibitor could function synergistically.
1.2.2
AM0010 Nonclinical Experience
Nonclinical studies of AM0010 have demonstrated a favorable benefit-to-risk profile and 
strongly support its clinical investigation in solid tumors. An overview of AM0010 
toxicology, pharmacology, and pharmacokinetics (PK) is provided below. Additional details 
can be found in the AM0010 Investigator’s Brochure.
1.2.2.1
AM0010 Toxicology
Good laboratory practice (GLP) toxicology studies with AM0010 were performed in CD-1 
mice (rodent species) and cynomolgus monkeys (non-human primate species [NHP]). These 
studies involved daily subcutaneous (SQ) administration for up to 28 days at doses up to 100 
and 1000 µg/kg/day in monkeys and mice, respectively.
Effects seen in the studies with AM0010 were predominantly confined to NHP; the no 
observed adverse effect level (NOAEL) in the mouse was considered 1000 µg/kg/day. 
Changes in red blood cell parameters (decreased red blood cell [RBC] counts, hemoglobin 
(Hgb) and hematocrit (Hct), and increased reticulocyte counts) consistent with a regenerative 
anemia due to extravascular hemolysis was evident following 2 weeks of dosing at doses 
≥20µg/kg/day. These changes resolved following the cessation of treatment (100 µg/kg/day) 
or continued dosing (doses > 20 µg/kg/day). Other findings consistent with previous 
experience with rHuIL 10 included a mild to moderate decrease in albumin and the albumin-
to-globulin ratio.  In monkeys, no effects upon cardiovascular, respiratory, or neurological 
parameters were noted at any dose. The NOAEL and highest non-severely toxic dose 
(HNSTD) in the monkey was 20 µg/kg/day.
The toxicology of AM0010 was evaluated in a 13-Week GLP toxicology study in 
cynomolgus monkeys.
No AM0010-related changes in PR interval, QRS duration, QT interval, corrected QT (QTc) 
interval, or heart rate were observed on Day 1 or 89 of the dosing phase in animals 
administered 5, 20, or 50 μg/kg/day. No rhythm abnormalities or qualitative ECG changes 
attributed to AM0010 were observed during qualitative assessment of the ECGs.

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AM0010 administration had no effect on peripheral blood immunophenotyping (IPT) test 
results.
No AM0010-related organ weight or macroscopic or microscopic findings were present at 
the terminal or recovery sacrifice.
Clinical observations were limited to the 50 µg/kg/day treatment group and consisted of low 
food consumption in 3 males (Days 10-16) and squinting and potential bilateral uveitis in two 
males and two females given 50 µg/kg/day (the latter noted upon veterinary examination on 
Day 15 of the dosing phase). The latter animals were treated with topical atropine and 
intramuscular flunixin meglumine and the finding was not present from Day 18 onward.  
These findings are considered AM0010-related but not adverse. 
Clinical pathology findings in animals were limited to dose-dependent hematological effects 
consisting of reductions in RBC parameters (decreased red blood cell mass, Hgb, and/or an 
increase in reticulocytes and platelets, the latter two reflecting a normal regenerative 
response) and transient increases in white blood cell (WBC) counts, predominantly 
lymphocytes.  The hematological effects were transient and seen during Weeks 2-4 of the 
dosing phase with the effects resolving with continued dosing.
The results of toxicokinetic and anti-AM0010 antibody response analysis were generally in 
line with the findings in the 28 days toxicology study with AM0010 in cynomolgus monkeys. 
The median exposure levels between dosing groups were dose proportional between the 
dosing cohorts in weeks two through five, with an increased variability between individuals 
later in the study due to anti-drug antibodies (ADA) development. All animals developed 
ADAs, but several animals in each high dose cohort of both sexes maintained high serum 
trough levels throughout the study, suggesting that the overall interpretation of the study was 
not compromised by the ADA development.
The effects observed in this study were consistent with those obtained in the prior 4-week 
toxicology study in monkeys. The predominant finding was transient reductions in RBC 
parameters which resolved with continued dosing. As in the 4-week study, the NOEL was 5 
µg/kg/day, the NOAEL and HNSTD was defined as 20 µg/kg/day.  
1.2.2.2
AM0010 Pharmacology
The findings from the nonclinical studies suggest that a PEGylated rHuIL-10 may have 
strong anti-tumor effects in oncology by inducing cytotoxic activity and proliferation of 
tumor infiltrating and tumor specific CD8+ T cells. PEGylated IL-10 induces partial 
response (PR), complete response (CR), and curative effects in murine models of human late 
stage cancer, including animals with very large tumor burdens, animals with widespread 
metastatic dissemination, and in tumor types resistant to other therapeutic intervention, 
including chemotherapy and immunotherapy. Mice cured by treatment with PEGylated IL-
10 remained tumor free and developed a protective immune memory against the tumor.

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AM0010 stimulates the cytotoxic activity of murine or human peripheral CD8+ T cells and 
the expression of cytotoxic enzymes and Interferon gamma (IFNγ) in memory CD8+ T cells.
1.2.2.3
AM0010 Pharmacokinetics and Metabolism
1.2.2.3.1
Non-Clinical Pharmacokinetics
The pharmacokinetics/toxicokinetics (PK/TK) of AM0010 was evaluated in CD1 mice and 
cynomolgus monkeys in non-GLP pharmacokinetic studies and further evaluated in GLP 
toxicokinetic studies in both species.
In cynomolgus monkeys, the pharmacokinetics of AM0010 were linear over the dose range 
of 1 to 20 µg/kg/day administered SQ daily. No accumulation was observed in preclinical 
species, but based on extrapolation from pre-clinical species to humans, the predicted half-
life (t½) of 14 hours upon SQ injections in humans would predict a mild accumulation of 
about 40% for the maximum drug concentration (Cmax) upon daily dosing. Low level ADAs 
developed in monkeys and high levels of ADAs were detected in mice. ADA positivity 
decreased AM0010 serum exposure in affected monkeys. Results of a 28 day daily SQ 
injection PK study conducted with AM0010 in cynomolgus monkeys showed a mean 
AM0010 half-life of approximately 9.94 hours after administration of the first dose. Volume 
of distribution of AM0010 was high, suggesting extravascular distribution and receptor 
mediated elimination.
The serum exposure of AM0010 in CD-1 mice (area-under-the-curve [AUC]0-∞ and Cmax) 
increased proportionally with dose after SQ administration of 1 and 20 µg/kg. Mean serum 
half-life of AM0010 was approximately 4.5 hours at 20 µg/kg. The trough serum AM0010 
concentration of approximately 1 – 2 ng/mL was associated with a highly efficacious SQ 
dosing regimen of 0.1 mg/kg given daily in a murine syngeneic tumor model.

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1.2.2.3.2
Human Pharmacokinetics
A summary of human PK is provided below. For the most current information on clinical 
PK, please refer to the current Investigator’s Brochure.
Due to its PEGylation, AM0010 has a prolonged exposure compared to rHuIL-10 upon SQ 
delivery. The serum concentration of AM0010 was determined at 6 time points at Day 1 and 
Day 29, and the pre-dose concentration (Cmin) was determined weekly in patients in the 
dose escalation cohorts throughout the dosing period. The pretreatment serum level of IL 10 
was found to be below the limit of detection (50 pg/mL) in all cancer patients analyzed.
At the starting dose (0.125 mg), patients had a serum concentration of AM0010 between 0.68 
and 1 ng/mL or equivalent to 10% effective concentration (EC10).  The average minimal 
AM0010 serum concentration at the 0.5 mg was 3.5 ng/mL or the equivalent to the EC25. 
The difference between Cmax and Cmin was approximately 33%, indicating a stable drug 
exposure with once daily dosing (Table 1).
Table 1.
Clinical Pharmacokinetics of AM0010
Dose (mg)
≥80 kg / <80 kg*
Cmax
(ng/mL)
Tmax
Cmin (24 h)
AUC 
(ng/mL•24 h)
0.125 / (0.1)
0.85
7.3
0.68
18.4
0.25 / (0.2)
1.45
9.2
1.08
30.6
0.5 / (0.4)
5.30
14.4
3.54
106
1 / (0.8)
5.35
9.2
3.60
108
2 / (1.6)
13.9
9.2
11.7
307
4 / (3.2)
31.1
12.5
28.5
716
* Patient weight.
Serum concentrations of AM0010 remained stable throughout the duration of dosing. No 
significant accumulation or attenuation of AM0010 levels were observed after the first week 
of dosing. The absence of high titer ADAs was confirmed in all patients tested.
An interim pharmacokinetic analysis has been conducted on the data available from 155 
subjects in AM0010-001. These patients received extended treatment with AM0010, and 
samples were obtained intermittently throughout their treatment course. The analysis is not 
complete and is ongoing. Results from this interim analysis support the following claims:
1. AM0010 is cumulative, reaching steady state conditions after approximately one week 
of daily dosing.
2. Apparent clearance (the sole determinant of -AUC) is proportional to weight, 
supporting a weight-normalized dosing regimen.
3. Apparent clearance (and, to a lesser extent, distribution volume) was smaller in subjects 
assigned to higher dose cohorts (values ranged from 1 to 40 µg/kg/dose).

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None of the other covariates evaluated (age, gender, race, organ function, chemotherapy 
regimen) appears to influence the pharmacokinetic parameters. Preliminary analysis 
suggested a small decrease in apparent clearance with increasing serum albumin; however, 
the relationship was not statistically significant.
1.2.3
AM0010 Clinical Experience
1.2.3.1
Clinical Trial AM0010-001
In this First in Human trial, over 350 patients in 12 selected advanced solid malignancies 
were treated with AM0010 in a dose escalation 3+3 design, followed by several dose 
expansion cohorts in specific cancers and combinations with immune-oncology checkpoint 
inhibitors or chemotherapies that are standard of care for that tumor type.
A total of 33 patients were enrolled in monotherapy dose escalation cohorts. AM0010 was 
self-administered SC at doses of 1 to 40 µg/kg on a continuous daily (qd) dose schedule. 
Objectives of the trial were safety and tolerability, and early evidence of efficacy and 
immune activation. AM0010 monotherapy was well tolerated in this heavily pretreated 
advanced cancer patient population.
AM0010 led to systemic immune activation with elevated immune stimulatory cytokines and 
reduced TGF-beta in the serum. AM0010 induced an expansion of new T cell clones in the 
blood and CD8+ T cells with elevated checkpoint proteins such as PD-1 and Lag3 
expression. PD-1 and Lag3 expression on CD8+ T cells isolated from the tumor or the blood 
of cancer patients, has been associated with tumor antigen reactivity (Gros, Robbins et al. 
2014, Gros, Parkhurst et al. 2016). These data suggest an expansion of tumor directed CD8+ 
T cells in AM0010 treated patients.
In the NSCLC cohort 5 patients were treated with AM0010 at 10 µg/kg plus pembrolizumab 
40% of the patients had at least 3 prior therapies, 20% had 2 prior therapies. The median 
number of prior therapies is 2 (range 0-5). Two patients had a best overall response of irPR 
(ORR=40%), and 3 patients had an irSD (disease control rate [DCR] = 100%).
The expected response rate of second-line NSCLC to anti-PD1 inhibitors is dependent on 
expression of PD-L1 in the tumor. The ORR to anti-PD1 therapy was 9.1-10.7% for patients 
with PD-L1 negative tumors (below 1% of tumor cells PD-L1 positive) and 45% for patients 
with ≥50% PD-L1 expressing tumor cells (Garon, Rizvi et al. 2015). The OS was 9.3 months 
for all patients and approximately 8.5 months for patients whose tumors were negative for 
PD-L1.
In this cohort, four of the five patients were evaluated for PD-L1 expression in the tumor, and 
all were negative for PD-L1 (<1% PD-L1 positive tumor cells), including both patients who 
had a PR.
Most patients enrolled in the escalation cohorts and expansion cohorts had previously 
progressed during or following multiple lines of therapy. Despite this fact, very encouraging 
objective tumor responses have been observed in most combination therapies with AM0010.

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The median PFS was 10.9 months (range 4.7-19.3+), the mOS has not been reached; 80% of 
patients who received AM0010 at 1 mg (10 µg/kg) plus pembrolizumab were alive with a 
median follow-up of 25.2 months (range 24.5-26.9+).
1.2.3.2
Clinical Trial AM0010-301
Clinical trial AM0010-301 is an ongoing 566 patient randomized, open-label, global Phase 3 
trial of AM0010 in combination with folinic acid, fluorouracil, and oxaliplatin (FOLFOX), 
compared with FOLFOX alone, as a second-line therapy in patients with metastatic 
pancreatic ductal adenocarcinoma (PDAC) that has progressed on a first-line gemcitabine-
based regimen. The objectives of this trial are to assess safety and efficacy, as measured by 
OS, PFS, ORR by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1, and other 
measures.
Trial Rationale and Design
1.3
In recent years, it has become apparent that cancers are recognized by human immune system 
and that under certain circumstances the immune system can obliterate tumors. Recently, the 
PD-1 pathway has emerged as a major immune checkpoint by which tumors suppress 
lymphocyte function. This pathway consists of PD-1, a protein expressed on activated 
immune cell types such as T cells and B cells, and its ligands, PD-L1 and PD-L2 which are 
expressed on many tumors. Cancer cells drive high expression levels of PD-L1 on their 
surface, allowing activation of the inhibitory PD-1 receptor on any T cells that infiltrate the 
tumor microenvironment, effectively switching those cells off. Indeed, up-regulation of PD-
L1 expression levels has been demonstrated in many different cancer types (eg, melanoma 
[40%-100%], NSCLC [35%-95%], and multiple myeloma [93%]), and high levels of PD-L1 
expression have been linked to poor clinical outcomes (Hino et al, 2010, Wang et al, 2011,
Dong et al, 2002, Konishi et al, 2004, Liu et al, 2007, Patel et al, 2015). 
Treatment of cancer patients with AM0010 alone in the Phase 1 trial led to an increase of 
CD8+ T cells positive for immune checkpoints, including PD-1 and Lag-3, suggesting the 
expansion of tumor reactive CD8+ T cells. Inhibition of those immune checkpoints with 
antibodies to PD-1 or Lag-3 should further enhance the anti-tumor activity. The treatment 
with AM0010 monotherapy lead to the expansion of T cell clones, which were previously not 
detected in the patient – “novel” T cell clones. The number of T cell clones which expand at 
least 10 fold during the treatment and their relative percentage in the patient’s T cell 
repertoire correlated with objective tumor response in patient treated with AM0010 
monotherapy.
AM0010 and anti-PD-1 stimulate the same cell, the tumor infiltrating CD8+ T cells, which 
recognize tumor antigens and up-regulate the IL-10 receptor and the immune checkpoint. 
The molecular signaling pathways of both molecules are however different, opening the 
possibility that combination of the stimulation by AM0010 and the inhibition of PD-1 may 
act synergistically. Early results observed in the Phase 1 trial using pembrolizumab or 
nivolumab in combination with AM0010 indeed support this hypothesis. The response rate 

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of the combination of AM0010 with pembrolizumab in a small number of NSCLC and RCC 
(n=5 and 8, respectively) was two fold over the expected response rate of pembrolizumab 
alone, progression free and overall survival was increased even stronger. Preliminary results 
from a combination of nivolumab and AM0010 appear to support this observation.
AM0010 induces an expansion of novel T cell clones in patients. This expansion was similar 
in patients treated with pembrolizumab and AM0010 at 1 mg (10 µg/kg) and 2 mg (20 
µg/kg), respectively. This and a comparable ORR on the cohorts treated with AM0010 at 1 
mg (10 µg/kg) and 2 mg (20 µg/kg) provides a rationale for a threshold based fixed dose in 
Phase 2 and 3 trials.
AM0010 has an acceptable safety profile and encouraging clinical activity in RCC, NSCLC, 
and PDAC. In addition, the safety profile of anti-PD-1 and AM0010 show mostly non-
overlapping treatment-related adverse events (TRAEs). In particular, immune checkpoint 
blockade frequently causes autoimmune toxicity, including colitis, gastritis or pneumonitis 
and endocrine disruptions, limiting the tolerability of combinations of immune checkpoint 
inhibitors. AM0010 monotherapy did not cause autoimmune toxicity. As a consequence, the 
combination of AM0010 with nivolumab (or another anti-PD-1 immune checkpoint 
inhibitor) was well tolerated (Section 1.2.3.1). The safety profile of AM0010 with PD-1 
inhibitors, may be better tolerated than combinations of two or more immune checkpoint 
inhibitors. PEGylated IL-10 (AM0010) offers a potent novel and non-redundant mechanism 
adding to the arsenal of clinically active immune-oncology drugs. The direct activation of 
the CD8+ T cells by AM0010 in absence of immune related adverse events should enable 
combinations with other immune-therapies which block inhibitory mechanisms.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) 
designed to target the programmed death-1 receptor and thus directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity 
of the target lymphocytes to facilitate tumor regression and ultimately immune rejection. 
Pembrolizumab only potentiates existing immune responses in the presence of antigen and 
does not non-specifically activate T cells. Evidence shows that PD-L1 expression levels 
correlate with increased response to pembrolizumab. For instance, in NSCLC phase 1 clinical 
trial data showed a correlation between PD-L1 expression and response to pembrolizumab, 
supporting the role of PD-L1 expression testing as a predictive biomarker (Garon et al, 2015).
In AM0010-001 Phase 1 trial, AM0010 in combination with pembrolizumab (and 
nivolumab) had substantially improved clinical efficacy compared to historical data with 
anti-PD-1 monotherapy in second line or greater metastatic NSCLC. Four of 5 NSCLC 
patients with high PD-L1 expression (≥ 50% of tumor cells positive for PD-L1) had a 
response and 100% had a durable clinical benefit (CR/PR or SD ≥ 6month).
Pembrolizumab is the only PD-1 inhibitor approved for use as first-line therapy of NSCLC in 
patients whose tumors have high PD-L1 expression (≥ 50% of tumor cells positive for 
PD-L1). It is the preferred treatment in the first line setting and has become the benchmark 

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comparator. Pembrolizumab was also chosen in this trial because its activity vs that of the 
AM0010 combination with pembrolizumab will show the contribution of components in this 
treatment setting.

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2.0
TRIAL OBJECTIVES
Primary
2.1

To evaluate the ORR
Secondary
2.2

To evaluate PFS

To evaluate OS

To evaluate DCR

To evaluate DoR

To evaluate the safety and tolerability profile
Exploratory
2.3

To characterize AM0010 LY3500518 PK in combination with pembrolizumab

To further evaluate the biomarkers including immune activation markers that may 
correlate with efficacy outcome measures.  These may include, but are not limited 
to:
o
FDA approved PD-L1 diagnostic assay
o
Immune cell infiltration
o
Tumor mutational burden test
o
Other assay, assessment, and test on residual tissue
o
to be conducted as part of exploratory analyses

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3.0
TRIAL DESIGN
This is an open-label, randomized, multicenter, Phase 2 trial in 100 adult male and female 
patients with treatment-naïve, Stage IV/metastatic NSCLC whose tumors are not known to 
have EGFR mutations or ALK rearrangements, but have high expression (≥50%) PD-L1 as 
determined with an FDA-approved PD-L1 IHC 22C3 assay.
Patients will be stratified according to tumor histology (squamous vs non-squamous).
Patients will be randomized in a 1:1 ratio into 1 of 2 treatment arms (Figure 1).
Figure 1.
Trial Design
Trial sites will provide best supportive care per institution’s standard of care including 
concomitant medications.
Arm 1 and 2 treatment will continue in the absence of disease progression, unacceptable 
toxicity, or patient’s withdrawal of consent.  Patients will be treated with a maximum of 
35 cycles of pembrolizumab every 3 weeks or 2 years, whichever is longer.
All radiological assessments will include at minimum, scans of the head, chest, abdomen, 
and pelvis.
At the time of documented disease progression (by Investigator assessment) patients in Arm 
1 will be discontinued from the treatment period of the trial and continue on the follow-up 
period. At the time of documented disease progression (by Investigator assessment), patients 
in Arm 2 may crossover to receive treatment with AM0010 and pembrolizumab.
Confirmation of complete response (CR) or partial response (PR) is required. Confirmatory 
scans will be performed as follows:

CR and PR criteria per RECIST v1.1 must be met again at least 4 weeks after initial 
documentation.

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Patients with suspected pseudoprogression on scans in the absence of clinical deterioration 
should remain on trial treatments and be rescanned at 4 weeks or later as outlined in
Section 7.6.
If progression is confirmed on follow up scan, then discontinue treatments and follow trial
procedures for end of treatment and survival follow-up or procedures for crossover patients.
Scans will include head and CAPs and will be sent to the central imaging vendor for 
archiving and possible assessment at a later date. If clinical progression is suspected, all 
relevant clinical documentation is to be submitted to the central imaging vendor.
For patients who were randomized, but withdraw consent, survival (date of death) will be 
obtained by use of publicly available information.
Tumor assessment will be performed for all randomized patients every 9 weeks (±7 days) 
during the study treatment and during the first year from discontinuation of the study 
treatment, every 12 weeks (±7 days) during the second year, and every 16 weeks (±7 days) 
thereafter. Tumor assessment will be repeated until disease progression, death, or receipt of 
new anti-cancer therapy, or until study completion, whichever is first, whether or not study 
treatment was administered.
All randomized patients will be followed for OS every 9 weeks (±7 days) during the first 
year from the 90-day follow-up visit, every 12 weeks (±7 days) during the second year, and 
every 16 weeks (±7 days) thereafter. The survival follow-up will be conducted until death or 
study completion, whichever is first, whether or not trial treatment was administered.
Number of Trial Centers
3.1
This trial will be conducted in multiple centers in the United States. 
Number of Patients
3.2
Approximately 100 (50 within each treatment arm)
Estimated Trial Duration
3.3
The duration of patient accrual, treatment, and follow-up, is expected to last approximately 
enrollment +36 months.
Trial Endpoints
3.4
3.4.1
Primary

The primary endpoint of this study is ORR defined as the proportion of patients 
who achieve a CR or PR as assessed by RECIST v.1.1.
3.4.2
Secondary
The secondary endpoints of the trial include:

PFS, defined as the time from date of the first documented tumor progression as 
determined by the Investigator (per RECIST v.1.1 criteria or clinical progression) 
or death due to any cause whichever occurs first;

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
OS, defined as the time from date of randomization to date of death due to any 
cause;

DCR, defined as the proportion of patients who achieve a CR, PR, or SD as 
assessed by RECIST v.1.1;

DoR, defined as the time from the date of the first documentation of objective 
tumor response (CR or PR) to the date of the first documentation of objective 
tumor progression or death due to any cause, whichever occurs first; and

Evaluation of the safety and tolerability profile (serious adverse events [SAEs], 
treatment-emergent adverse events [TEAEs], electrocardiogram [ECG]
parameters, vital signs, performance status, and laboratory parameters). TEAEs 
and laboratory findings will be graded according to the National Cancer Institute 
(NCI) - Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03.
3.4.3
Exploratory

Characterize AM0010 PK in combination with pembrolizumab .

Baseline and change from baseline in immune and molecular biomarkers and their 
relationship to clinical efficacy endpoints may be explored.
End of Treatment/Follow-Up Period
3.5
End of Treatment Visit
After patients receive their last dose of AM0010 and/or pembrolizumab, there will be a 
28-day (±7 days) follow-up period, after which patients will return to the trial site to 
complete end of treatment assessments (Section 7.9). Then, follow-up will begin on Day 35
(±7 days) after the last dose of trial treatment.
Follow-Up Period
During the extended safety observation period, all randomized patients will be followed for 
safety 60 and 90 days (±7 days) after the last dose of study treatment and monitored 
according to the schedule of assessments (SOA; Appendix A).  
During the long-term follow-up period, all randomized patients will be followed for OS 
every 9 weeks (±7 days) during the first year from the 90-day follow-up visit, every 
12 weeks (±7 days) during the second year, and every 16 weeks (±7 days) thereafter. The 
survival follow-up will be conducted until death or study completion, whichever is first, 
whether or not trial treatment was administered.
Study Completion Definition
3.6
This study will be considered complete when the final analysis of the primary and secondary 
objectives is complete.  This includes a 3-year follow-up for OS after the last patient is 
randomized. Investigators will continue to follow the study schedule for all patients until 
notified by Lilly that study completion has occurred. After study completion, the patients 
who are on treatment and continuing to receive clinical benefit may continue receiving study 
drugs during the continued-access period.

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Continued-Access Period
3.7
All patients remaining on study treatment without disease progression following study 
completion will enter the continued-access period of the study.  The continued-access period 
begins after study completion and ends at the end of trial.  During the continued-access 
period, patients on AM0010 who continue to experience clinical benefit may continue to 
receive study treatment until disease progression, death, unacceptable toxicity, or end of trial.  
Patients who are in the follow–up, but have not yet completed the visits will complete the 
necessary follow-up visits when the continued-access period begins and then discontinue the 
study. The continued-access period includes 3 follow-up visits; 28, 60, and 90 days (±7 
days) after the last dose of study treatment.  If it is deemed to be in the best interest of the 
patient to start a new anti-cancer treatment prior to a scheduled follow-up visit, the follow-up 
visit duration may be shortened. In this case, the follow-up assessments should be completed 
prior to the initiation of the new therapy.
Lilly will notify investigators when the continued-access period begins.
During the continued-access period, all relevant assessments will be done according to 
Appendix B and recorded on the case report form (CRF). 
Serious adverse events will also be reported to Lilly Global Patient Safety and collected in 
the pharmacovigilance system.  In the event that an SAE occurs, additional information (such 
as local laboratory results, concomitant medications, and hospitalizations) may be requested 
by Lilly in order to evaluate the reported SAE. 
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, Lilly will not routinely collect the results of these assessments.
End of Trial Definition
3.8
End of the trial is defined as the date of the last visit or last scheduled procedure for the last 
patient. The end of trial occurs after study completion after the continued-access period (if 
any).

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4.0
PATIENT ELIGIBILITY
Eligibility criteria for this trial have been carefully considered to ensure the safety of the trial
patients and to ensure the integrity of the trial results. It is imperative that patients meet in 
full all eligibility criteria and requirements.
Confirmation of eligibility criteria is required for all potential trial patients PRIOR to 
randomization. A trial waiver will not be granted for study entry.
Patients will be eligible for trial participation as defined by the inclusion and exclusion
criteria as follows.
Inclusion Criteria
4.1
Eligible patients must meet the following criteria to be enrolled in the trial:
1. Signed Written Informed Consent (ICF). Patients must have signed and dated an 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved written 
ICF in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
patient care.
a.
Patients must be willing and able to comply with scheduled visits, treatment 
schedule, laboratory tests, and other requirements of the trial.
2. Target Population
a.
Patients must have histologically or cytologically confirmed NSCLC that is stage 
IV / metastatic.
b. Patients must not have had systemic treatment for incurable disease.  If patients had 
chemotherapy as part of curative intent radical radiotherapy or surgery they should 
have completed the last dose of chemotherapy 6 months prior to randomization.
c.
Patients with tumor tissue high expression of PD-L1 as defined by Tumor 
Proportion Score (TPS) ≥ 50% and as determined by a FDA-approved PD-L1 IHC 
22C3 assay is mandatory
d. Patients ≥18 years of age.
e.
Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1.
f.
Patients with measurable disease by CT or MRI per RECIST v.1.1 criteria.
g. Patients with Radiographic Tumor Assessment performed within 30 days prior to 
randomization.
i) Target lesions may be located in a previously irradiated field if there is 
documented (radiographic) disease progression at that site.
h. Patients that have completed prior radiotherapy or radiosurgery at least 2 weeks 
prior to randomization.
i) Patients with brain metastases are eligible if they are asymptomatic, or are treated 
and are neurologically stable for at least 2 weeks without the use of steroids or on 
stable or decreasing dose of ≤10 mg daily prednisone (or equivalent).

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i.
Patients with baseline laboratory values obtained 21 days prior to randomization 
meeting the following criteria:
i) WBCs ≥ 2000/µL.
ii) Neutrophils ≥ 1500/µL.
iii) Platelets ≥ 100×10³/µL.
iv) Hemoglobin ≥ 9.0 g/dL.
v) Creatinine of ≤1.5× upper limit of normal (ULN) or calculated creatinine clearance 
>60 mL/minute per institutional standard. For patients with a body mass index 
(BMI) > 30 kg/m2, lean body weight should be used instead of actual body 
weight.
vi) Aspartate transaminase (AST) ≤1.5×ULN (<5×ULN for patients with liver 
metastasis).  
vii) Alanine transaminase (ALT) ≤1.5×ULN (<5×ULN for patients with liver 
metastasis).  
viii) Total bilirubin ≤1.5×ULN (except Patients with Gilbert Syndrome who must have 
total bilirubin <3.0 mg/dL).
ix) Alkaline phosphatase <2.5×ULN (<5×ULN for patients with liver metastasis).  
x) Prothrombin Time (PT) <1.5×ULN unless receiving anticoagulation therapy; 
activated Partial Thromboplastin Time (aPTT) <1.5×ULN unless receiving 
anticoagulation therapy.
3. Reproductive Status
a.
Women of childbearing potential (WOCBP) must agree to use method(s) of 
contraception.
b. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 24 hours 
prior to the start of investigational product.
c.
Male or non-pregnant, non-lactating female, ≥ 18 years of age:
i) If sexually active, the patients must agree to use contraception considered 
adequate and appropriate by the Investigator during the period of trial drug 
administration. In addition, male and female patients must utilize contraception 
after the end of the treatment in the individual drugs product’s Prescribing 
Information provided in the trial manual and the Clinical Trial Facilitation Group, 
provided in Appendix B
Exclusion Criteria
4.2
Eligible patients must not have the following criteria (except where indicated) to be enrolled 
in the trial:
1. Medical History and Concurrent Diseases
a.
Patients with carcinomatous meningitis.
b. Patients with active central nervous system (CNS) metastases. 

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i) Patients are eligible if CNS metastases are adequately treated and neurologically 
stable at baseline (except for residual signs or symptoms related to the CNS 
treatment) for at least 2 weeks prior to enrollment. In addition, patients must be 
either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent) at the time of consent for the trial.
c.
Patients with life expectancy of < 3 months.
d. Patients with non-squamous NSCLC with known EGFR mutation or ALK 
rearrangement.
e.
Patients currently using medicinal or recreational cannabis.
f.
Patients with any serious or uncontrolled medical disorder or active infection with 
the hepatitis virus or the human immunodeficiency virus (HIV).
g. Patients with other active malignancies requiring concurrent intervention other than 
hormone antagonists.
h. Patients with previous malignancies (except non-melanoma skin cancers and the 
following in situ cancers: bladder, gastric, colon, cervical/dysplasia, endometrial, 
melanoma, or breast) are excluded unless a complete remission was achieved at 
least 2 years prior to trial entry AND no additional therapy other than hormone 
antagonists is required or anticipated to be required during the trial period.
i.
Patients with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications at 
the time of consent for the trial. Inhaled or topical steroids and adrenal replacement 
steroid doses >10 mg daily prednisone equivalent are permitted in the absence of 
active autoimmune disease.
j.
Patients with known prior history of hemophagocytic lymphohistiocytosis (HLH).
k. Patients with active known or suspected autoimmune disease that required systemic 
therapy within 2 years of treatment, or a medical condition that required 
immunosuppression. Patients with vitiligo, Type I diabetes mellitus, residual 
hypothyroidism requiring hormone replacement, or conditions not expected to recur 
in the absence of an external trigger are permitted to enroll.
l.
Patients with Grade 1 (NCI-CTCAE v.4.03) toxicities attributed to prior anti-cancer 
therapy (other than alopecia and fatigue prior) to randomization.
m. Patients that have received therapy with anti-tumor vaccines or other 
immuno-stimulatory antitumor agents.  Non-cancer vaccines (non-attenuated and 
non-live) are permitted.
n. Patients that have received therapy with anti-PD-1, anti-PD-L1, anti-PD-L-2, 
anti-CD-137, and/or anti CTLA-4 antibodies (including ipilimumab or any other 
antibody or drug specifically targeting T cell co-stimulation or checkpoint 
pathways).
o. Patients with a history of symptomatic interstitial lung disease.
p. Patients not completely recovered from the effects of major surgery or significant 
traumatic injury at least 14 days before the first dose of trial treatment.
2. Physical and Laboratory Test Findings

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a.
Patients with active Hepatitis B or C infections.
b. Patients known to be human immunodeficiency virus (HIV) positive.
3. Allergies and Adverse Drug Reaction
a.
Patients with a history of severe hypersensitivity reactions to monoclonal 
antibodies.
b. Patients with a history of allergy or intolerance (unacceptable adverse event) to trial
drug components, Polysorbate-80-containing infusions.
4. Sex and Reproductive Status
a.
WOCBP who are pregnant or breastfeeding.
b. Women with a positive pregnancy test at enrollment or prior to administration of 
trial drug.
5. Prohibited Treatments and/or Restricted Therapies
a.
Patients requiring ongoing or planned administration of anti-cancer therapies other 
than those specified in this trial.
b. Patients requiring the use of corticosteroids or other immunosuppressive 
medications (>10 mg daily prednisone equivalent for more than 14 sequential days). 
Corticosteroids or other immunosuppressive medications for more than 14 
sequential days require approval of the Medical Monitor.
c.
Patients receiving any investigational agent within 28 days of first administration of 
trial treatment.
6. Other Exclusion Criteria
a.
Patients with any other serious or uncontrolled medical disorder, active infection, 
physical exam finding, laboratory finding, altered mental status, or psychiatric 
condition that, in the opinion of the Investigator, would limit the individual’s ability 
to comply with the trial requirements, substantially increase risk to their well-being, 
or impact the interpretability of trial results.

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5.0
PATIENT ENROLLMENT
Before patients may be entered into the trial, all patients or legally acceptable representatives 
must personally sign and date, and receive a copy of the ICF before any trial-specific 
screening procedure is performed that is not part of standard medical practice.
All patients who enter into the screening period of the trial (defined as the point at which the 
patient signs the informed consent) will receive a patient identification number (PIN). This 
number will be used to identify the patient throughout the trial and must be used on all trial
documentation related to that patient. The patient identification number (PIN) will remain 
constant throughout the entire trial; it will not be changed at the time of enrollment. A 
patient is considered enrolled on this trial when s/he signs the IRB approved informed 
consent (ICF). A patient will need to pass the screening assessments/procedures before they 
are randomized to one of two trial arms and then dosed accordingly.
Treatment Arms
5.1
Patients will be randomized in a 1:1 ratio into one of two arms according to histology type 
(squamous vs non-squamous) as follows:
Arm 1: Patients will receive AM0010 and pembrolizumab
Arm 2: Patients will receive pembrolizumab alone

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6.0
TREATMENT PROCEDURES
AM0010 will be the only non-FDA approved drug used in this trial.
Investigational Product Dosage, Administration, and Schedule
6.1
AM0010 is provided by Lilly. AM0010 is provided as a sterile, single-use prefilled syringe, 
with a clear solution. AM0010 drug product is stored refrigerated. Refer to the product label 
for full storage instructions.
A pharmacy guide will be provided, which contains details regarding packaging, labeling, 
storage, (re)ordering and administration of AM0010.
A trial-defined AM0010 and pembrolizumab treatment will begin on trial day 1. Patients on 
Arm 1 will dose with AM0010 prior to initiation of pembrolizumab dosing. Patients’ on 
Arm 1 will dose AM0010 according to their weight:
≤80 kg body weight = 0.8 mg
>80 kg body weight = 1.6 mg
AM0010 dose recalculations are only required if a patient’s body weight changed from 
≤80 kg to >80 kg or vice versa. Change in bodyweight should be calculated based on change 
from baseline weight or last weight taken per protocol.
Patients will be trained to self-administer AM0010 and will self-administer the dose 
throughout the trial starting with the first dose. A patient’s caregiver may also be trained to 
perform SQ injections. Both the patient’s and caregiver’s training must be recorded in the 
patient’s medical records. The Investigator or a qualified designee must be present during 
administration of the first dose. An AM0010 administration diary must be kept for dosing 
compliance monitoring.
Pembrolizumab Administration
6.2
Pembrolizumab should be obtained by each site as per routine institutional practice. Sites 
will be responsible for storage and destruction of pembrolizumab.  For preparation and 
complete prescribing information, refer to the most current prescribing information in the 
region. Investigators or designees will review the patient’s hematology and chemistry 
panels, liver function tests (LFTs), and the incidence of hematologic and non-hematologic 
toxicities prior and during study treatment.
Pembrolizumab will be administered on Day 1 of each 21-day cycle.  Patients will be treated 
for a maximum of 35 cycles of pembrolizumab every 3 weeks or 2 years, whichever is 
longer.
Medications used to treat pembrolizumab-related infusion reactions are (eg, 
diphenhydramine, acetaminophen/paracetamol, corticosteroids) considered 
non-investigational medicinal products (NIMPs) and will not be provided by the sponsor. 
These will be obtained by the investigational sites as marketed products, which should be 
stored in accordance to the package insert.

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Pembrolizumab for injection (lyophilized powder): carton containing one 50-mg single-dose 
vial (NDC 0006-3029-02).  Vials should be stored refrigerated. Refer to the product label for 
full storage instructions.
Pembrolizumab injection (solution): carton containing one 100-mg/4 mL (25 mg/mL), 
single-dose vial (NDC 0006-3026-02).  Vials should be stored refrigerated. Refer to the
product label for full storage instructions..
Dosing Schedule
6.3
Patients will be treated on an outpatient basis with AM0010 plus pembrolizumab or 
pembrolizumab alone (Figure 2).
Arm 1 consists of AM0010 at 0.8 mg for patients ≤80 kg body weight or 1.6 mg for patients 
>80 kg body weight, self-administered SQ QD (abdomen, thigh, or back of upper arm) plus 
pembrolizumab at 200 mg over approximately 30 minutes IV infusion on Day 1 of a 21-day 
cycle.
Arm 2 consists of pembrolizumab alone at 200 mg over approximately 30 minutes IV 
infusion on Day 1 of a 21-day cycle.
Figure 2.
Dosing Schedule
Patients will continue on treatment until they experience progressive disease per Investigator 
assessment, unacceptable toxicity, require subsequent anticancer therapy, withdraw consent, 
or their physician feels it is no longer in their best interest to continue on treatment.
Crossover of patients from the pembrolizumab-only treatment arm (Arm 2) into the 
pembrolizumab plus AM0010 treatment arm (Arm 1) is permitted at the time of disease 
progression (as assessed by the Investigator). Supportive care per the institution’s normal 
standard of care, including concomitant medications, can be provided at the Investigator’s 
discretion. 
The documentation of the investigational product administration (AM0010) will be noted on 
the case report form (CRF) page and in the source documentation/patient diary. The date, 

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dose volume, dose amount, and time of administration for each dose when the PK samples 
are collected (including the 2-day dosing history prior to a PK draw day), the first and last 
administered dose for the patient, doses withheld and missed, and dose schedule adjustments
will be recorded on the respective CRF page. Details of preparing and administering 
AM0010 will be provided to the patient and are included in the Pharmacy Binder provided 
by the Lilly/designee.
Treatment Withhold, Dose or Schedule Reduction, or Discontinuation for 
6.4
Toxicity
If an adverse event (AE) occurs, the Investigator should determine if the AE could be 
attributed to either drug (AM0010 or pembrolizumab) or both, or if other factor(s) were the 
cause of the AE. Continued treatment with the study drugs is based on the Investigator’s 
assessment of risk-benefit per the guidelines outlined below. Both the study drugs in Arm 1 
should be discontinued if 1 study drug is discontinued.
6.4.1
Treatment Withhold and Discontinuation
6.4.1.1
AM0010
AM0010 dosing will be withheld or permanently discontinued based on the criteria provided 
in Table 2.
Table 2.
Toxicity Management Guideline for AM0010
Toxicity/Adverse Event
Toxicity Grade (CTCAE) or 
Conditions
Action Taken to 
AM0010
Fatigue
Grade 3 or 4
Withhold
AST, ALT
Grade 3 or 4
Withhold
>5-10×ULN for >2 weeks; 
drug-related
Permanently 
discontinue
>10×ULN; drug-related
Permanently 
discontinue
Total bilirubin
Grade 3 or 4
Withhold
>5×ULN; drug-related
Permanently 
discontinue
Concurrent AST or ALT and total bilirubin 
elevation
AST or ALT>3×ULN and total 
bilirubin >2×ULN; drug-related
Permanently 
discontinue
Alkaline phosphatase
Grade 3 or 4
Withhold
Diarrhea, nausea, vomiting, abdominal pain, or 
bloating
Grade 3 or 4
Withhold
Other non-hematologic toxicities with an impact on 
organ function
Grade 3 or 4
Withhold
Skin drug-related AE
Grade 3 or 4
Withhold
Any adverse event, laboratory abnormality, or 
intercurrent illness
Presents a substantial clinical 
risk to the patient in the 
judgment of the Investigator
Permanently 
discontinue
Any adverse event including laboratory 
abnormalities, except

Grade 4 neutropenia ≤21 days

Grade 4 lymphopenia or leukopenia <21 days
Grade 4; drug-related
Permanently 
discontinue
Any event
Life-threatening and related
Permanently 
discontinue

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Toxicity/Adverse Event
Toxicity Grade (CTCAE) or 
Conditions
Action Taken to 
AM0010
Any adverse event, laboratory abnormality, or 
inter-current illness that, in the judgment of the 
Investigator, warrants delaying the dose
Grade ≥2
Withhold
Any dosing delay 
Lasting >12 weeks
Permanently 
discontinue
Thrombocytopenia
Grade 3 or 4
Withhold
Grade 3 or 4 with Grade 3 or 4 
bleeding; drug-related
Permanently 
discontinue
Anemia
Grade 3 or 4
Withhold
Notes:

AM0010 doses may be withheld for ≤12 weeks (ie, up to 84 consecutive doses).

AM0010 doses should be withheld until resolution to Grade 1 or pretreatment baseline.

Withholding dose to allow prolonged steroid tapers to manage drug-related adverse events is allowed.

Patients receiving AM0010 may receive growth factors (including G-CSF and erythropoietin) for febrile 
neutropenia or Grade 3 or greater anemia at the discretion of the Investigator.

Anemia can be due to a direct effect of AM0010 on the scavenger receptor, leading to higher turnover of 
red blood cells. While this can be managed by withholding dose until resolution to Grade 1 or baseline, 
blood transfusion is permitted as well if the Investigator deems it necessary.

Tumor assessments should continue as per protocol even if dosing is withheld.

See Table 3 for dose schedule reduction criteria for AM0010.
For Grade 3 or 4 toxicities that are related to AM0010 and do not require dose 
discontinuation, dose schedule reduction will be performed according to Table 3.
Table 3.
Dose and Dose Schedule Reduction of AM0010
Dose Schedule
Schedule Modification Criteria
AM0010
SC QD (continuous daily 
dosing)
-
Starting dose schedule
5 Days on/2 days off
First Grade 3 or 4 event(s)
First dose schedule reduction
4 Days on/3 days off
Second Grade 3 or 4 event(s)
Second dose schedule reduction
2 Days on/5 days off
Third Grade 3 or 4 event(s)
Third dose schedule reduction
Dosing will be withheld until return of the AE to Grade 1 or baseline.  If Grade 3 or 4 
toxicity occurs after 3 dose reductions of AM0010, patients will be discontinued from study.  
Once the dose schedule has been reduced, it should not be increased.
6.4.1.2
Pembrolizumab
Pembrolizumab dosing can be withheld up to 12 weeks according to Table 4, based on the 
most current package insert, dated July 2018. This document can be downloaded from the 
following Web sites:
FDA home page: 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplN
o=125514,

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DailyMed: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-
4538-a9f0-71b91a02b287#S5.1,
Please ensure you are using the most current version of the package insert as updates by drug 
manufacturers are continuous.
Pembrolizumab infusion-related reactions should be managed according to Table 5.
Patients may resume treatment with pembrolizumab when drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline value, with the following exceptions:

Patients may resume treatment in the presence of Grade 2 fatigue.

Patients who have not experienced a Grade 3 drug-related skin adverse event may resume 
treatment in the presence of Grade 2 skin toxicity.

Patients with baseline AST/ALT or total bilirubin in the Grade 1 toxicity range who 
require dose withholds for reasons other than a 2-grade shift in AST/ALT or total 
bilirubin may resume treatment in the presence of Grade 2 AST/ALT or total bilirubin.

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.
Patients who do not meet the minimum re-treatment criteria on Day 21 of the cycle and do 
not meet the criteria for discontinuation will withhold treatment and be followed for 
resolution of toxicity to levels specified in package insert for resuming pembrolizumab.  
Dose reduction is not permitted for pembrolizumab.

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Table 4.
Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with Pembrolizumab
General instructions:
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
For situations in which pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
For severe and life-threatening immune-related AEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if immune-related AEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.03)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms of 
pneumonitis.
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment.
Add prophylactic antibiotics for opportunistic 
infections.
Grade 3 or 4 or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus).
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 
Participants with 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.
Grade 4
Permanently 
discontinue
AST/ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold
Administer corticosteroids (initial 
dose of 0.5-1 mg/kg prednisone or 
equivalent) followed by taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable.
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

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Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold
Initiate insulin-replacement therapy 
for participants with T1DM 
Administer anti-hyperglycemic in 
participants with hyperglycemia 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency).
Grade 3 or 4 
Withhold or 
permanently 
discontinue 
Hyperthyroidism 
Grade 2
Continue 
Treat with non-selective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue
Hypothyroidism
Grades 2-4
Continue 
Initiate thyroid-replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
renal dysfunction
Grade 2
Withhold 
Administer corticosteroids 
(prednisone 1-2 mg/kg or equivalent) 
followed by taper
Monitor changes of renal function.
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold
Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes.
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold
Based on type and severity of AE 
administer corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 

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discontinuation 
include, and are not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
Withholding or permanently discontinuing pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy for whom withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤Grade 2 and is controlled with hormonal-replacement therapy or achieved metabolic control (in case of T1DM).  
Abbreviations:  AE = adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; GI = 
gastrointestinal; irAE = immune-related adverse event; IV = intravenous; T1DM = Type 1 diabetes mellitus.
Note: Patients who have asymptomatic or clinically non-significant Grade 3 or 4 lipase or amylase elevations (that is, not associated with clinical symptoms or 
radiological signs of pancreatitis) that are transient as demonstrated by a decrease of at least 1 CTCAE Grade within 7 days ±3 days of onset will not require 
pembrolizumab discontinuation or modification. If the elevation has not decreased at least 1 CTCAE Grade within this time window, pembrolizumab treatment may 
only continue after consultation and discussion with the Sponsor.

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Table 5.
Pembrolizumab Infusion-Related Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Stop infusion and monitor symptoms.
Additional appropriate medical therapy 
may include, but is not limited to:

IV fluids

Antihistamines

NSAIDS

Acetaminophen

Narcotics
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within 1 hr of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (eg, from 100 mL/hr to 50 mL/hr).  
Otherwise, dosing will be held until 
symptoms resolve and the patient should 
be premedicated for the next scheduled 
dose.
Patients who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration.
Patient may be premedicated 
1.5 hr (±30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic).

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Pembrolizumab Infusion-Related Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:  Prolonged (ie, not rapidly 
responsive to symptomatic medication 
and/or brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(eg, renal impairment, pulmonary 
infiltrates)
Grade 4:  Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion
Additional appropriate medical therapy 
may include, but is not limited to:

IV fluids

Antihistamines

NSAIDS

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids

Epinephrine
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Patient is permanently discontinued 
from further trial treatment 
administration.
No subsequent dosing.
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
Abbreviations:  IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; NSAID = non-steroidal anti-inflammatory drug; po = by mouth.
6.4.2
Toxicity
Toxicities will be graded and reported according to the NCI-CTCAE version 4.03 (Appendix 
E). This document can also be downloaded from the Cancer Therapy Evaluation Program 
(CTEP) home page
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50.
6.4.3
Data Monitoring Committee (DMC)
No DMC will be formed for this trial. Safety will be evaluated on an ongoing basis.
Concomitant Medication
6.5
Throughout the trial, Investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for the following:

Use of anti-cancer therapies (eg, chemotherapy, investigational agent) other than those 
specified in this protocol are not allowed.  Palliative radiation is permitted.

Immunomodulatory agents including but not limited to anti-CTLA4, anti-PD1, anti-PD-
L1, sipuleucel-T, cyclosporine, and tacrolimus.

Coumadin

Patients on coumadin should be changed to SQ administered low-molecular weight 
heparin (LMWH) or oral Factor II or Xa inhibitors with a half-life of less than 24 hours.

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
Factor II or Xa inhibitor with a half-life of greater than 24 hours.

High dose steroids (eg, dexamethasone >10 mg/day for more than 14 sequential days).  
Surgery During Trial Period
6.6
Patients should not schedule any elective surgeries during their participation in the trial, 
through 7 days after the last administration of AM0010 or pembrolizumab. If a patient 
undergoes any unexpected surgery during the course of the trial, that patient must discontinue 
trial treatment immediately, and Lilly or designee should be notified as soon as possible.

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7.0
TRIAL ASSESSMENTS AND PROCEDURES
General Trial Procedures
7.1
Both trial Arm 1 and Arm 2 will follow the same schedule of assessment, unless otherwise 
noted.
A signed and dated IRB-approved ICF must be obtained before performing any trial-specific 
screening procedures that is not part of standard medical practice. All screening tests and 
assessments must be performed within 21 days of trial day 1, unless noted below.
During the trial, every effort should be made to keep the SOA on time for each patient 
(Appendix A). All visits should be performed on the visit specified ±3 days, unless 
otherwise noted.
Patients will continue to receive trial treatment until they experience progressive disease, 
unacceptable toxicity, require subsequent anticancer therapy, withdraw consent, or their 
physician feels it is no longer in their best interest to continue on treatment.
Tumor assessment will be performed for all randomized patients every 9 weeks (±7 days) 
during the study treatment and during the first year from discontinuation of the study 
treatment, every 12 weeks (±7 days) during the second year, and every 16 weeks (±7 days) 
thereafter. Tumor assessment will be repeated until disease progression, death, or receipt of 
new anti-cancer therapy, or until study completion, whichever is first, whether or not study 
treatment was administered.
Scans will include head and CAPs and will be sent be to the central imaging vendor for 
archiving and possible assessment at a later date and possible archiving at a later date. If 
clinical progression is suspected, all relevant clinical documentation is to be submitted to the 
central imaging vendor for archiving.
Tumor assessment of all sites of disease will follow RECIST v.1.1 (Appendix B): CT (or 
MRI if allergic to contrast). The same radiographic procedure used to define measurable 
lesions must be used throughout the study for each patient. Assessment should be obtained 
regardless of cycle number and regardless of any dose withholds until tumor progression.
Patients with clinical progression must obtain an unscheduled scan to document disease 
status per RECIST v1.1. Patients with suspected radiographic pseudoprogression, in the 
absence of clinical deterioration should remain on trial treatments and be rescanned at 4 
weeks or later. If progression is confirmed on follow-up scan per RECIST v1.1, then 
discontinue study treatments and follow study procedures for end of treatment and follow-
ups.  At the time of disease progression, patients randomized to trial Arm 2 may crossover to 
Arm 1 to receive AM0010 and pembrolizumab.
All randomized patients will be followed for OS every 9 weeks (±7 days) during the first 
year from the 90-day follow-up visit, every 12 weeks (±7 days) during the second year, and 
every 16 weeks (±7 days) thereafter. The survival follow-up will be conducted until death or 
study completion, whichever is first, whether or not trial drug was administered. For patients 

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who were randomized, but withdraw consent, survival (date of death) will be obtained by use 
of publicly available information. 
Safety assessment will follow the guidelines provided in NCI-CTCAE v4.03 (Appendix E).
Overview
7.2
The trial consists of the following procedures:
(1) Screening: The screening period must occur within 21 days prior to dosing, unless 
otherwise stated. The screening visit may be counted as baseline (Day 1) if completed within 
72 hours prior to dosing.
(2) Treatment: Patient will be randomized to either:

Trial Arm 1: AM0010 self-administered as a SQ injection QD (≤80 kg body 
weight = 0.8 mg or >80 kg body weight = 1.6 mg). Pembrolizumab will be 
administered as intravenous (IV) infusion on Day 1 of a 21-day cycle (200 mg over 
approximately 30 minutes)
OR

Trial Arm 2: Pembrolizumab will be administered as an IV infusion on Day 1 of a 
21-day cycle (200 mg over approximately 30 minutes)
(3) Clinical and Laboratory Assessments:
Complete history, physical examination (Site/Organ System Status [includes: General 
appearance, skin, H/E/E/N/T – Thyroid, Pulmonary, Cardiovascular, Gastrointestinal, 
Musculoskeletal/ Extremities, Genitourinary/Breast, Lymph Nodes, Neurological and 
Psychiatric]), ECOG performance status, height (screening only), weight, vital signs, and 
documentation of concomitant medications.
Laboratory studies: see Section 7.11.
(4) Continued Treatment:
At the time of disease progression (as assessed by the Investigator), patients randomized to 
trial Arm 2 may crossover to Arm 1 receive AM0010 and pembrolizumab.  
(5) End of Treatment: Patients will return to the trial site 28 days (±7 days) after the last 
dose of trial drug for end of treatment assessments.
(6) Follow-Up Period:
During the extended safety observation period, all randomized patients will be followed for 
safety 60 and 90 days (±7 days) after the last dose of study treatment and monitored 
according to the SOA (Appendix A).  
During the long-term follow-up period, all randomized patients who discontinue trial 
treatment before disease progression or patients randomized but not treated will be followed 
for OS every 9 weeks (±7 days) during the first year from the 90-day follow-up visit, every 

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12 weeks (±7 days) during the second year, and every 16 weeks (±7 days) thereafter. The 
survival follow-up will be conducted until death or study completion, whichever is first.
The Investigator (or designee) will acquire the following information from patients who were 
randomized:
Tumor assessment for all randomized patients who discontinue the trial treatment before 
disease progression or patients randomized but not treated. Tumor assessment will be 
repeated every 9 weeks (±7 days) during the study treatment and during the first year 
from discontinuation of the study treatment, every 12 weeks (±7 days) during the second 
year, and every 16 weeks (±7 days) thereafter, until study completion, disease 
progression, death or receipt of new anti-cancer therapy, whichever is first.
Subsequent cancer treatments (all randomized patients).
Any SAEs considered to be related to trial treatment >90 days post last day of trial 
treatment, follow until resolution.
Date and cause of death (all randomized patients).
Scans will include head and CAPs and will be sent to the central imaging vendor for 
archiving.  If clinical progression is suspected, all relevant clinical documentation is to be 
submitted to the IRR for archiving and possible assessment at a later date.  If clinical 
progression is suspected, all relevant clinical documentation is to be submitted to the central 
imaging vendor.
Screening
7.3
Informed consent must be obtained before any trial specific tests or evaluations are 
conducted.
The screening visit will occur within 21 days (unless otherwise stated) before administration 
of trial treatment and may be combined with baseline laboratory evaluations if both are done 
within 72 hours of initial dosing. Baseline scans for tumor assessment must be performed 
within 30 days prior to randomization.  Trial eligibility will be based on fulfilling trial
inclusion and exclusion criteria. The Investigator will use clinical judgment when 
determining the clinical significance of laboratory values at baseline and throughout the trial.
At the screening visit, information will be collected and patients will have clinical 
evaluations as follows:
Informed consent
Demographics
Medical and Cancer history
Physical examination (including pregnancy results, Site/Organ System Status [includes: 
General appearance, skin, H/E/E/N/T – Thyroid, Pulmonary, Cardiovascular, 
Gastrointestinal, Musculoskeletal/ Extremities, Genitourinary/Breast, Lymph Nodes, 
Neurological and Psychiatric]), including height and weight
Vital signs (5-minute sitting blood pressure, pulse, respiratory rate, oxygen saturation, and 
oral temperature)

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ECOG performance status assessment

Activated partial thromboplastin (aPTT) and International Normalized Ratio (INR) or 
Prothrombin (PT)

Clinical laboratory tests (hematology, chemistry panel, thyroid function (TSH, T3, and 
T4), and urinalysis)

12-lead electrocardiogram (ECG)

Pregnancy test (urine or serum) in women of childbearing potential

Radiologic tumor assessment (within 30 days prior to randomization)

PD-L1 expression as determined by FDA-approved PD-L1 IHC 22C3 PD-L1 assay.

Concomitant medications

Obtain pathology report of archival tissue.
If screening evaluations are not done within 72 hours of the initial dose of trial drug, the 
following evaluations will be repeated at a baseline visit:
Physical examination (including pregnancy results, Site/Organ System Status [includes: 
General appearance, skin, H/E/E/N/T – Thyroid, Pulmonary, Cardiovascular, 
Gastrointestinal, Musculoskeletal/ Extremities, Genitourinary/Breast, Lymph Nodes, 
Neurological and Psychiatric]), including weight
Vital signs (5-minute sitting blood pressure, pulse, respiratory rate, oral temperature)
ECOG performance status assessment 
Clinical laboratory tests (hematology, chemistry panel, coagulation tests, and urinalysis)
Non-radiologic tumor assessment (if applicable)
Clinical Visits 
7.4
7.4.1
Clinic Evaluations
Once a patient is enrolled, a mandatory tumor tissue sample for biomarker research should be 
submitted (preferably from the same block used for PD-L1 testing).
Physical examination, vital signs, 12-lead ECG, ECOG performance status assessment, 
thyroid function, urinalysis, concomitant medications, and AEs will be assessed at Cycles 1, 
3, 5, etc.  Clinical laboratory tests (hematology, chemistry panel, and coagulation tests) will 
be assessed at every cycle.
Physical examination (including pregnancy results, Site/Organ System Status [includes: 
General appearance, skin, H/E/E/N/T – Thyroid, Pulmonary, Cardiovascular, 
Gastrointestinal, Musculoskeletal/ Extremities, Genitourinary/Breast, Lymph Nodes, 
Neurological and Psychiatric]) including weight
Vital signs (5-minute sitting blood pressure, pulse, respiratory rate, oxygen saturation, 
and oral temperature)
12-lead electrocardiogram (ECG)
ECOG performance status assessment
Clinical laboratory tests (hematology, chemistry panel, coagulation tests, thyroid 
function, and urinalysis)

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Concomitant medications
Adverse Events
Note: The physical examination, weight measurement, and clinical laboratory tests may be 
performed up to 24 hours before dosing. Complete blood count (CBC) results must be 
available prior to infusion for every dose.  If chemistry results are abnormal, assess again 
before dosing.
Tumor Assessments
7.5

CT or MRI (if allergic to contrast media) scans will be performed every 9 weeks 
(±7 days) during the study treatment and during the first year from discontinuation of the 
study treatment, every 12 weeks (±7 days) during the second year, and every 16 weeks 
(±7 days) thereafter to evaluate response to treatment by RECIST v.1.1.

The same radiographic procedure (includes head, chest, abdomen, and pelvis) to define 
measurable lesions must be used throughout the trial for each patient.

Patients will continue the assigned trial treatments until tumor progression (by RECIST 
v.1.1 criteria) by CT or MRI (if allergic to contrast media), withdrawal from the trial, or 
intolerance of therapy not manageable with dose modifications outlined in the 
protocol/package insert and/or supportive care. Note: Patients with suspected 
radiographic pseudoprogression, in the absence of clinical deterioration, should remain 
on trial treatments and be rescanned at 4 weeks or later. If progression is confirmed on 
follow-up scan, study treatments will be discontinued or patients on Arm 2 may be 
eligible for crossover. Refer to Section 7.6.

Patients who discontinue trial treatments with response of CR, PR, or SD will undergo 
CT or MRI scan evaluations per protocol until time of PD, or death, or until study 
completion, or initiation of subsequent anti-cancer therapy, whichever is first.

Patients who demonstrate clinical progression before their scans are due will have an 
unscheduled scan conducted to document disease status by RECIST v.1.1. 

The first scheduled tumor response assessment will be performed at 9 weeks (±7 days), 
and responders (CR or PR per RECIST v1.1) will have a confirmatory scan at ≥4 weeks 
after response has been established using the same technique as baseline scans.

All CT/MRI scans for all patients randomized on the trial will be collected prospectively 
and submitted to a central imaging vendor for archiving.  These scans may be 
independently reviewed at a later time at the request of Lilly.
Pseudoprogression and Confirmation of Disease Progression
7.6
Accumulating evidence indicates a minority of patients treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.
Patients will be permitted to continue treatment beyond initial RECIST 1.1 defined PD if 
they meet the following criteria:

Investigator-assessed clinical benefit, and do not have rapid disease progression

Continue to meet all other study protocol eligibility criteria

Tolerance of study drug

Stable performance status

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Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases).
A radiographic assessment/scan should be performed 4 weeks (±7 days) after original PD to 
determine whether there has been a decrease in tumor size, or continued PD.  The assessment 
of clinical benefit should be balanced by clinical judgment as to whether the patients is 
clinically deteriorating and unlikely to receive any benefit from continued treatment with 
AM0010 and/or pembrolizumab.  A confirmatory scan will be required in the case of clinical 
deterioration suspected to be disease progression.
For patients who continue AM0010 and/or pembrolizumab beyond initial progression, 
confirmed progression is defined as an additional 10% increase in tumor burden volume from 
the time of initial PD.  This includes an increase in the sum of all target lesions and/or the 
development of new measurable lesions.  Treatment beyond confirmed progression is not 
allowed.
When assessing disease progression, the Investigator should use a new baseline tumor burden 
that includes new lesions that developed at the time of initial progression.  New lesions are 
considered measurable at the time of initial progression if the longest diameter is at least 
10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm).  Any new lesion considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden volume if the longest 
diameter increases to at least 10 mm (except for pathological lymph nodes which must have a 
short axis of at least 15 mm).
For patients in both treatment arms, global deterioration of health status (to ECOG 
Performance Status 2 for example) requiring discontinuation of study treatments without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document objective progression (ie, 
radiographic confirmation) even after discontinuation from study treatments.
Trial Drug Administration
7.7
AM0010 is provided as a sterile, single use prefilled syringe, with a clear solution formulated 
at a concentration of 4 mg/mL. A pharmacy guide will be provided, which contains details 
regarding packaging, labeling, storage, (re)ordering and administration of AM0010 as well as 
FDA approved labeling of pembrolizumab.
A trial-defined AM0010 and pembrolizumab treatment will begin on trial day 1. Patients on 
Arm 1 will dose AM0010 prior to initiation of pembrolizumab. Patients on Arm 1 will dose 
AM0010 according to their weight:
≤80 kg body weight = 0.8 mg
>80 kg body weight = 1.6 mg

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AM0010 dose recalculations are only required if a patient’s body weight changed from 
≤80 kg to >80 kg or vice versa.  Change in body weight should be calculated based on 
change from baseline weight or last weight taken per protocol.
Patients will be trained to self-administer AM0010 and will self-administer the dose 
throughout the trial starting with the first dose. A patient’s caregiver may also be trained to 
perform SQ injections.  Both the patient’s and caregiver’s training must be recorded in the 
patient’s medical records. The Investigator or a qualified designee must be present during 
administration of the first dose. An AM0010 administration diary must be kept for dosing 
compliance monitoring.
Pembrolizumab will be administered on Day 1 of each 21-day cycle;
Patients on Arm 1 (including crossover patients) will be administered pembrolizumab at a 
fixed dose of 200mg over approximately 30 minutes IV infusion
Patients on Arm 2 will be administered pembrolizumab at a fixed dose of 200mg over 
approximately 30 minutes IV infusion
Pembrolizumab should be obtained by each site as per routine institutional practice. For 
preparation and complete prescribing information, refer to the most current prescribing 
information in the region. Investigators or designees will review the patient’s hematology 
and chemistry panels, liver function tests, and the incidence of hematologic and non-
hematologic toxicities prior to and during immunotherapy regimens.
Medications used to treat pembrolizumab-related infusion reactions (eg, diphenhydramine, 
acetaminophen/paracetamol, corticosteroids) considered non-investigational medicinal 
products (NIMPs) and will not be provided by the sponsor. These will be obtained by the 
investigational sites as marketed product, which should be stored in accordance to the 
package insert.
Continued Treatment
7.8
7.8.1
Crossover
At the time of disease progression (as assessed by the Investigator) patients randomized to 
trial Arm 2 may crossover to study Arm 1 to receive AM0010 and pembrolizumab. When 
progressive disease is noted on the scan for an Arm 2 patient, no more than 21 days should 
pass before the patient crosses over to Arm 1. The scans and/or clinical assessment at 
crossover will be used as a new baseline to determine response or PD on Arm 1.
End of Treatment Visit
7.9
Twenty-eight (28) days (±7 days) after the last dose of trial treatment, patients are expected 
to return to the trial site to complete all end of treatment assessments as follows:

Physical (including pregnancy results, Site/Organ System Status [includes: General 
appearance, skin, H/E/E/N/T – Thyroid, Pulmonary, Cardiovascular, Gastrointestinal, 
Musculoskeletal/ Extremities, Genitourinary/Breast, Lymph Nodes, Neurological and 
Psychiatric]), including weight

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
Vital signs (5-minute sitting blood pressure, pulse, respiratory rate, oral temperature)

12-lead ECG

Activated partial thromboplastin (aPTT) and International Normalized Ratio (INR) or 
Prothrombin (PT)

ECOG performance status assessment

Clinical laboratory tests (hematology, chemistry panel, thyroid function, and urinalysis)

Biomarker blood sample

Pregnancy test (urine or serum) in women of childbearing potential

Concomitant medications

Adverse events
Follow-Up Period
7.10
During the extended safety observation period, all randomized patients will be followed for 
safety 60 and 90 days (±7 days) after the last dose of study treatment and monitored 
according to the SOA (Appendix A).
During the long-term follow-up period, all randomized patients will be followed for OS
every 9 weeks (±7 days) during the first year from the 90-day follow-up visit, every 
12 weeks (±7 days) during the second year, and every 16 weeks (±7 days) thereafter. The 
survival follow-up will be conducted until death or study completion, whichever is first, 
whether or not trial treatment was administered.
For patients who were randomized, but withdrew consent, survival (date of death) will be 
obtained by use of publicly available information.
The Investigator (or designee) will acquire the following information from patients who were 
randomized:

Tumor assessment will be repeated every 9 weeks (±7 days) during the study treatment 
and during the first year from discontinuation of the study treatment, every 12 weeks (±7 
days) during the second year, and every 16 weeks (±7 days) thereafter. Tumor 
assessment will be repeated until study completion, disease progression, death, or receipt 
of new anti-cancer therapy for patients who were randomized, and not treated or 
discontinue treatment before disease progression, and do not withdraw consent.

Subsequent cancer treatments (all randomized patients).

Any SAEs considered to be related to trial treatment, follow until resolution.

Date and cause of death (all randomized patients).
Laboratory Assessments
7.11
Local laboratories will perform the following laboratory tests, and results will be provided to 
the Investigator. Blood and urine samples for hematology, chemistry, activated partial 
thromboplastin (aPTT) and International Normalized Ratio (INR) or Prothrombin (PT),
thyroid function, and urinalysis will be prepared using standard procedures. Laboratory 
panels are defined as follows:

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Hematology 
WBC count with differential, RBC count, hemoglobin, hematocrit, 
reticulocyte count, and platelet count
Chemistry
albumin, ALP, ALT, AST, BUN, calcium, carbon dioxide, chloride, 
creatinine, glucose, potassium, sodium, total bilirubin, lactate 
dehydrogenase, and total protein
Coagulation Tests:
aPTT and International Normalized Ratio (INR) or PT
Thyroid Function Test
TSH, free T3, and free T4
Urinalysis
appearance, color, pH, specific gravity, ketones, protein, glucose, bilirubin, 
nitrite, urobilinogen, and occult blood (microscopic examination of 
sediment will be performed only if the results of the urinalysis dipstick 
evaluation are positive)
Pregnancy Test
Serum or urine pregnancy test for women of child bearing potential
Abnormalities in clinical laboratory tests that lead to a change in patient management (ie, 
dose withhold or modification, requirement for additional medication or monitoring) are 
considered clinically significant for the purposes of this trial and will be recorded on the AE 
CRF page. If values meet criteria defining them as serious, they must be reported as SAEs 
(Section 9.1.2).
Pharmacokinetics
7.12
Blood samples for PK with sparse sampling techniques will be obtained on all patients on 
Arm 1 (including crossover patients). Serum samples will be collected to characterize PK of 
AM0010 in combination with pembrolizumab and to explore exposure-safety and 
exposure-efficacy relationships. Data from these investigations may be evaluated for 
correlations with response, survival, and safety data.
PK samples will be drawn pre-dose (AM0010 and pembrolizumab)

Day 1 of Cycles 1, 2, 3, 4, and every fourth cycle thereafter (eg, 8, 12, 16, etc.)

End of treatment visit

Day-60 and -90 follow-up visits after the last dose of study treatment.
Bioanalytical samples collected to measure investigational product concentration will be 
retained for a maximum of 1 year following last participant visit for the study.
Immunogenicity (ADA [anti-drug antibodies])
7.13
Blood samples for immunogenicity analysis will be obtained on all patients on Arms 1 and 2
(including crossover patients). Samples will be evaluated for development of anti-drug 
antibodies (ADAs) by a validated immunoassay.
ADA samples will be drawn pre-dose at the following time points:

Day 1 of Cycles 1, 2, 3, 4, and every fourth cycle thereafter (eg, 8, 12, 16, etc.)

End of treatment visit

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
Day-60 and -90 follow-up visits after the last dose of study treatment.
All immunogenicity samples will be retained for a maximum of 15 years after the last 
participant visit, or for a shorter period if local regulations and Ethical Review Boards 
(ERBs) allow, at a facility selected by the sponsor.  The duration allows the sponsor to 
respond to future regulatory requests related to the investigational product.  Any samples 
remaining after 15 years will be destroyed.
Biomarkers
7.14
Blood samples for biomarker analysis will be obtained on all patients in Arms 1 and 2. A 
variety of factors that may impact the immunomodulatory properties and efficacy of 
AM0010 in combination with pembrolizumab will be investigated in peripheral blood.  Data 
from these investigations may be evaluated for correlations with response, survival, and 
safety data.

Biomarker samples will be drawn pre-dose (AM0010 and pembrolizumab) on Day 1 of 
Cycles 1, 2, 3, 5, 7, 9, 11, etc. and at the end of treatment visit.
All biomarker samples (both tissue and blood) will be retained for a maximum of 15 years 
after the last participant visit, or for a shorter period if local regulations and ERBs allow, at a 
facility selected by the sponsor.  The duration allows the sponsor to respond to future 
regulatory requests related to the investigational product.  Any samples remaining after 
15 years will be destroyed.

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8.0
REMOVAL AND REPLACEMENT OF PATIENTS
Removal of Patients
8.1
Patients have the right to withdraw from the trial at any time and for any reason without 
prejudice to his or her future medical care by the physician or at the institution.
Any patient who withdraws consent to participate in the trial will be removed from the trial
immediately upon the date of request. The Investigator will make every effort to contact the 
patient and perform end-of-treatment procedures. Should a patient (or a legally acceptable 
representative) request or decide to withdraw from the trial, all efforts will be made to 
complete and report the observations as thoroughly as possible in addition to follow up for 
OS. All information should be reported on the applicable CRFs.
The patient who requests to stop trial treatment or has withdrawn from trial treatment 
because of the Investigator’s or Sponsor’s concern before completion of the protocol-
specified treatment duration will be strongly encouraged to continue the schedule of trial
observations, in addition to follow up for OS.
If the patient has withdrawn because of toxicities, the Investigator should arrange for the 
patient to be followed for a minimum of 90 days or until any drug-related toxicities resolve to 
grade 1 according to CTCAE Version 4.03, or return to the patients’ baseline values, in 
addition to follow up for OS. All end-of-treatment procedures should be completed for such 
a patient.
Reasons for removal from investigational product or observation may include:

Withdrawal of consent

Administrative decision by the Investigator or Sponsor

The patient’s physician feels it is no longer in their best interest of the patient to continue 
on treatment.

Require subsequent systemic anticancer therapy

Pregnancy (report on Pregnancy Notification Worksheet/CRF)

Ineligibility determined after enrollment

Significant protocol deviation

Patient noncompliance

Adverse event (disease progression is not considered an AE)

Progression of disease (clinical and/or radiological)

Lost to follow-up
The reason for withdrawal, the date of administration of the final trial treatment, and the date 
of withdrawal should be recorded on the End-of-Treatment CRF.
All randomized patients will be followed for OS every 9 weeks (±7 days) during the first 
year from the 90-day follow-up visit, every 12 weeks (±7 days) during the second year, and 
every 16 weeks (±7 days) thereafter. The survival follow-up will be conducted until death or 
study completion, whichever is first, whether or not trial treatment was administered.

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For patients who were randomized, but withdraw consent, survival (date of death) will be 
obtained by use of publicly available information.
All randomized patients who discontinue trial treatment before disease progression or 
patients randomized but not treated will be followed for PFS per protocol until study 
completion, disease progression, or death or receipt of new anti-cancer therapy, whichever is 
first. Scans will include head and CAPs and will be sent to the central imaging vendor for 
archiving and possible assessment at a later date. If clinical progression is suspected, all 
relevant clinical documentation is to be submitted to the central imaging vendor for 
archiving.
The Investigator (or designee) will acquire the following information from patients who were 
randomized:

Tumor assessment for all randomized patients who discontinue the trial treatment before 
disease progression or patients randomized but not treated. Tumor assessment will be 
repeated until study completion, disease progression, death or receipt of new anti-cancer 
therapy, whichever is first.

Subsequent cancer treatments (all randomized patients).

Any SAEs considered to be related to trial treatment, follow until resolution.

Date and cause of death (all randomized patients).
Replacement of Patients
8.2
Randomized patients who withdraw from the trial will not be replaced.

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9.0
ADVERSE EVENT REPORTING
Definitions
9.1
9.1.1
Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not necessarily have a 
causal relationship with this treatment.  An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.
Investigators are responsible for:

monitoring the safety of patients in this study and for alerting Lilly or its 
designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient,

the appropriate medical care of patients during the study,

documenting their review of each laboratory safety report, and

following, through an appropriate healthcare option, AEs that are serious or 
otherwise medically important, considered related to study treatment or the 
study, or that caused the patient to discontinue study treatment before 
completing the study.  The patient should be followed until the event resolves, 
stabilizes with appropriate diagnostic evaluation, or is reasonably explained.  
Frequency of follow-up evaluation is left to the discretion of the investigator.
A worsening of an existing medical condition occurs when a condition present at the time the 
informed consent form is signed (eg, diabetes, migraine headaches, gout) becomes more 
severe, more frequent, or increases in duration during investigational product treatment.
Abnormal laboratory values should not be reported as an AE, unless they are considered 
clinically significant by the Investigator; however, any clinical consequences of the 
abnormality should be reported as an AE. Abnormalities in clinical laboratory tests that lead 
to a change in patient management (ie, dose schedule reduction or withhold, requirement for 
additional medication or monitoring) are considered clinically significant for the purposes of 
this trial and will be recorded on the AE CRF page.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study 
is to establish treatment effect.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a study patient experiences elevated ALT5×ULN and elevated total bilirubin 2×ULN, or 
ALT8×ULN, liver tests (Appendix E), including ALT, AST, total bilirubin, direct bilirubin, 
gamma-glutamyl transferase (GGT), and creatine phosphokinase (CPK), should be repeated 
within 3 to 5 days to confirm the abnormality and to determine if it is increasing or 

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decreasing.  If the abnormality persists or worsens, clinical and laboratory monitoring should 
be initiated by the investigator, based on the hepatic monitoring tests (Appendix E) and in 
consultation with the Lilly Clinical Research Physician (CRP).  Monitoring of ALT, AST, 
and total bilirubin should continue until levels normalize or return to approximate baseline 
levels.
9.1.2
Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or 
result in death or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the patient 
and may require intervention to prevent 1 of the other outcomes listed in the 
definition above.
Suspected Unexpected Serious Adverse Reactions
9.2
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not 
listed in the IB and that the investigator identifies as related to study treatment or study 
procedure.  United States 21 CFR 312.32 and Regulation (EU) No. 536/2014 and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs. Lilly has procedures that will be followed for the 
recording and expedited reporting of SUSARs that are consistent with global regulations and 
associated detailed guidances.
9.2.1
Pregnancy
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the 
definition of an AE, but should be reported.  However, to fulfill regulatory requirements any 
pregnancy should be reported following the SAE process to collect data on the outcome for 
both mother and fetus.
The Investigator will inform Lilly within 24 hours of awareness by any study personnel of 
any case of pregnancy and collect information on any exposure to the study drug(s) during 
pregnancy (female patient or male patient’s partner).  An exposure during pregnancy (also 
referred to as exposure in utero) occurs if a female is or has been found to be pregnant after 
being exposed to the study drug(s) directly, indirectly, or via her partner (paternal exposure).  
If any study subject becomes or is found to be pregnant and exposed to investigational 
product as described above, the Investigator must submit this information to Lilly on a 

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Pregnancy Report Form irrespective of whether an AE has occurred and within 24 hours of 
awareness of the pregnancy.  The information submitted should include the anticipated date 
of delivery.  Follow-up is conducted to obtain pregnancy outcome information on all 
exposure during pregnancy reports with an unknown outcome.  The Investigator will follow 
the pregnancy until completion or until pregnancy termination (ie, induced abortion) and then 
notify Lilly of the outcome.  The Investigator will provide this information as a follow-up to 
the initial Pregnancy Report Form.  The reason(s) for an induced abortion should be 
specified.  A report is not created when an ectopic pregnancy report is received since this 
type of pregnancy is not usually viable.  Rather, an SAE case is created with the event of
ectopic pregnancy.  If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (ie, spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly [including that in an aborted fetus, still birth, or neonatal death]), the Investigator 
should follow the procedures for reporting SAEs.  In the case of a live birth, the “normality” 
of the newborn can be assessed at the time of birth (ie, no minimum follow-up period of a 
presumably normal infant is required before a Pregnancy Report Form can be completed), 
and birth information will be provided as a follow-up of the initial Pregnancy Report Form.  
Case processing at Lilly will be performed as described above for SAE reports. Additional 
information regarding the exposure during pregnancy may be requested from the 
Investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental withholds).
Reporting Procedures for All Adverse Events
9.3
After the ICF is signed, study site personnel will record via electronic case report form (eCRF)
the occurrence and nature of each patient’s preexisting conditions, including clinically 
significant signs and symptoms of the disease under treatment in the study.  In addition, 
study site personnel will record via eCRF any change in the preexisting conditions and any 
new conditions as AEs.  Investigators should record their assessment of the potential 
relatedness of each AE to study treatment via eCRF.
All AEs, regardless of grade and occurring after obtaining informed consent, observed by the 
Investigator or reported by the patient (whether or not attributed to investigational product), 
will be reported on the AE CRF. Please note that disease progression should not be 
considered an AE, but shall be documented on the appropriate CRF.
Medically significant AEs considered to be related to the investigational product by the 
Investigator or Sponsor will be followed until resolved or considered stable. The Investigator 
must assign the following attributes: description (concise diagnosis, if available); dates of 
onset and resolution; severity; assessment of relatedness to investigational product; and 
action taken. The Investigator may be asked to provide follow-up information, medical 
records, and extracts from medical records or CRFs.
The SAE reporting to Lilly or its designee begins after the patient has signed the ICF and has 
received study treatment.  However, if an SAE occurs after signing the ICF, but prior to

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receiving study treatment, it needs to be reported ONLY if it is considered reasonably 
possibly related to study procedure. “Death” as an outcome of an AE may occur and should 
not be reported as an AE, but the cause of death should be reported on the AE eCRF.  
For the purpose of this study, progression of underlying malignancy is not considered an 
(S)AE. Hospitalization, prolonged hospitalization, or death due solely to the progression of 
underlying malignancy will be captured on the AE CRF, but will NOT be reported as an 
SAE. Clinical symptoms of progression may be reported as AEs if they cannot be 
determined to be exclusively due to the progression, or if they do not fit the expected pattern 
of progression for late stage NSCLC cancer.
SAEs which are considered related to study drug occurring >90 days after last trial treatment 
must be reported on both a CRF and on a SAE Report Form (with an autopsy report if 
available).
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued (the patient summary CRF has been completed).  However, if the investigator 
learns of any SAE, including a death, at any time after a patient has been discontinued from 
the study, and he/she considers the event reasonably possibly related to the study treatment or 
study participation, the investigator must promptly notify Lilly or its designee.
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
If it is deemed to be in the best interest of the patient to start a new anti-cancer treatment 
prior to the follow-up visit, the visit duration may be shortened.  In this case, the follow-up 
assessments should be completed prior to the initiation of the new therapy. If an anti-tumor 
treatment is initiated within 90 days of the last dose of trial treatment, the start date of this 
treatment should be documented on the appropriate CRF.
The Investigator must notify the IRB of SAEs occurring at the site and other AE reports 
received from Lilly/designee in accordance with local procedures/site IRB policies.
It will be left to the Investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require the patient’s removal from treatment. A patient may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable AE. If either of 
these occurs, the patient must undergo an end-of-treatment assessment and be given 
appropriate care under medical supervision until symptoms cease or the condition becomes 
stable. If the patient is permanently withdrawn from the trial or investigational product due 
to an SAE, this information must be included in either the initial or follow-up SAE Report 
Form or the End-of-Treatment CRF.
Study site personnel must report any treatment discontinuations that result from AEs to Lilly
or its designee via eCRF, clarifying, if possible, the circumstances leading to the 
discontinuation of treatment.

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The trial will use the Common Terminology Criteria for grading AEs that are experienced by 
research patients. If the AE is not specified in the NCI-CTCAE v4.03
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50) the 
severity will be assessed on the following scale with appropriate clinical definitions:
1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, 5 = fatal
The investigator will interpret and document whether or not an AE has a reasonable 
possibility of being related to study treatment or a study procedure, taking into account the 
disease, concomitant treatments, or pathologies.
The relationship of the AE to the investigational product will be assessed by means of the 
question: ‘Is there a reasonable possibility that the event may have been caused by the 
investigational product?’ Answer Yes or No.
Determination of expectedness will be based on the contents of the Investigator’s Brochure.
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to classify the 
events.
Serious Adverse Event Reporting Procedures
9.4
Study site personnel must notify Lilly or its designee of any SAE within 24 hours of 
investigator awareness of the event via a Lilly-approved method.  If alerts are issued via 
telephone, they are to be immediately followed with official notification on study-specific 
SAE forms.  This 24-hour notification requirement refers to the initial SAE information and 
all follow-up SAE information.
Complaint Handling
9.5
Lilly collects product complaints on investigational products and drug delivery systems used 
in clinical studies in order to ensure the safety of study participants, to monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.

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10.0
STATISTICAL CONSIDERATIONS
Trial Design
10.1
This is an open-label, randomized, multicenter Phase 2 trial in adult male and female patients 
with treatment-naïve, Stage IV/metastatic NSCLC whose tumors are not known to have 
EGFR mutation or ALK rearrangement, and have high expression (≥50%) of PD-L1 as 
determined by the FDA-approved PD-L1 IHC 22C3 assay.
Patients will be stratified according to tumor histology (squamous vs non-squamous).
Patients will be randomized in a 1:1 ratio into 1 of 2 treatment arms.  

Arm 1: Patients will receive AM0010 as a subcutaneous (SQ) daily (QD) injection plus 
pembrolizumab as IV infusion on Day 1 of a 21-day cycle.

Arm 2: Patients will receive pembrolizumab as IV infusion on Day 1 of a 21-day cycle.
Trial Endpoints
10.2
10.2.1
Primary Endpoint

Objective Response Rate
Objective response rate is defined as the proportion of patients with a confirmed CR or 
confirmed PR relative to the total analysis population. The ORR is determined by the best 
response designation per RECIST v1.1 recorded between the date of randomization and the 
date of objectively documented progression or the date of subsequent anti-cancer therapy, 
whichever occurs first.  For patient without documented progression or subsequent anti-
cancer therapy, all available response designations will contribute to the ORR determination. 
Confirmed responses are those that persist on repeat imaging scan ≥4 weeks after initial 
documentation of response. For patients who continue treatment beyond progression due to 
suspected pseudoprogression as outlined in Section 7.6. The objective response should be 
determined based on response assessment recorded at the CT scan done no less than 4 weeks 
after suspected pseudoprogression. If the patient subsequently responds or returns to 
baseline, that assessment of objective tumor response is achieved after pseudoprogression as 
the true response per RECIST v.1.1.
10.2.2
Secondary Endpoints

Progression-Free Survival
Progression-free survival is defined as the time from randomization to the date of the first 
documented tumor progression as determined by the Investigator (per RECIST v.1.1 criteria
or clinical progression) or death due to any cause whichever occurs first. Patients who 
experience clinical disease progression should undergo scanning to document radiographic 
disease progression per RECIST v.1.1. In this case, the date of the confirmatory CT scan 
will be used as the date of disease progression. Patients who die without a reported prior 
progression will be considered to have progressed on the date of their death. Patients who 
did not progress or die will be censored on the date of their last tumor assessment. Patients 

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who did not have any on-trial tumor assessment and did not die will be censored on the date 
they were randomized with a duration of 1 day. Patients who received any subsequent anti-
cancer therapy without a prior documented progression will be censored at the last tumor 
assessment prior to initiation of the subsequent anti-cancer therapy. Any additional 
censoring rules that may be needed will be specified in the statistical analysis plan.

Overall Survival
Overall survival is defined as the time from the date of randomization to the date of death.  
Patients who are no longer on trial treatments should be followed for survival.  A patient who 
is alive will be censored at the date last known to be alive.

Disease Control Rate (DCR)
Disease control rate is defined as the proportion of patients who achieve Stable Disease (SD)
≥9 weeks (±7 days) plus confirmed CRs + confirmed PRs as determined by the Investigator 
using RECIST v.1.1.

Duration of Response (DoR)
The DoR is defined as the time from the date of the first documentation of objective tumor 
response (CR or PR) to the date of the first documentation of objective tumor progression or 
death due to any cause, whichever occurs first.
Sample Size Considerations
10.3
Approximately 100 patients will be randomized to the 2 arms in a 1:1 ratio. With 100 
patients, this study has more than 80% power to detect an absolute increase in ORR of 25% 
(ie 45% vs 70%) in the ORR between AM0010 in combination with pembrolizumab and 
pembrolizumab alone at a 1-sided 5% type I error rate.
Schedule of Analyses
10.4
Table 6 provides schedule of analyses for key endpoints.
Table 6.
Schedule of Analyses
Type of Analysis
Key Endpoint(s)
Expected Timing of Analysis
Interim Analysis
PK, Safety
~3 months after the 50th patient randomized
Primary Analysis
ORR
~6 months after the 100th patient randomized
A planned interim analysis maybe performed when the 50th randomized patient has been 
followed up for approximately 3 months. No statistical boundaries or alpha spending will be 
applied for this interim analysis as the primary purpose of this analysis is to assess safety and
PK. At the time of interim data lock, all patients on study will continue study per protocol.
Analysis Populations
10.5

All Enrolled Patients: all patients who signed an informed consent form and were 
registered into the IWRS.

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
ITT Population: All patients who are randomized.  This is the primary population for 
analyses of efficacy and baseline characteristics.

Safety Population: All randomized patients who received any amount of study drug.  
This is the primary population for exposure and safety.

PK Population: All treated patients with available serum time-concentration data from 
randomized patients dosed with AM0010.

Biomarker Population: All treated patients with available biomarker data from 
randomized patients.
Planned Method of Analysis
10.6
10.6.1
General Approach/Considerations
Unless otherwise stated, descriptive statistics will be provided for all endpoints for each 
treatment group and overall. Continuous measurements will be summarized using the mean, 
standard deviation, median, interquartile range, range, and number of patients.
All efficacy analyses will be stratified by the histology type at randomization.
10.6.2
Demographic and Baseline Characteristics
Demographics (age, sex, and race) and other baseline disease characteristics will be 
summarized using descriptive statistics.
10.6.3
Efficacy Analyses
10.6.3.1
Primary Efficacy Analyses
Objective response rate, defined as the proportion of patients who achieve confirmed 
CR+PR, will be summarized by treatment arm and compared using a Cochran-Mantel 
Haenszel (CMH) 2-sided test stratified by the histology type at a type I error rate of 10%.
The odds ratio and 90% CI will also be provided.
10.6.3.2
Secondary Efficacy Analyses
PFS will be summarized by median PFS (including 95% CI) for each treatment arm along 
with the hazard ratio (including 95% CI). The Kaplan-Meier curve for PFS will be presented 
for each treatment arm and the difference in the curves will be tested using the stratified 
log-rank test.
Overall survival will be summarized by median survival time (including 95% CI) for each 
treatment arm along with the hazard ratio (including 95% CI). The Kaplan-Meier curve for 
survival will be presented for each treatment arm and the difference in the curves will be 
tested using the stratified log-rank test. 
Disease control rate will be analyzed in the same manner as objective tumor response.
Duration of response is defined as the time from the date of the first documentation of 
objective tumor response (CR or PR), as determined by the Investigator using RECIST v.1.1, 
that is subsequently confirmed to the date of the first documentation of objective tumor 
progression or to death due to any cause, whichever occurs first. Duration of response will 

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be censored on the date of the last tumor assessment on trial for patients who do not have 
objective tumor progression and who do not die due to any cause while on trial. For patients 
who have an ongoing objective response but discontinued to have tumor scans assessments 
before disease progression, the duration of response will be censored at the date of the last 
tumor assessment.
Duration of response will be estimated for each treatment arm using the Kaplan-Meier 
product-limit method for patients who have CR or PR. Duration of SD will be summarized as 
well.
Time to response is defined as the time from date of randomization to the date of the first 
documentation of objective tumor response that is subsequently confirmed. Duration of 
response and time to response will only be evaluated in patients with objective response of 
CR or PR and will be summarized by trial treatment arm.
10.6.4
Safety Analyses
All safety summaries and analyses will be performed on the Safety Population.
Safety and tolerability will be measured by:

Adverse events

Physical examinations (including neurological examination)

Vital Signs

ECGs

Laboratory assessments
o
Hematology
o
Chemistry
o
Coagulation Tests
o
Thyroid Function
o
Urinalysis
10.6.5
Extent of Exposure
Extent of exposure will be summarized, variables include duration of treatment, number of 
cycles, total dose administered, and relative dose intensity for the entire treatment duration as 
well as for each cycle. Number and percentage of patients experiencing dose modifications
for each treatment arm, and reasons will be provided as well.
10.6.6
Adverse Events
Adverse events will be analyzed in terms of treatment-emergent AEs defined to be any AEs 
that begin or worsen in intensity after trial drug initiation through 90 days after the last dose 
of trial drug. All AEs will be coded based on MedDRA terms.
Descriptive statistics of safety will be presented using NCI-CTCAE v4.03 by treatment arm.  
All treatment emergent AEs due to any cause, treatment-related AEs, SAEs, treatment-
related SAEs, and AEs leading to discontinuation from the trial treatments will be tabulated 
using the worst grade per NCI-CTCAE v4.03 criteria by system organ class and preferred 

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term. Additional summaries include AEs by intensity (Grade 1 to 4 or/and Grades 3 and 4).
All AEs will be listed.
10.6.7
Clinical Laboratory Data
Summary and change in laboratory data will be provided over time for hematology, 
chemistry parameters and urinalysis.
The NCI-CTCAE v4.03 grade for selected hematology parameters will be summarized by the 
worst grade in each treatment cycle and the worst grade during the trial for each treatment 
arm. The number and percent of patients with NCI-CTCAE v4.03 hematology value of 
Grade 3 or 4 that occur after the first dose of trial drugs also will be presented. Shift tables 
may be provided.
Liver and renal function will be summarized using NCI-CTCAE v4.03 grade for selected 
chemistry parameters. The number and percent of patients with NCI-CTCAE v4.03
chemistry values of Grade 3 or 4 that occur after the first dose of trial drugs also will be 
presented. Shift tables may be provided.
10.6.8
ECOG Performance Status
Descriptive statistics will be provided for ECOG performance status at each assessment time.
10.6.9
Vital Signs
Vital signs (blood pressure, heart rate, temperature, and oxygen saturation), weight, and 
change from baseline will be summarized by treatment arm.
10.6.10
12-Lead ECG
ECG parameters including QTc and change from baseline will be summarized by visit and by
treatment arm. Number and percent of patients for each QTc parameter for the following 
categories will be summarized:

QTc <450, 450 to <480, 480 to 500, and >500 ms.

QTc change from baseline 30 to <60 ms and ≥60 ms.
10.6.11
Immunologic Biomarkers
Associations between biomarkers and efficacy outcomes (OS, ORR, and PFS) may be 
analyzed on all patients with available biomarker data.  Models to predict clinical activity 
based on combinations of biomarkers may also be investigated.
Additional post hoc statistical analyses not specified in the protocol or statistical analysis 
plan, such as alternative modeling approaches, may be conducted.  All analyses are based on 
the availability of the data.
10.6.12
Pharmacokinetic Analyses
The concentration vs time will be collected for all patients treated with AM0010 in 
combination with pembrolizumab and used for exposure-response analyses (exposure-safety 

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and exposure-efficacy) of selected safety and efficacy endpoints. Results of PK and 
exposure-response analyses will be reported separately.

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11.0
INVESTIGATIONAL PRODUCT
AM0010
11.1
AM0010 will be manufactured and packaged by a third-party under the direction of Lilly and 
distributed using Lilly’s/designee clinical trial drug distribution procedures. AM0010 is 
provided as a sterile, single use prefilled syringe, with a clear solution formulated at a 
concentration of 4 mg/mL.
Each patient (Arm 1) will receive weight-based doses of single use prefilled syringes, 
instruction for self-administration and an AM0010 dosing diary. 
AM0010 drug product is stored refrigerated. Refer to the product label for full storage 
instructions..
AM0010 should be stored in a secure location with limited access under controlled 
temperature conditions. Prefilled syringes should be stored in their original folding carton
and should not be dispensed until patient is randomized or patient resupply is required.
The packaging lot number of AM0010 will be recorded on each patient’s Drug 
Administration CRF.
Additional AM0010 details including labeling, storage, and preparation information are 
provided in the Pharmacy Guide. It should be noted that this manual may be updated/revised 
as additional information becomes available.
Compliance in Investigational Product Administration
11.2
When investigational product is dispensed for administration to the patient during a trial, the 
Investigator or responsible person will determine the extent to which the patient complies 
with the recommended administration of the investigational product. The patient’s 
investigational product compliance will be recorded on the drug administration case report 
form.  Because this trial involves the self-administration of an SQ drug product, patients will 
need to complete an AM0010 dosing diary.

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12.0
ETHICAL CONSIDERATIONS
Local Regulations
12.1
The trial must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” (GCP) ICH E6 R2 Tripartite Guideline (June 2017). The Investigator will ensure 
that the conduct of the trial complies with the basic principles of GCP as outlined in the 
current version of 21 CFR, Subpart D, Part 312, “Responsibilities of Sponsors and 
Investigators,” Part 50, “Protection of Human Subjects,” and Part 56, “Institutional Review 
Boards.”
Informed Consent
12.2
It is the responsibility of the Investigator, or a person designated by the Investigator, to 
obtain written informed consent from each patient participating in this trial after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the trial. In 
the case where the patient is unable to read, an impartial witness should be present during the 
entire informed consent discussion. After the patient has orally consented to participation in 
the trial, the witness’ signature on the form will attest that the information in the consent 
form was accurately explained and understood.
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated as necessary. All patients (including those 
already being treated) should be informed of the new information, should be given a copy of 
the revised form, and should give their consent to continue in the trial.
Institutional Review Board
12.3
A copy of the protocol and proposed informed consent form, other written patient 
information, and any proposed advertising material related to patient recruitment must be 
submitted to the IRB for written approval. A copy of the written IRB approval of the 
protocol and informed consent form must be received by Lilly or its designee before the 
recruitment of patients into the trial and the shipment of investigational product.
The Investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document. The 
Investigator should notify the IRB of deviations from the protocol or SAEs occurring at the 
site and other AE reports received from Lilly in accordance with local procedures/IRB 
policies.
The Investigator will be responsible for obtaining annual IRB approval/renewal throughout 
the duration of the trial. Copies of the Investigator’s reports and the IRB continuance of 
approval must be sent to Lilly or its designee.

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Documentation Requirements
12.4
The Investigator is responsible for forwarding the following documents to Lilly or its 
designee for review before trial initiation can occur:

Signed and dated protocol signature page (Investigator’s Agreement)

Copy of the IRB approval of the protocol, consent form, and patient information sheet

Up-to-date curricula vitae of the Principal Investigator and all co/sub-investigators

IRB composition and/or written statement that IRB is in compliance with regulations

Laboratory normal ranges and documentation of laboratory certification (or equivalent)

Current patient/Investigator indemnity insurance

Signed trial contract

Completed FDA form 1572 (Laboratories providing primary and secondary endpoint data 
and any central laboratories for the trial must be listed on the form.)

Completed Financial Disclosure statements for the Principal Investigator, all co/sub-
investigators, and their spouses or legal partners and dependent children.
Patient Confidentiality
12.5
The Investigator must ensure that the patient’s confidentiality is maintained. On the case 
report forms or other documents submitted to Lilly or its designee, patients should be 
identified by their initials and/or a patient trial number only. Documents that are not for 
submission to Lilly (eg, signed informed consent forms) should be kept in strict confidence 
by the Investigator.
In compliance with Federal regulations/ICH GCP Guidelines, the Investigator and institution 
are required to permit authorized representatives of Lilly, of the regulatory agency(s), and the 
IRB direct access to review the patient’s original medical records for verification of trial-
related procedures and data. Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the trial. The 
Investigator is obligated to inform and obtain the consent of the patient to permit such 
representatives to have access to his/her trial-related records without violating the 
confidentiality of the patient.

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13.0
ADMINISTRATIVE AND LEGAL OBLIGATIONS
Protocol Amendments and Trial Termination
13.1
Protocol amendments, except where necessary to eliminate an immediate hazard to patients, 
must be made only with the prior approval of Lilly. Agreement from the Investigator must 
be obtained for all protocol amendments and amendments to the informed consent document. 
The IRB must be informed of all amendments and give approval. The Investigator must send 
a copy of the approval letter from the IRB to Lilly.
Both Lilly and the Investigator reserve the right to terminate the trial according to the trial
contract. The Investigator should notify the IRB in writing of the trial’s completion or early 
termination and send a copy of the notification to Lilly.
Trial Documentation and Archive
13.2
The Investigator shall maintain a list of appropriately qualified persons to whom he/she has 
delegated trial duties. All persons authorized to make entries and/or corrections on case 
report forms will be included on a Site Signature Log.
Source documents are original documents, data, and records from which the patient’s case 
report form data are obtained. These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and 
correspondence.
The Investigator and trial staff are responsible for maintaining a comprehensive and 
centralized filing system of all trial-related (essential) documentation, suitable for inspection 
at any time by representatives from Lilly and/or applicable regulatory authorities.  These 
elements should include:

Patient files containing completed CRFs, ICFs, and patient identification list

Trial files containing the protocol with all amendments, Investigator’s Brochure, copies
of pre-trial documentation (Section 12.4), and all correspondence to and from the IRB 
and Lilly

Proof of receipt, Investigational Product Accountability Record, Return of Investigational 
Product for Destruction, Final Investigational Product Reconciliation Statement, and all 
drug-related correspondence
In addition, all original source documents supporting entries in the CRFs must be maintained 
and be readily available.
No trial document should be destroyed without prior written agreement between Lilly and the 
Investigator. Should the Investigator wish to assign the trial records to another party or move 
them to another location, he/she must notify Lilly in writing of the new responsible person 
and/or the new location.

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Trial Monitoring and Data Collection
13.3
The Lilly representative and Regulatory Authority inspectors are responsible for contacting 
and visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the clinical trial (eg, CRFs and other pertinent data) 
provided that patient confidentiality is respected.
The Lilly monitor/designee is responsible for verifying the CRFs at regular intervals, 
approximately once per month, throughout the trial to verify adherence to the protocol, 
completeness, accuracy, and consistency of the data; and adherence to local regulations on 
the conduct of clinical research. The monitor should have access to patient medical records 
and other trial-related records needed to verify the entries on the CRFs.
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits, including delays in completing CRFs, are resolved.
In accordance with ICH GCP and the Sponsor’s audit plans, this trial may be selected for 
audit by representatives from Lilly Clinical Quality Assurance Department (or designees).  
An inspection of site facilities (eg, pharmacy, drug storage areas, and laboratories) and a 
review of trial-related records will occur to evaluate the trial conduct and compliance with 
the protocol, ICH GCP, and applicable regulatory requirements.
If an anti-tumor treatment is initiated within 90 days of the last dose 
(AM0010/pembrolizumab), the start date of this treatment should be documented on the 
appropriate CRF, and no further recording of concomitant medications will occur unless it is 
to treat AM0010-related AEs.
To ensure the quality of clinical data across all patients and sites, a clinical data management 
review will be performed on patient data received at Lilly or its designee. During this 
review, patient data will be checked for consistency, omissions, and any apparent 
discrepancies. In addition, the data will be reviewed for adherence to the protocol and GCP. 
To resolve any questions arising from the clinical data management review process, data 
queries and/or site notifications will be sent to the site for completion and returned to Lilly or 
its designee.
The Principal Investigator will sign and date the indicated places on the CRF. These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the 
CRF, the data queries, and the site notifications, and agrees with the content.

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Language
13.4
All written information and other material to be used by patients and investigative staff must 
use vocabulary and language that are clearly understood.
Publication Policy
13.5
To coordinate the dissemination of data from this trial, a publication committee may be 
formed consisting of both Principal Investigators and appropriate Lilly staff. The committee 
is expected to solicit input and assistance from other Investigators and Lilly staff as 
appropriate. Membership on the committee (both for Investigators and Lilly staff) does not 
guarantee authorship. The criteria described below should be met for every publication.
Authorship of any publications resulting from this trial will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors, 2016), which states:

Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version 
to be published.  Authors should meet conditions 1, 2, and 3.

When a large, multi-center group has conducted the work, the group should identify the 
individuals who accept direct responsibility for the manuscript.  These individuals should 
fully meet the criteria for authorship defined above.

Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship.

All persons designated as authors should qualify for authorship, and all those who qualify 
should be listed.

Each author should have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content.
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) based on 
this trial must be submitted to Lilly for corporate review. The Clinical Trial Agreement 
between the institution, principal Investigator, and Lilly will detail the procedures for and 
timing of Lilly review of publications.

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15.0
APPENDICES

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Appendix A – Schedule of Assessments
a
All randomized patients will be followed for OS every 9 weeks (±7 days) during the first year from the 90-
day follow-up visit, every 12 weeks (±7 days) during the second year, and every 16 weeks (±7 days) 
thereafter. The survival follow-up will be conducted until death or the study completion, whichever is first, 
whether or not trial drug was administered.
b
A fresh tissue biopsy is only required if no archival tissue is available within 60 days of informed consent or unless 
approved by the Medical Monitor.
c
Mandatory tumor tissue sample for biomarker research should be submitted once the patient is enrolled (preferably from 
the same block used for PD-L1 testing).
d
Tumor assessment will be performed for all randomized patients every 9 weeks (±7 days) during the study treatment and 
during the first year from discontinuation of the study treatment, every 12 weeks (±7 days) during the second year, and 
every 16 weeks (±7 days) thereafter. Tumor assessment will be repeated until disease progression, death, or receipt of 
new anti-cancer therapy, or until study completion, whichever is first, whether or not study treatment was administered. 
A baseline tumor assessment is required at crossover.
e
ADA and PK samples will be collected on Day 1 of Cycles 1, 2, 3, 4, every fourth cycle thereafter, and at end of 
treatment visit, and at the follow-up visits 60 and 90 days after the last dose of study treatment.
f
Specific biomarker blood collection tubes may vary by time point.  See the Lab Manual for details.
Assessments
Both trial Arm 1 and Arm 2 will 
follow the same schedule of 
assessments unless otherwise noted.
Screening
Clinic Visit (Cycle)
End of 
Treatment
Extended 
Safety 
Observation 
Period
Long-
Term 
Follow-
Up
Within         
21 Days of  
Randomization
1, 3, 5, 
etc.  
±3 Days
2 
±3 Days
4, 6, 8, 
etc. 
±3 Days
28 Days     
±7 Days 
from Last 
Dose 
60 and 
90 Days  ±7 
Days from 
Last Dose
GENERAL and SAFETY AWARENESS
Informed Consent
X
Medical/Cancer History and
Demographics
X
Physical examination 
(include Ht [screening only] and Wt)
X
X
X
Vital signs 
X
X
X
ECOG performance status
X
X
X
12-Lead ECG
X
X
X
Concomitant Medication
Adverse Event
Post Randomization
Survivala and Treatment Status
X
LABORATORY ASSESSMENTS
Hematology, Chemistry
X
X
X
X
X
aPTT and INR or PT
X
X
X
X
X
Thyroid Function Test (TSH, T3, and 
T4)
X
X
X
Pregnancy Test
X
X
X
Urinalysis
X
X
X
PD-L1 Status
Xb
Submission of tumor sample for 
biomarker research
Xc
TRIAL TREATMENT ARM 1 and ARM 2
Arm 1 AM0010
Self-Administration QD SQ
Arm 1 and Arm 2  Pembrolizumab
200 mg 30 min IV Q3W
IMAGING ASSESSMENT
Tumor Assessmentd
Within 30 days 
of randomization
X
X
X
ADA, PK and Biomarker BLOOD SAMPLES
ADA (required Arms 1 and 2)e
X
X
X
X
X
PK (required Arm 1 and crossover)e
X
X
X
X
X
Biomarkers (required Arms 1 and 2)f
X
X
X

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Appendix B – Continued-Access Period Assessments
Continued-Access 
Treatment Visits ±3 Days
Continued-Access Follow-Up Visits
28, 60, and 90 days ±7 Days after 
the Last Dose of Study Treatment
Arm 1 AM0010
X
Arm 1 and Arm 2 Pembrolizumab
X
Adverse event
X
X
ADAa
X
X
PKa
X
X
a
ADA and PK samples will be collected on Day 1 of every 4th cycle during the continued access treatment 
visits and at the continued access follow-up visits 28-, 60-, and 90-days after the last dose of study treatment.

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Appendix C – Birth Control Methods that May Be Considered as Highly Effective
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods. Such methods include:

combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 1:
oral
intravaginal
transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation 1:
oral
injectable
implantable 
intrauterine device (IUD)
intrauterine hormone-releasing system ( IUS)
bilateral tubal occlusion
vasectomized partner
sexual abstinence
Guidance on the acceptable contraception methods can be found here:
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf

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Appendix D – RECIST v.1.1 Criteria
The primary efficacy endpoint is ORR.  Tumor response will be assessed by RECIST v.1.1 
guidelines on images obtained with CT scans.  CT scans will be performed at Baseline during 
Screening (within 4 weeks prior to Day 1), at Week 9 (±7 days) and every 9 weeks (±7 days) 
during the study treatment and during the first year from discontinuation of the study 
treatment, every 12 weeks (±7 days) during the second year, and every 16 weeks (±7 days) 
thereafter. Tumor assessment will be repeated until disease progression, death, or receipt of 
new anti-cancer therapy, or until study completion, whichever is first, whether or not study 
treatment was administered. Radiologic studies for antitumor response will be repeated at 
the end of treatment visit only if required per the defined study imaging schedule.
Definition of Measurable and Non-Measurable Lesions
Measurable Lesions at Baseline
The definition of a measurable lesion at Baseline is dependent on the technical factors of the 
imaging studies that were used to evaluate the patient. The recommendations for the imaging 
parameters are based on the American College of Radiology (ACR) Practice Guidelines and 
Technical Standards. The ACR Practice Guidelines and Technical Standards define 
principles and technical parameters of radiologic and radiation oncology practice, which 
should generally produce desired health care outcomes. They describe a range of acceptable 
approaches for the diagnosis and/or treatment of disease for most patients, in most 
circumstances. Given differences in training, experience, and local conditions, the ACR 
Practice Guidelines and Technical Standards acknowledge the need for health care providers 
to exercise their independent medical judgment in making decisions regarding the use and 
specific details of any procedure.
For CT scanning, the recommendation is for a slice thickness of 5 mm or less.
The RECIST v.1.1 guideline recommends CT images for chest, abdomen, and pelvis should 
be performed using 5 mm reconstructions, but it is not explicitly stated as a requirement 
(Eisenhauer, Therasse et al. 2009).
In preparing the technical specifications, we have followed the guidelines of the ACR, as 
5 mm reconstructions are not the standard in the US or the rest of the world. Our proposal 
for modifying the size of measurable lesions at Baseline to 2 times the reconstruction interval 
of the Baseline/Screening studies is consistent with the RECIST definition for a measurable 
lesion.
Conventional CT should be performed with contiguous cuts of 10 mm or less in 
reconstruction interval. CT should be performed by use of a 5–8 mm contiguous 
reconstruction interval or less, where the neck and brain CTs should be done at 5 mm or 
less.
Lesions that can be accurately measured in at least 1 dimension with the longest diameter 
(LD) ≥20 mm with conventional techniques when the conventional scans are performed 
with a reconstruction interval of 10 mm or less are measurable lesions.

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Lesions that can be accurately measured in at least 1 dimension with the LD being 2 
times the reconstruction interval (RI) of the CT scan.  Depending on the RI of the CT 
(5–8 mm or less recommended) measurable lesion size may be ≥10–16 mm.  For 
example, a CT scan done at 8 mm RI would have a minimum lesion size of 16 mm in 
the longest dimension.  The minimum size of a measurable lesion is 10 mm.
Although initially identified as measurable lesion ≥10 mm, target lesions may in time 
reduce to <5 mm in their LD.  In those circumstances where the target lesion LD is less 
than the 5 mm minimum for measurability, the lesion LD should be recorded as 5 mm.
In the instance where the reconstruction interval has changed from the Baseline to 
subsequent time points, it would be at the discretion of the radiologist whether this 
would affect interpretation. A note is made in the comment section of the source 
document, if applicable. The definition for target disease would not change and would 
be determined on the basis of the Baseline scan.
Non-Measurable Lesions
All other lesions that do not meet the criteria for measurable disease as well as other truly 
non-measurable lesions (eg, ascites, bone lesions, pleural effusion, etc.), are considered non-
measurable.
Definition of Target, Non-Target and New Lesions (RECIST v1.1 Guidelines)
Target Lesions
Up to 5 target lesions, a maximum of 2 per organ, will be chosen for measurement over the 
course of the study.  The distribution of these target lesions should be representative of the 
patient’s overall disease.  Target lesions should not be chosen from a previously irradiated 
area unless lesions in those areas have documented progression.
Target lesions must be measurable at Baseline.  These lesions will generally be the largest 
lesions, most reliably measured, and most representative of the patient’s sites of disease.
For any target lesion at any time point, measurements will be taken and recorded 
unidimensionally.  The longest dimension of each target lesion will be measured and 
recorded.  The longest dimension of the target lesions will be summed to obtain the Sum of 
the Longest Diameters (SLD).  The Baseline SLD will be used as reference to further 
characterize the objective tumor response of the target lesions.  For the consideration of 
progressive disease, the nadir of the SLD for the target lesions will be used as reference.
For cases where there is no target lesion identified, tumor assessment for progression should 
be done based on non-target lesion assessments or the development of new lesions.  
Response (PR or CR) and SD will not be assessed in patients where target lesions are not 
identified at Baseline.  The following conventions will be applied in selecting target lesions 
in patients who have received prior radiation therapy:

Intrathoracic measurable lesions in the periphery of the lung, just deep to the radiated 
chest wall concordant with the radiation portal cannot be selected as target lesions.  
However, if the lesions are more centrally located in the chest and do not appear in 
regions showing evidence of radiation injury (eg, scarring, radiation pneumonitis, etc.), 

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they can be selected as target lesions.  The assigned radiologist will document 
descriptions of radiation damage in the comments field.  

Prior bone radiation (eg, vertebral, rib, pelvis, femur, etc., as stated on the Prior Radiation 
Therapy Form would not preclude the selection of measurable lesions in adjacent 
structures unless signs of radiation injury are evident (eg, scarring).

Prior soft tissue radiation (eg, supraclavicular radiation, radiation of internal mammary 
lymph nodes, etc., as recorded on the Prior Radiation Therapy Form would preclude the 
selection of measurable disease in the site of radiation unless the site confirms on the 
Prior Radiation Therapy Form that the lesions are new since radiation was completed.
Non-Target Lesions
All of the sites of disease present at Baseline not classified as target lesions will be classified 
as non-target lesions. Non-target lesions must be qualitatively assessed at each subsequent 
time point.  Examples of non-target lesions include:
All bone lesions, irrespective of the modality used to assess them;
Leptomeningeal disease;
Lymphangitis of the skin or lung;
Cystic lesions;
Irradiated lesions that have not shown progression;
Measurable lesions beyond the maximum number of 10;
Groups of lesions that are small and numerous; and
Pleural effusion/pericardial effusion/ascites.
New Lesions
Unequivocal new lesions are those that were not present at Baseline.  At each time point, the 
presence of new lesions will be determined.  New multi-focal or miliary disease of any size is 
considered a new lesion.
Lesions that are encountered (subsequent to the Baseline) in anatomic locations that were not 
scanned at Baseline will be considered new lesions and will represent progressive disease.
Lesions that were present which subsequently resolved and then recurred will be considered 
new lesions and will represent progressive disease.
Antitumor Response (RECIST v1.1 Guidelines)
Antitumor response will be defined as the percent of patients who achieve an objective 
confirmed response (complete or partial response).  Disease control rate (SD for at least 
16 weeks or confirmed CR or PR) also will be reported.  Response will be determined 
according to RECIST guidelines.  The original RECIST guidelines were developed and 
published in the Journal of the National Cancer Institute (Therasse, Arbuck et al. 2000).

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Target Lesion Response (RECIST v1.1 Guidelines)
Percentage change in SLD will be evaluated by the following formulae:
1.
When determining complete response or partial response:
(Post value – Baseline value) / Baseline value)×100
2. When determining progressive disease:
(Post value – Nadir value since treatment started) / 
(Nadir value since treatment started)×100
The following definitions will be used to evaluate response based on target lesions at each 
time point after Baseline:
Complete Response (CR): Disappearance of all target lesions.
Partial Response (PR): At least a 30% decrease in the SLD of target lesions, taking as 
reference the Baseline SLD.
Stable Disease (SD): Neither sufficient shrinkage of target lesions to qualify for PR, nor 
sufficient increase to qualify for PD, taking as reference the nadir SLD since the treatment 
started.
Progressive Disease (PD): At least a 20% increase in the SLD of target lesions, taking as 
reference the nadir SLD recorded since the treatment started, or, the presence of one or more 
new lesions.  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  The appearance of one or more new lesions is also 
considered progression.  PET scans will not be used to determine target lesion progression or 
as a criterion for patient withdrawal from the study.  Only CT scans or MRIs will be used for 
those purposes.
Not evaluable (NE): A target lesion present at Baseline which was not measured or which 
was unable to be evaluated leading to an inability to determine the status of that particular 
tumor for the time point in question.  If the SLD cannot be determined at a time point and the 
rules for PD do not apply, a response of CR, PR, or SD cannot be assigned for that time 
point, and the time point response will be NE.
Not Applicable (NA): No target lesions were identified at Baseline.  Patients with no target 
lesions identified at Baseline cannot be assessed for response. These patients will be 
assessed for progression only.
Not Done (ND): Scans were not performed at this time point to evaluate the target lesions.
Non-Target Lesion Response (RECIST v1.1 Guidelines)
Each non-target lesion will be qualitatively evaluated at each time point.  Response of each 
lesion at each time point will be assessed with respect to the Baseline status.  Progression 
will be assessed with respect to nadir size of the non-target lesions.  The overall non-target 
lesion response for each time point will be assessed as the worst case for the non-target 

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lesions for that particular time point.  If a non-target lesion is classified as NE/ND, the 
non-target response will be NE/ND unless progression is identified in the available 
non-target lesions.  Response assessments are defined as follows:
Complete Response (CR): Disappearance of all non-target lesions, and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Non-CR / Non-PD:  Persistence of one or more non-target lesions and or maintenance of 
tumor marker level above the normal limits.  
Progressive Disease (PD): The “unequivocal progression” of existing non-target lesion(s) 
or appearance of one or more new lesion(s) is considered progressive disease.
Not Evaluable (NE): Any non-target lesion present at Baseline which was not measured or 
was unable to be evaluated leading to an inability to determine the status of that particular 
tumor for the time point in question.
Not Applicable (NA): No non-target lesions were identified at Baseline.
Not Done (ND): Scans were not performed at this time point to evaluate the non-target 
lesions.
Pseudoprogression: Patients whose scans show radiographic progression in the absence of 
clinical deterioration including worsening performance status as assessed by the Investigator 
may remain on study treatments and additional scan 4 weeks (±7 days) later.  If this 
subsequent scan shows disease progression, the patient will be discontinued from study 
treatments.

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Response Determination (RECIST v1.1 Guidelines)
Response at each time point will be assessed as a combination of the target and non-target 
responses as well as the presence of new lesions according to the table below:
Time Point Response / Target and Non-Target and Best Response
Target
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, and NE = not evaluable 
Non-Target
Time Point Response: Patients With Non-Target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes 
PD
CR = complete response, PD = progressive disease, and NE = not evaluable
* “Non-CR/non-PD is preferred over “stable disease” for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised.

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Best Overall Response – Confirmation of CR and PR
Best Overall Response When Confirmation of CR and PR Required
Overall Response 
First Time Point
Overall Response
Subsequent Time 
Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD or PR*
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
evaluable
*If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that time point (since, disease must have reappeared 
after CR).  Best response would depend on whether minimum duration for SD was met.  However, sometimes 
‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in fact the 
patient had PR, not CR at the first time point.  Under these circumstances, the original CR should be changed to 
PR and the best response is PR.
Source: (Eisenhauer, Therasse et al. 2009).

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Appendix E - Hepatic Monitoring Tests for Treatment Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and 
may be required in follow-up with patients in consultation with the Lilly CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin (HGB)
Hematocrit (HCT)
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time (PT)
Leukocytes (WBC)
Prothrombin time, INR
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets (PLT)
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine transaminase (ALT)
Recommended Autoimmune Serology
Aspartate aminotransferase (AST)
Anti-nuclear antibodya
Gamma-glutamyl transferase (GGT)
Anti-smooth muscle antibodya
Creatine phosphokinase (CPK) 
Anti-actin antibodya
Abbreviations:  CRF = case report form; IgG = immunoglobulin G; IgM = immunoglobulin M; 
INR = international normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by laboratory.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. Whenever a manual differential is needed to report the neutrophils, the segmented and band forms 
should be added together and recorded on the CRF, unless the CRF specifically provides an entry field for 
bands.
c
Confirmation dependent on regulatory requirements and/or testing availability.

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Appendix F – NCI-CTCAE Version 4.03
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50

Leo Document ID = db69faeb-a0e2-4f99-bb58-94006f526e8c
Approver:
Approval Date & Time: 04-Nov-2018 17:15:47 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 06-Nov-2018 19:46:50 GMT
Signature meaning: Approved
PPD
PPD