Phase 1 Study of IMC-CS4, a Monoclonal Antibody Targeted to the CSF-1 Receptor (CSF-1R), In Subjects With Advanced Solid Tumors Refractory to Standard Therapy or for Which No Standard Therapy is Available
Phase: PHASE1
Conditions: Neoplasms
Sponsor: Eli Lilly and Company

Protocol I5F-IE-JSCA (v7.0) 
Phase 1 Study of IMC-CS4, a Monoclonal Antibody Targeted to the CSF-1 Receptor (CSF-1R), 
In Subjects With Advanced Solid Tumors Refractory to Standard Therapy or for Which No 
Standard Therapy is Available 
NCT01346358 
Approval Date: 03-Sep-2015 

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Clinical Trial Protocol:IMCL CP24-1001
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Clinical Trial Protocol
IMCL CP24-1001
I5F-IE-JSCA
Study Title:
Phase 1 Study of IMC-CS4, a Monoclonal Antibody Targeted to the CSF-1 
Receptor (CSF-1R), in Subjects With Advanced Solid Tumors Refractory to 
Standard Therapy or for Which No Standard Therapy Is Available
Study Number:
IMCL CP24-1001(I5F-IE-JSCA)
Study Phase:
Phase 1
Product Name:
IMC-CS4(LY3022855)
IND Number:
110490
Indication:
Advanced Solid Tumors
Investigators:
Multicenter
Sponsor:
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Amendment Version 7.0: Electronically signedand approved by Eli Lilly and 
Company on date provided below.
ConfidentialInformation
This documentcontains trade secrets, or commercial or financial information, privileged and
confidential, delivered in confidence and reliance that such information will not be released to 
the public without the express written consentof Eli Lilly and Company.
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 4and may 
not be reproduced or otherwise disseminated without the written approval of Eli Lilly and 
Company or its subsidiaries.
Approval Date: 03-Sep-2015 GMT

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PROTOCOL CHANGES FROM VERSION 6.0 TO VERSION 7.0
Overview
Protocol IMCL CP24-1001 Phase 1 Study of IMC-CS4, a Monoclonal Antibody Targeted to the 
CSF-1 Receptor (CSF-1R), in Subjects With Advanced Solid Tumors Refractory to Standard 
Therapy or for Which No Standard Therapy Is Available has been amended.  The new protocol 
is indicated by Amendment Version 7.0 and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Updated Sponsor name and address, including deletion of ImClone logo on cover page, 
for consistency with the current template.

Revised confidentiality statement (cover page), for consistency with required language.

Added LY number (document header), for consistency with the current template.

Added clinical experience for Cohorts 4 and 5 (Section 1.4.3).

Increased the number of study sites from approximately 3 to approximately 6 
(Section 4.1).

Deleted information throughout the protocol regarding weight-based dosing Cohorts 6, 7, 
and 8, since these cohorts will not be examined as was planned in Protocol Amendment 
Version 6.0.

(MAIN REASON FOR AMENDMENT) Added information throughout the protocol 
regarding new non-weight-based dosing Cohorts 6a (and 6b and 6c), 7a (and 7b and 7c), 
and 8a (and 8b and 8c), including a justification for non-weight-based dosing (new 
Section 1.4.4).

Added details for Parts A and B throughout the protocol, where Part A comprises 
Cohorts 1 through 5 (weight-based dosing) and Part B comprises new Cohorts 6a (and 6b 
and 6c), 7a (and 7b and 7c), and 8a (and 8b and 8c) (non-weight-based dosing).  This 
includes revisions to Sections 1.4.4, 1.5, 4.1, 5.1.1, 7.2, 7.6, 7.7, and 10.1.2.

Added the definition of evaluable subjects (Section 4.1.1).

Revised the secondary objective to define the recommended Phase 2 dose (RP2D) as 
2 objectives in which an RP2D will be defined for each of Parts A and B (Section 2.2).

Revised the following entry criteria (Section 3.3):
o
Inclusion of subjects who agree to undergo mandatory biopsies (pretreatment and 
posttreatment) was clarified by the addition of a separate criterion.

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o
Exclusion of subjects with clinically significant hypercalcemia within 28 days 
prior to first dose of study therapy was deleted.  Hypercalcemia has not been a 
safety concern.
o
Exclusion of subjects who received treatment with any monoclonal antibodies 
was revised from “within 6 weeks prior to first dose of study therapy” to “within 
4 weeks prior to first dose of study therapy” for consistency with Exclusion 
Criterion [6].
o
Exclusion of subjects receiving radiotherapy was revised from “within 4 weeks 
prior to study entry” to “within 2 weeks prior to first dose of study entry.”  This 
revision will enhance accrual and 2 weeks is sufficient to recover from side 
effects of radiotherapy.
o
Exclusion of subjects who received treatment with agents specifically targeting 
CSF-1 or CSF-1R was deleted.  This revision will enhance accrual and excluding 
these subjects is not necessary where safety is the primary objective.

Revised number of subjects planned to be enrolled from 47 to 72 (Sections 4.1 and 12), 
based on the addition of new non-weight-based cohorts.

Added language regarding examination of the maximum tolerated dose (MTD) for each 
regimen (weight-based and non-weight-based dosing), in place of RP2D (Section 4.1), to 
establish the safety profile of IMC-CS4.

Clarified that the observation period for Cycle 1 is for Part A only, not for Part B.

Revised RP2D determination (Section 4.1.2), so that once an RP2D is reached, options 
will be to expand at the RP2D OR to conclude (end) enrollment (whereas, prior to this 
amendment, the only option was to expand at the RP2D).

Revised dose-limiting toxicity (DLT) definition for nonhematologic toxicity 
(Section 4.1.4), making exceptions for certain liver function test abnormalities, transient 
bilirubin elevations, and laboratory abnormalities in order to allow flexibility for 
continued dosing in the event of certain non-drug-related laboratory abnormalities.  
Additionally, language has been included to permit the treatment of immune-related 
adverse events (irAEs) with steroids for 7 days before an irAE is considered a DLT.

Revised “extension period” to “continued access period” (Section 4.4), for consistency 
with the current template.

Revised assessment of troponin T to also permit assessment of troponin I or whatever is 
the institutional standard (Sections 6.5, 6.8.4, 7.1, 7.2.1, 7.2.2.4, 7.3, 7.4, and 7.7), since
not all institutions use the same assessment.

Revised tissue sampling (Section 6.7), so that fine needle aspiration (FNA) and
previously acquired tumor tissue are no longer permitted as assessments of 
pharmacodynamic effect.  To improve the scientific validity of this study, only 
prospective core needle or excisional biopsy specimens will be permitted as assessments 
of pharmacodynamic effect moving forward, with skin punch biopsy as an acceptable 
posttreatment biopsy alternative for subjects unable to tolerate core needle or excisional 
biopsy.

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
Revised language regarding retention of tissue samples (Sections 6.7 and 6.11.1), to align 
with the protocol template language.

Revised language regarding validation of analytical methods (Section 6.8.1) to align with 
the current PK template language.

Revised language so that triplicate electrocardiogram (ECG) will not be necessary for 
subjects in Part B (Section 6.9.1), based on data already collected.

Added a section for suspected unexpected serious adverse reactions (new Section 8.3), to 
inform sites, some of which may be new, of recording and reporting of these events.

Added a section for management of irAEs (Section 9.1.1), as additional guidance for the 
treatment of irAEs, particularly with immunomodulatory agents such as steroids.

Updated American Society of Clinical Oncology (ASCO) guidelines for use of 
granulocyte colony-stimulating factors (Section 10.6.1).

Clarified that premedication for IMC-CS4, such as antihistamines or steroids for the 
prophylaxis of hypersensitivity, is not recommended prior to the first infusion of 
IMC-CS4 (Section 10.6.5).

Revised statistical language (Sections 12.1, 12.3, and 12.6), to include the standard 
statistical language for protocols.

Added details regarding pharmacodynamic assessments (Section 12.7.2).

Revised authorship criteria (Section 13.11) according to current International Committee 
of Medical Journal Editors (ICMJE) requirements.
The changes above were also made in the Synopsis, as needed.
In addition, minor revisions were made for clarity or consistency within the document or with 
Lilly style, or to correct grammar, redundancy, or typographical errors; these minor revisions do 
not affect the planned conduct of the study or the planned analyses of data.

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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
Clinical Trial Protocol
IMCL CP24-1001
I5F-IE-JSCA
Sponsor:
ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company
33 ImClone Drive
Branchburg, NJ 08876Indianapolis, Indiana USA 46285
Clinical Research 
Physician:
440 Route 22 East
Bridgewater, NJ 08807
Tel:  
E-mail:
Protocol Amendment Version 67.0:  Electronically signed and approved by ImClone LLC, 
a wholly-owned subsidiary of Eli Lilly and Company,on date provided below.
Confidentiality Statement
Confidential Information
This Clinical Trial Protocoldocumentcontains trade secrets, or commercial or financial 
informationthat is , privileged and confidentialand proprietary, delivered in confidence and 
reliance that such information will not be releasedtoImClone LLC, a wholly-owned subsidiary
the public without the express written consentof Eli Lilly and Company(ImClone [Sponsor]).
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.
PPD
PPD
PPD
PPD

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SYNOPSIS
Sponsor:
ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company
Secondary Objectives:
The secondary objectives of this study are:

Part A only:  To define the recommended Phase 2 dose (RP2D);) using weight-based dosing;

Part B only:  To define the RP2D using non-weight-based dosing;

To characterize the pharmacodynamic profile of IMC-CS4 on circulating levels of CSF-1; and

To assess the development of antibodies against IMC-CS4 (immunogenicity).
Study Design:
This open-label, dose-escalation, Phase 1 study will enroll (that is, assign to a dose cohort) approximately 
47 subjects; the72 subjects to 2 parts – Parts A and B.  Part A consisted of dose escalation of IMC-CS4 
using weight-based dosing; Part B will consist of dose escalation of IMC-CS4 using non-weight-based 
dosing.  The actual enrollment will depend on the number of dose-limiting toxicities (DLTs) observed and 
the resultant size of each cohort.
Dose cohorts, including dose and dosing schedule, are summarized in the table below.  For each cohort, 
one cycle is 6 weeks.  In each cohort, subjects will receive IMC-CS4 by intravenous (I.V.) infusion (with 
an observation period for weekly [qw] and every-2-week [q2w] cohorts in Cycle 1 only, as described in 
the following table).
Dose Cohort Assignment
Cohort
Dose Level
(mg/kg)
Dosing Schedulea
Cycle 1
Observation Periodb
Number of Infusions
Part A (weight-based dosing)
1
2.5 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
2
0.3 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
3
0.6 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
4
1.25 mg/kg
q2w
3 weeks (Weeks 4-6)
Cycle 1:  2
Subsequent cycles:  3
5
1.25 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
Part B (non-weight-based dosing)
6a
100 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
66bc,d
2.5100 mg
q2wqw on Weeks 1, 2, 4, and 
5
3 weeksNone (Weeks 4-3 
and 6 are rest)
Cycle 1:  24
Subsequent cycles:  34
6cc
75 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
7a
150 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
77bc,d
2.5c150 mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4d4
7cc
125 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6

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8a
200 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
8e8bc,d
3.75c200 
mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4d4
8cc
175 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
Abbreviations:  aEC = approving Ethics Committee; CRP = clinical research physician; DLT = dose-limiting toxicity; 
IRB = Institutional Review Board; PK = pharmacokinetic(s); qw = weekly; q2w = every 2 weeks.
a – At the highest dose level where major toxicity is observed and that requires a longer recovery period between infusions, 
a change in the periodicity of dosing (that is, other dosing schedules based on safety and PK considerations) will be agreed 
upon with the Investigator and communicated to IRBs/aECs.
b – Observation following the fourth infusion in Cohorts 1, 2, 3, and 5 (qw dosing) and the second infusion in Cohorts
Cohort 4 and 6 (q2w dosing) in Cycle 1 only.  No Cycle 1 observation period for Cohorts 6a, 6c, 7a, 7c, 8a, or 8c.  Weeks 3 
and 6 of all cycles are rest weeks in Cohorts 76b, 7b, and 88b (qw dosing on Weeks 1, 2, 4, and 5).
c – In case of unacceptable toxicity in Cohorts 7 or 8 (qw dosing on Weeks 1, 2, 4, and 5), the following reduced doses will be 
explored, beginning no sooner than Cycle 2:  Cohort 7 dose will be reduced to 2.5 mg/kg q2w; Cohort 8 dose will be reduced 
to 2.5 mg/kg qw on Weeks 1, 2, 4, and 5.  In the event that 2 DLTs are observed in 6 subjects in Cohort 7, the next cohort will 
receive doses of 2.2 mg/kg qw on Weeks 1, 2, 4, and 5, which is an intermediate dose between that of Cohorts 6 and 7.
c – Concurrently enroll to Cohorts 6b/7b/8b and 6c/7c/8c, should ≥2 subjects in Cohort 6a/7a/8a experience DLT events.
d – For all cycles:  Infusions on Weeks 1, 2, 4, and 5, and rest on Weeks 3 and 6.
e – The dose level for cohorts beyond Cohort 8 will be agreed among the investigators and the ImClone CRP at the safety 
review meeting following Cohort 8.  Further dose escalations beyond Cohort 8 may occur by following the same dosing 
schedule (qw on Weeks 1, 2, 4, and 5) but increasing the dose level by 1.25 mg/kg until a DLT has occurred, unless otherwise 
agreed among the investigators and the ImClone CRP.
Following the first cycle of therapy (Cycle 1), subjects may continue to receive IMC-CS4 at the same 
dose and schedule until there is unequivocal evidence of disease progression or other withdrawal criteria 
are met.  Radiographically confirmed disease progression (that is, numerical disease progression, per 
Response Evaluation Criteria in Solid Tumors [RECIST]) only is not sufficient to discontinue treatment 
(refer to “Duration of Treatment” section in this Synopsis for further details).  Radiographic assessment of 
tumor response will be performed at the end of the initial cycle (that is, prior to administration of any 
study therapy in Cycle 2) and the end of every subsequent cycle; radiographic assessment should be 
performed prior to the start of a cycle so that results are available before the subject receives a new cycle 
of treatment.  However, if a DLT is observed in Cycle 1, and in a subject who is benefitting from 
treatment, Cycle 2 dosing is may be initiated within 4 weeks of Cycle 1, Day 1, with Sponsor approval; in 
this case, no radiographic disease assessment is required prior to dosing in Cycle 2.
Each cohort will initially enroll at least 3 subjects.
For all cohorts, all subjects who complete the first treatment cycle (that is, receive all scheduled 
treatments for Cycle 1 and complete the observation period, as needed) or discontinue therapy due to a 
DLT will be considered evaluable subjects and will be included in the DLT analyses.  Subjects who do 
not complete Cycle 1 for reasons other than a DLT will be replaced for the analysis until the cohort 
includes 3 evaluable subjects (or 6 evaluable subjects in case of one DLT in the first 3 subjects); however, 
if benefitting from treatment (that is, no disease progression or other withdrawal criteria), any subject in 
Cohort 3 and beyond who experiences a DLT may continue to receive IMC-CS4 upon agreement of the 
Sponsor and according to the dose reduction guidelines for this study.
If the first 3 evaluable subjects in a cohort complete Cycle 1 of therapy with no DLT, dose escalation to 
the next cohort may proceed.  If 1 of the first 3 evaluable subjects in a cohort experiences a DLT, 
enrollment will proceed until there are at least 6 evaluable subjects in that cohort.  If no additional subject 
experiences a DLT, dose escalation may proceed.  If 2 or more subjects experience a DLT in a cohort 
(whether in the initial 3-subject cohort or following expansion to 6 subjects), dose escalation will not 
occur and the recommended Phase 2 dose (RP2D) will be determined according to the instructions that 

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follow.
Each subsequent cohort will be opened upon completion of the previous cohort.  A safety review meeting 
will be held prior to each dose escalation.
The provisional RP2D will be defined as the dose level at which pharmacodynamic effects are observed 
in the absence of clinically relevant toxic effects (that is, measurable pharmacodynamic effects with no 
DLT in the first 3 subjects or ≤1 DLT in the first 6 subjects enrolled at that dose level).  WhenAfter 
discussion with the RP2D is identified, at least 6 Investigator, the Sponsor may choose to enroll 
additional subjects will be enrolled to ensure a total of at least 9 evaluable (in terms of PK analysis) 
subjects treated at the RP2D.
Consideration will be given to enrollment of up to 12 subjects into 1 or 2 additional cohorts below the 
RP2D rather than at the RP2D, if appropriate based on PK, pharmacodynamic, and/or safety findings 
from this study.
A DLT is defined as any IMC-CS4-related adverse event (AE) that occurs during Cycle 1, as follows and 
does not improve to Grade ≤2 (unless stated otherwise), despite medical management , including steroids 
(if applicable) within 7 days of documented occurrence.  The following are considered DLTs:

Grade 4 neutropenia lasting ≥7 days;

Grade 3 or 4 neutropenia complicated by fever ≥38.0°C or infection;

Grade 4 thrombocytopenia;

Grade 3 thrombocytopenia complicated by hemorrhage;

Grade 3 or 4 anemia;

Grade ≥3Grade 3 or 4 nonhematologic toxicity.  Exceptions maybe be made for the following, if 
agreed upon by the Sponsor AND the Investigator:
o
Grade ≥3 liver function test (LFT) abnormality, such as alkaline phosphatase, gamma 
glutamyl transferase (GGT),
aspartate aminotransferase (AST)/), and alanine 
aminotransferase (ALT) elevation (exceptions may be made for transient [that is, lasting 
<7 days] Grade 3 elevations of AST/ALT ), without evidence of hepatic injury
o
Transient Grade ≥2 bilirubin elevation in the presence of known liver metastases and 
without evidence of other hepatic injury, if agreed by the Investigator and ImClone 
clinical research physician [CRP]);lasting ≤7 days

Grade ≥2 AST/ALT elevation and Grade ≥2 bilirubin elevation (exceptions may be made for 
transient [that is, lasting <7 days] elevations of ALT/AST and bilirubin in the presence of known 
liver metastases without evidence of other hepatic injury, if agreed by the Investigator and 
ImClone CRP); and/or

Grade 3 or 4 nonhematologic toxicity (excluding fatigue or anorexia lasting <7 days, or Grade 3 
nausea and/or vomiting that persists for <2 days following appropriate supportive care).
o
Laboratory abnormalities that are reversible to Grade ≤2 or baseline levels within 7 days 
after initial documentation or that are deemed not clinically significant
o
Grade 3 elevation of CK WITHOUT elevation in serum and urine myoglobin is NOT
considered a DLT.
Throughout this protocol, “days” refers to calendar days, unless otherwise indicated.
Study Population:
It is anticipated that approximately 47 72 subjects will be enrolled in approximately 3 6 study sites in the 
United States.

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Inclusion/Exclusion Criteria:
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study:
1. The subject has a histologic or cytologic confirmation of advanced solid tumors that are 
refractory to standard therapy or for which no standard therapy is available.
2.   The subject has measurable or nonmeasurable disease according to the Response 
Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1).
3. The subject has resolution to Grade ≤1 by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03, of all clinically 
significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy 
(with the exception of alopecia).
4.   The subject has an Eastern Cooperative Oncology Group performance status (ECOG 
PS) score of 0-2.
5.   The subject has adequate hematologic function, as defined by:
Absolute neutrophil count (ANC) ≥1500/L;
Hemoglobin ≥9 g/dL (5.58 mmol/L); and
Platelets ≥100,000/L.
6.   The subject has adequate hepatic function, as defined by:
Bilirubin ≤1.5 times the upper limit of normal (× ULN); and
AST and ALT ≤2.5 × ULN (or ≤5 × ULN in the presence of known liver metastases).
7.   The subject has adequate renal function as defined by creatinine clearance ≥50 mL/min 
measured either by 24-hour urine collection or calculated using the Cockcroft-Gault 
formula.
8.   The subject must have adequate coagulation function as defined by:
International Normalized Ratio (INR) ≤1.5; and
Prothrombin time (PT) and partial thromboplastin time (PTT) or activated PTT ≤1.5 × ULN.
9.   The subject has CK ≤ ULN.
10. The subject has a life expectancy >3 months.
11. The subject is 18 years of age or older.
12. The subject (women of childbearing potential [WOCBP] or fertile men with partners of 
childbearing potential) agrees to use adequate contraception during the study period and for 
12 weeks after the last dose of study therapy.
13. The subject has provided signed informed consent.
14. The subject is accessible for treatment and follow-up, including one pretreatment and 
one posttreatment tumor biopsy procedure; subjects enrolled in this trial must be treated at 
the study center.
15. The subject must undergo mandatory biopsies, including one pretreatment and one 
posttreatment tumor biopsy procedure.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1.  The subject has experienced acute pathologic fracture, or spinal cord compression, or clinically 
significant hypercalcemia within 28 days prior to first dose of study therapy.
2.  The subject has a known hypersensitivity to monoclonal antibodies or to agents of similar biologic 
composition as IMC-CS4.

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3.  The subject has received treatment with any monoclonal antibodies within 64 weeks prior to first 
dose of study therapy.
4.  The subject has undergone a major surgical procedure, radiation therapy, open biopsy, 
radiofrequency ablation, or has experienced a significant traumatic injury within 28 days prior to 
enrollment.
5.  The subject has a history of another primary cancer, with the exception of:  a) curatively resected 
non-melanomatous skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary 
solid tumor treated with curative intent, no known active disease present, and no treatment 
administered during the last 3 years prior to study entry.
6.  The subject is receiving concurrent treatment with other anticancer therapy, including other 
chemotherapy, immunotherapy, radiotherapy, chemoembolization, targeted therapy, or any 
investigational agent within 4 weeks prior to study entry., or radiotherapy within 2 weeks prior to 
study entry.  An exception is that subjects with metastatic breast or prostate cancer who have been on 
a stable dose (≥28 days) of an approved hormonal agent will not be excluded (ie, they will be 
eligible).  Subjects with breast cancer may also continue with concurrent human epidermal growth 
factor receptor 2 (HER2)-directed therapy.
7. The subject has received treatment with agents specifically targeting the CSF-1 or CSF-1R 
including (but not limited to) imatinib, nilotinib, and sunitinib.
8.7.  The subject has known muscle damage due to a primary, traumatic, or other muscle disease.
9.8.  The subject is known to be human immunodeficiency virus (HIV) seropositive.
10.9. The subject has a known and uncontrolled infection (presumed or documented) with progression 
after appropriate therapy for greater than one month.
11.10. The subject is known to have active tuberculosis, leishmaniasis, or listeriosis.
12.11.  The subject has a history of and/or current:  symptomatic coronary artery disease, confirmed 
left ventricular ejection fraction (LVEF) ≤50% or any cardiac insufficiency > New York Heart 
Association (NYHA) class II,* uncontrolled hypertension, or serious cardiac arrhythmia (well-
controlled atrial fibrillation is permitted).
13.12.  Subjects with known history or clinical or laboratory evidence of liver disease.  Notably, 
subjects with any of the following liver function abnormalities will be excluded:
a
Cirrhosis with evidence of portal hypertension or bridging fibrosis
b
Alcoholic hepatitis
c
Esophageal varices
d
A history of bleeding esophageal varices
e
Hepatic encephalopathy
f
Ascites related to portal hypertension
g
Chronic viral hepatitis with total serum bilirubin >3 mg/dL
14.13.  The subject has active bleeding.
15.14.  The subject has leukemia or lymphoma.
16.15.  The subject has a known psychiatric illness/social situation (including alcohol and/or drug 
dependency) that would, in the Investigator’s opinion, limit compliance with study requirements.
17.16.  The subject has known or suspected primary brain or leptomeningeal tumors or metastases 
(subjects with a history of brain metastases must have received definitive surgery or radiotherapy, be 
clinically stable, and may not be taking steroids; subjects receiving anticonvulsants are eligible).
18.17.  The subject is pregnant (confirmed by serum beta human chorionic gonadotropin [β-hCG] 
test performed within 7 days prior to first dose of study therapy) or breastfeeding.
19.18.  The subject has received a solid organ transplant.
20.19.  The subject has any other serious uncontrolled medical disorders, which, in the opinion of the 
Investigator, would compromise the subject’s safety or the ability of the subject to participate in the 
study.

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*NYHA Congestive Heart Failure Classification (NYHA 1994):
Class I – Patients with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II – Patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion.
Class III – Patients with marked limitation of activity; they are comfortable only at rest.
Class IV – Patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and 
symptoms occur at rest.
Efficacy Assessments:
Radiographic assessment of disease response and tumor assessments, according to RECIST 1.1, will be 
performed at baseline and at the end of every cycle.  Radiographic assessment should be performed prior 
to the start of a cycle so that results are available before the subject receives a new cycle of treatment.  
However, if a subject experiences a DLT is observed in Cycle 1, and the subject’s in a subject who is 
benefitting from treatment, Cycle 2 dosing ismay be initiated within 4 weeks of Cycle 1, Day 1, with 
Sponsor approval; in this case, no radiographic disease assessment is required prior to dosing in Cycle 2.
Tissue Assessments:
To assess the pharmacodynamic effect of IMC-CS4 administration on tumor-associated myeloid cells, 
including macrophages, all subjects enrolled in Cohort 2 and beyond will undergo tumor biopsies before 
study enrollment (unless medically contraindicated and if acceptable archived tumor material is 
available).  The.  For these cohorts, investigators will carry out a tumor (core needle or excisional) biopsy
(attempt to obtain at least 3 cores) before starting the treatment and at the end of Cycle 1 (to be done in 
the week prior to Cycle 2, at the same time as tumor evaluation), if the subject’s condition allows it.  
If the subject’s condition allows it an enrolled subject undergoes a pretreatment tumor biopsy but is 
unable to tolerate a posttreatment tumor biopsy, then a skin punch biopsy will be acceptable.  At the time 
of disease progression, the Investigator will also perform a tumor biopsy if disease progression is 
diagnosed.  If a tumor core biopsy is not possible, the Investigator may consultthe subject consents to it 
and if the ImClone CRP to evaluate the possibility of performing a tumor fine-needle aspiration 
(FNA).subject’s condition allows it.
Statistical Methods:
Overall response rate (number of subjects who achieve a best response of complete response [CR] or 
partial response [PR] during therapy, divided by the total number of subjects treated) and disease control 
rate (number of subjects who achieve a best response of CR or PR or stable disease [SD] during therapy, 
divided by the total number of subjects treated) will be presented for each cohort of subjects.Tumor 
response data will be summarized, if appropriate.
Version History:
Version 6.0:  31 March 2014
LIST OF ABBREVIATIONS AND DEFINITIONS
CRPCRS
clinical research physicianscientist
GGT
gamma glutamyl transferase
HER2
human epidermal growth factor receptor 2
irAE
immune-related adverse event
LFT
liver function test
MTD
maximum tolerated dose
q4w
every 4 weeks
SUSAR
suspected unexpected serious adverse reaction

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1.4.1 Rationale for Starting Dose
The optimal dose and regimen of IMC-CS4 in humans are not known.  The proposed starting 
dose and regimen of IMC-CS4 iswas 2.5 mg/kg administered qw by I.V. infusion.  This starting 
dose iswas based on the following rationale:
1.4.2 Clinical Experience from Cohort 1
IMC-CS4 was administered to 6 subjects at the starting dose of 2.5 mg/kg qw.  Two of the first 
3 subjects experienced Grade 2 creatine kinase (CK) serum level elevations, associated to with
elevated levels of AST (Grade 1-2), LDH, and CSF-1.  A muscle biopsy was performed, 
independently of the protocol, in one of the subjects with elevated CK values and did not reveal 
any signs of rhabdomyolysis, nor of muscle damage of inflammatory or non-inflammatory 
origin.  However, because of the serum enzyme elevation and subjects’ general conditions, 
Cycle 1 was not completed as per protocol in 2 of the 3 subjects.
1.4.3 Clinical Experience from CohortCohorts 2 and Beyondthrough 5
This section describes the clinical experience after the revised dose-escalation scheme was 
implemented in Protocol Amendment Version 3.0, specifically, the clinical observations for 
Cohorts 2, 3, 4, and 4.  (Note that Cohort 4 is still ongoing.)  To date, no5.  No DLTs were 
observed in Cohorts 2 and 3.  The clinical data generated for subjects treated in Cohorts 2 and 3 
indicate that IMC-CS4 is safe and well tolerated when administered as 4 qw doses (0.3 or 0.6 
mg/kg) followed by 2 weeks of recovery.
In Cohort 4, (1.25 mg/kg q2w), one subject with a history of cardiac dysfunction developed a 
Grade 3 left ventricular systolic dysfunction (verbatim) after one dose of IMC-CS4; the event 
was considered by the Investigator to be related to IMC-CS4.  Because DLT could not be ruled 
out for this event, 2 additional subjects are to be enrolled into Cohort 4.  Following completion 
of Cycle 1 by these 2 additional subjects, a safety review is to be conducted to determine whether 
IMC-CS4 is safe and well tolerated when administered as 2 biweekly doses (1.25 mg/kg) 
followed by 3 weeks of recovery.were enrolled into Cohort 4 and completed protocol-defined 
therapy without experiencing DLT events.
In Cohort 5 (1.25 mg/kg qw), 2 subjects experienced DLT events:  1 subject was diagnosed with 
rhabdomyolysis complicated by acute renal failure following 1 dose of IMC-CS4, and the second 

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subject was diagnosed with pancreatitis after receiving 3 doses of IMC-CS4.  The subject 
diagnosed with pancreatitis slowly developed symptoms in conjunction with rising amylase and 
lipase levels during the course of treatment; these signs and symptoms, which were consistent 
with pancreatitis, resolved upon discontinuation of IMC-CS4 and initiation of systemic steroids.  
As a result of these 2 DLT events, the RP2D was determined to be 1.25 mg/kg every 2 weeks.
1.4.4 Exploring Non-Weight-Based Dosing (Cohorts 6a through 8c)
Exploratory graphical analysis of the pharmacokinetics of IMC-CS4 in Cohorts 1 to 5 indicates 
no clear relationship between body weight and drug clearance (Figure 1).  Furthermore, weekly 
dosing results in sustained elevation of CSF-1, an indicator of target engagement, for the 
duration of the dosing period (Figure 2).  In contrast, dosing every 2 weeks allows CSF-1 levels 
to return to baseline, indicating reduced target engagement with a more intermittent dosing 
schedule.  Therefore, additional cohorts are being added in this protocol amendment, 
Version 7.0, to evaluate safety, pharmacokinetics, and pharmacodynamics of non-weight-based 
dosing of IMC-CS4 administered on a weekly schedule.  As was done for weight-based dosing 
cohorts, doses for non-weight-based dosing cohorts will be escalated to identify RP2D.  To 
accommodate these new non-weight-based dosing cohorts, the definition of DLT has been 
revised and an algorithm added to initiate steroid therapy early during the course of an immune-
related adverse event (irAE) (refer to Section 9.1.1 for additional details).

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Abbreviations:  QW = weekly; Q2W = every 2 weeks.
Figure 1. Reported body weight versus LY3022855 drug clearance (as determined 
using non-compartmental analysis) for eligible subject data from Study JSCA 
(IMCL CP24-1001.)

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Profile plot of CD14DIM CD16BR MONO (CELLS/uL) 
Program Location: F:/lillyce/prd/ly3022855/i5f_ie_jsca/misc1/programs_nonsdd/CS4_jsca_CD14dimCD16br_C4-C5.r 
Data Location: F:/lillyce/prd/ly3022855/i5f_ie_jsca/misc1/data/shared/custom/dm.csv  
Data Location: F:/lillyce/prd/ly3022855/i5f_ie_jsca/misc1/data/shared/custom/lb.csv 
Output Location: F:/lillyce/prd/ly3022855/i5f_ie_jsca/misc1/programs_nonsdd/tfl_output/CS4_JSCA_CD14dimCD16br_C4-C5.rtf
Figure 2. Profile review of CD14DIM CD16BR MONO (cells/µL).
Additional cohorts are being added in this protocol amendment, Version 6.0, to permit further 
dose escalation beyond the previously planned cohorts.  Newly added Cohorts 7 and 8 will 
provide for the following doses:  2.5 mg/kg in Cohort 7 and 3.75 mg/kg in Cohort 8.  In these 
new cohorts, study drug will be administered qw on Weeks 1, 2, 4, and 5 of every 6-week cycle, 
with Weeks 3 and 6 as rest weeks.  This dosing regimen was selected to correspond to other 
standard-of-care anticancer regimens.  Further dose escalations beyond Cohort 8 may occur by 
following the same dosing schedule (qw on Weeks 1, 2, 4, and 5) but increasing the dose level 
by 1.25 mg/kg until a DLT has occurred (that is, dose escalation will occur only if the criteria 
described in Section are met), unless otherwise agreed among the investigators and the ImClone 
clinical research physician (CRP).

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1.5  Human Experience
NOTE:
Protocol Amendment Version 7.0 describes additional cohorts for non-weight-based dosing of 
IMC-CS4, which will be referred to as Part B of the study.  Cohorts described in the protocol 
prior to Protocol Amendment Version 7.0 (that is, for weight-based dosing of IMC-CS4) will 
now be referred to as Part A of the study.  Refer to Section 4.1 for details of the dose 
assignments for Parts A and B.
Throughout the protocol, information relevant only to Part A (weight-based dosing) or only to 
Part B (non-weight-based dosing) is indicated as such.  Any information not indicated as “Part A 
only” or “Part B only” is relevant to both parts.
2.2  Secondary Objectives
The secondary objectives of this study are:

Part A only – To define the recommended Phase 2 dose (RP2D) using weight-based 
dosing;

Part B only – To define the RP2D using non-weight-based dosing;

To characterize the pharmacodynamic profile of IMC-CS4 on circulating levels of 
CSF-1; and

To assess the development of antibodies against IMC-CS4 (immunogenicity).
3.1  Study Population
Subjects will be recruited from a population of cancer subjects treated at the investigational 
centers.  A record of the most recent pretreatment evaluations will be reviewed to determine the 
eligibility of a subject for this study.  It is anticipated that approximately 47 subjects will be 
enrolled (that is, assigned to a dose cohort) in approximately 3 study sites in the United States.
3.2  Inclusion Criteria
14. The subject is accessible for treatment and follow-up; subjects enrolled in this trial must
      be treated at the study center.
15. The subject must undergo mandatory biopsies, including one pretreatment and one
       posttreatment tumor biopsy procedure (refer to tumor biopsy Section 7.2.1.1); subjects
      enrolled in this trial must be treated at the study center.).
3.3  Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:

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1.  The subject has experienced acute pathologic fracture, or spinal cord compression, or 
clinically significant hypercalcemia within 28 days prior to first dose of study therapy.
2.  The subject has a known hypersensitivity to monoclonal antibodies or to agents of 
similar biologic composition as IMC-CS4.
3.  The subject has received treatment with any monoclonal antibodies within 64 weeks 
prior to first dose of study therapy.
4.  The subject has undergone a major surgical procedure, radiation therapy, open biopsy, 
radiofrequency ablation, or has experienced a significant traumatic injury within 28 days 
prior to enrollment.
5.  The subject has a history of another primary cancer, with the exception of a) curatively 
resected non-melanomatous skin cancer; b) curatively treated cervical carcinoma in situ; or 
c) other primary solid tumor treated with curative intent, no known active disease present, 
and no treatment administered during the last 3 years prior to study entry.
6.  The subject is receiving concurrent treatment with other anticancer therapy, including 
other chemotherapy, immunotherapy, radiotherapy, chemoembolization, targeted therapy, or 
any investigational agent within 4 weeks prior to study entry, or radiotherapy within 2 
weeks prior to study entry.  An exception is that subjects with metastatic breast or prostate 
cancer who have been on a stable dose (≥28 days) of an approved hormonal agent will not 
be excluded (ie, they will be eligible).  Subjects with breast cancer may also continue with 
concurrent human epidermal growth factor receptor 2 (HER2)-directed therapy.
7.  The subject has received treatment with agents specifically targeting the CSF-1 or 
CSF-1R including (but not limited to) imatinib, nilotinib, and sunitinib.
8.7.  The subject has known muscle damage due to a primary, traumatic, or other muscle 
disease.
9.8.  The subject is known to be human immunodeficiency virus (HIV) seropositive.
10.9.  The subject has a known and uncontrolled infection (presumed or documented) with 
progression after appropriate therapy for greater than one month.
11.10.  The subject is known to have active tuberculosis, leishmaniasis, or listeriosis.
12.11.  The subject has a history of and/or current:  symptomatic coronary artery disease, 
confirmed left ventricular ejection fraction (LVEF) ≤50% or any cardiac insufficiency 
> New York Heart Association (NYHA) class II,* uncontrolled hypertension, or serious 
cardiac arrhythmia (well-controlled atrial fibrillation is permitted).
13.12.  Subjects with known history, or clinical or laboratory evidence of, liver disease.  
Notably, subjects with any of the following liver function abnormalities will be excluded:
a
Cirrhosis with evidence of portal hypertension or bridging fibrosis
b
Alcoholic hepatitis
c
Esophageal varices
d
A history of bleeding esophageal varices
e
Hepatic encephalopathy
f
Ascites related to portal hypertension
g
Chronic viral hepatitis with total serum bilirubin >3 mg/dL.
14.13.  The subject has active bleeding.
15.14.  The subject has leukemia or lymphoma.
16.15.  The subject has a known psychiatric illness/social situation (including alcohol and/or 
drug dependency) that, in the Investigator’s opinion, would limit compliance with study 
requirements.

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17.16.  The subject has known or suspected primary brain or leptomeningeal tumors or 
metastases (subjects with a history of brain metastases must have received definitive surgery 
or radiotherapy, be clinically stable, and may not be taking steroids; subjects receiving 
anticonvulsants are eligible).
18.17.  The subject is pregnant (confirmed by serum beta human chorionic gonadotropin 
[β-hCG] test performed within 7 days prior to first dose of study therapy) or breastfeeding.
19.18.  The subject has received a solid organ transplant.
20.19.  The subject has any other serious uncontrolled medical disorders that, in the opinion 
of the Investigator, would compromise the subject’s safety or the ability of the subject to 
participate in the study.
3.4  Subject Enrollment
Individuals who do not meet the criteria for participation in this study (screen failure) within 
14 days after study entry may be rescreened once.  Sites are responsible for determining if the 
subject must sign a new ICF, based on regulatory and institutional or central IRB/aEC 
guidelines.  The subject should meet all eligibility criteria beforeAll subjects who have signed an 
informed consent form will be assigned a study identification (ID) number is assigned.
4.1  Overall Study Design and Plan
This open-label, dose-escalation, Phase 1 study will enroll approximately 47 subjects a total of 
approximately 72 subjects to 2 parts - Parts A and B, in approximately 6 study sites in the United 
States.  Part A consists of dose escalation of IMC-CS4 using weight-based dosing (Part A 
enrollment is planned to be discontinued as of 30 September 2015); Part B will consist of dose 
escalation of IMC-CS4 using non-weight-based dosing; the actual enrollment will depend on the 
number of DLTs observed and the resultant size of each cohort.
In addition, the cohort identified as the RP2D  Throughout this protocol, any information not 
indicated as “Part A only” or “Part B only” is relevant to both parts.  In Part A, additional 
subjects were enrolled to the maximum tolerated dose (MTD) of 1.25 mg/kg q2w, in order to 
help establish the safety profile of IMC-CS4.  In Part B, the cohort associated with the dose 
identified as the MTD may be expanded (up to a maximum of 12 evaluable subjects) in order to 
help establish the safety profile of IMC-CS4 at an expected biologically effective dose.  
Alternately, consideration will be given to enrollment of up to 12 subjects into 1 or 2 additional 
cohorts below the RP2D rather than at the RP2D, if appropriate based on PK, pharmacodynamic, 
and/or safety findings from this study. .  Enrollment to the MTD expansion cohort may cease if 

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the Sponsor (after conferring with the investigators) deems the toxicity profile precludes further 
enrollment.  Refer also to Section 4.1.2.
Dose cohorts, including dose and dosing schedule, are summarized in Table 1.  For each cohort, 
one cycle is 6 weeks.  In each cohort, subjects will receive IMC-CS4 by I.V. infusion (with an 
observation period, in Part A only, for weekly ([qw)] and every-2-week ([q2w)] cohorts, in 
Cycle 1 only, as described in Table 1).  Beginning with Protocol Amendment Version 7.0, 
enrollment to Part B of the study will start with Cohort 6a, then escalate to Cohorts 7a and 8a.  In 
the event 2 or more subjects on Cohort 6a experience a DLT event, concurrent enrollment of 3 to 
6 subjects to each of Cohorts 6b and 6c will start and further dose escalation (that is, to 
Cohort 7a) will cease.  Likewise, the same algorithm will apply for Cohorts 7a and 8a if 
enrollment to those cohorts occurs.  Subjects will be assigned to “b” and “c” cohorts by the 
Sponsor.  Note that there will be no Cycle 1 observation period for Part B cohorts.  No intra-
subject dose-escalation is permitted for any subject.  Dose escalation may be reduced or ceased 
at any time based on safety and PK behavior.

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Table 1.  Dose Cohort Assignment
Cohort
Dose Level
(mg/kg)
Dosing Schedulea
Cycle 1
Observation Periodb
Number of Infusions
Part A (weight-based dosing)
1
2.5 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
2
0.3 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
3
0.6 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
4
1.25 mg/kg
q2w
3 weeks (Weeks 4-6)
Cycle 1:  2
Subsequent cycles:  3
5
1.25 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
Part B (non-weight-based dosing)
6a
100 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
66bc,d
2.5100 mg
q2wqw on Weeks 1, 2, 4, and 5
3 weeksNone (Weeks 4-3 
and 6 are rest)
Cycle 1:  24
Subsequent cycles:  34
6cc
75 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
7a
150 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
77bc,d
2.5c150 mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4d4
7cc
125 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
8a
200 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
8e8bc,d
3.75c200 
mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4d4
8cc
175 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
Abbreviations:  aEC = approving Ethics Committee; CRP = clinical research physician; DLT = dose-limiting toxicity; 
IRB = Institutional Review Board; PK = pharmacokinetic(s); qw = weekly; q2w = every 2 weeks.
a – At the highest dose level where major toxicity is observed and that requires a longer recovery period between infusions, a 
change in the periodicity of dosing (that is, other dosing schedules based on safety and PK considerations) will be agreed upon 
with the Investigator and communicated to IRBs/aECs.
b – Observation following the fourth infusion in Cohorts 1, 2, 3, and 5 (qw dosing) and the second infusion in CohortsCohort 4 
and 6 (q2w dosing) in Cycle 1 only.  No Cycle 1 observation period for Cohorts 6a, 6c, 7a, 7c, 8a, or 8c.  Weeks 3 and 6 of all 
cycles are rest weeks in Cohorts 76b, 7b, and 88b (qw dosing on Weeks 1, 2, 4, and 5).
c – In case of unacceptable toxicity in Cohorts 7 or 8 (qw dosing on Weeks 1, 2, 4, and 5), the following reduced doses will be 
explored, beginning no sooner than Cycle 2:  Cohort 7 dose will be reduced to 2.5 mg/kg q2w; Cohort 8 dose will be reduced to 
2.5 mg/kg qw on Weeks 1, 2, 4, and 5.  In the event that 2 DLTs are observed in 6 subjects in Cohort 7, the next cohort will 
receive doses of 2.2 mg/kg qw on Weeks 1, 2, 4, and 5, which is an intermediate dose between that of Cohorts 6 and 7.
c – Concurrently enroll to Cohorts 6b/7b/8b and 6c/7c/8c, should ≥2 subjects in Cohort 6a/7a/8a experience DLT events.
d – For all cycles:  Infusions on Weeks 1, 2, 4, and 5, and rest on Weeks 3 and 6.
e – The dose level for cohorts beyond Cohort 8 will be agreed among the investigators and the ImClone CRP at the safety review 
meeting following Cohort 8.  Further dose escalations beyond Cohort 8 may occur by following the same dosing schedule (qw on 
Weeks 1, 2, 4, and 5) but increasing the dose level by 1.25 mg/kg until a DLT has occurred, unless otherwise agreed among the 

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investigators and the ImClone CRP.
It is recognized that in the course of clinical cancer care, it is not always possible to schedule 
therapeutic infusions at precise intervals (because of holidays, travel difficulties, or other 
circumstances).  Accordingly, infusions administered within 2 days (qwall cohorts other than 
q2w dosing) or 3 days (q2w dosing) before or after the planned infusion time point will be 
considered acceptable.  Deviations beyond this window are not permitted in Cycle 1 and will be 
allowed thereafter only if medically indicated or if the subject cannot be treated on the scheduled 
day.
Following the first cycle of therapy (Cycle 1), subjects should continue to receive IMC-CS4 at 
the same dose and schedule until there is unequivocal evidence of disease progression 
(per immune-related response criteria [Wolchok et al. 2009]) or other withdrawal criteria are 
met.  Radiographically confirmed disease progression (that is, numerical disease progression, per 
RECIST) only is not sufficient to discontinue treatment.*  Radiographic assessment of tumor 
response will be performed at the end of the initial 6-week cycle and at the end of every 
subsequent cycle; radiographic assessment should be performed prior to the start of a cycle so 
that results are available before the subject receives a new cycle of treatment.  However, if a 
DLT is observed in Cycle 1, and in a subject who is benefitting from treatment, Cycle 2 dosing 
ismay be initiated within 4 weeks of Cycle 1, Day 1, with Sponsor approval; in this case, no 
radiographic disease assessment is required prior to dosing in Cycle 2.
*Note:  Subjects with disease progression (per RECIST) but without clinical deterioration at 
Week 6 (the first response assessment) may continue to receive IMC-CS4, at the discretion of the 
Investigator; study treatment will be discontinued if, at the next disease assessment (performed at 
least 4 weeks later), disease progression is unequivocal (that is, radiographically confirmed 
disease progression alone is sufficient).  On the other hand, subjects with disease progression 
(per RECIST) and with clinical deterioration (unequivocal) at Week 6 (the first response 
assessment) will be discontinued from study treatment.
The treatment schedule, radiographic tumor assessment schedule, and observation period for 
each dosing schedule are summarized in Table 2, Table 3, Table 4, and Table 5.

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Table 2.  Treatment Schedule (Part A - Weekly Dosing – Cohorts 1, 2, 3, and 5)
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Txa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
O.P.b
X
X
Tumor
evalc
Xd
X
X
X
X
Abbreviations:  eval = evaluation; O.P. = observation period; Tx = treatment.
a – Administer IMC-CS4; b – Observation period; c – Radiographic assessment of tumor status; d – Baseline assessment, within 28 days prior to 
the first dose of study therapy; subsequent assessment should be performed in the week prior to the onset of the new cycle.
Table 3.  Treatment Schedule (Part A - Every-2-Week Dosing – CohortsCohort 4
and 6)
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Txa
X
X
X
X
X
X
X
X
X
X
X
O.P.b
X
X
X
Tumor
evalc
Xd
X
X
X
X
Abbreviations:  eval = evaluation; O.P. = observation period; Tx = treatment.
a – Administer IMC-CS4; b – Observation period; c – Radiographic assessment of tumor status; d – Baseline assessment, within 28 days prior to 
the first dose of study therapy; subsequent assessment should be performed in the week prior to the onset of the new cycle.
Table 4.  Treatment Schedule (Part B - Weekly Dosing on Weeks 1, 2, 4, and 5 –
Cohorts 76a, 6c, 7a, 7c, 8a, and 88c)
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Txa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
O.P.b
Tumor
evalc
Xd
X
X
X
X
Abbreviations:  eval = evaluation; O.P. = observation period; Tx = treatment.
a – Administer IMC-CS4; b – Observation period; c – Radiographic assessment of tumor status; d – Baseline assessment, within 28 days prior to 
the first dose of study therapy; subsequent assessment should be performed in the week prior to the onset of the new cycle.

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Table 5.  Treatment Schedule (Part B - Weekly Dosing on Weeks 1, 2, 4, and 5 –
Cohorts 6b, 7b, and 8b)
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Txa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
O.P.b
Tumor
evalc
Xd
X
X
X
X
Abbreviations:  eval = evaluation; O.P. = observation period; Tx = treatment.
a – Administer IMC-CS4; b – Observation period; c – Radiographic assessment of tumor status; d – Baseline assessment, within 28 days prior to 
the first dose of study therapy; subsequent assessment to be performed in the week prior to the onset of the new cycle.
4.1.1 Cohort Enrollment and Dose Escalation
For all cohorts, all subjects who complete the first treatment cycle (that is, receive all scheduled 
treatments for Cycle 1 and complete the observation period, as needed) or discontinue therapy 
due to a DLT will be considered evaluable subjects and will be included in the DLT analyses.  
Subjects who do not complete Cycle 1 for reasons other than a DLT will be replaced for the 
analysis until the cohort includes 3 evaluable subjects (or 6 evaluable subjects in case of one 
DLT in the first 3 subjects); however, if benefitting from treatment (that is, no disease 
progression or other withdrawal criteria), any subject in Cohort 3 and beyond who experiences a 
DLT may continue to receive IMC-CS4 upon agreement of the Sponsor and according to the 
dose reduction guidelines for this study.  Refer to Section 10.1 for details of general dose 
modifications for IMC-CS4.
In all cases, dose escalation will occur only if the criteria described in this section (Section 4.1.1)
are met.  Each subsequent cohort will be opened upon completion of the previous cohort.  
A safety review meeting will be held prior to each dose escalation.
4.1.2 Determination of the Recommended Dose for Phase 2
The provisional RP2D will be defined as the dose level at which pharmacodynamic effects are 
observed in the absence of clinically relevant toxic effects (that is, measurable pharmacodynamic 
effects with no DLT in the first 3 subjects or ≤1 DLT in the first 6 subjects enrolled at that dose 
level).  When the RP2D is identified, at least 6 additional subjects will be enrolled to ensure a 
total of at least 9 evaluable (in terms of PK analysis) subjects treated at the RP2D to further 
characterize the toxicity, PK, and/or pharmacodynamics of IMC-CS4.  Consideration will be 
given to enrollment of up to 12 subjects into 1 or 2 additional cohorts below the RP2D rather 

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than at the RP2D, if appropriate based on PK, pharmacodynamic, and/or safety findings from 
this studyAfter discussion with the Investigator, the Sponsor may choose to enroll additional 
subjects at or below the RP2D.
4.1.4 Dose-Limiting Toxicity Definition
A DLT is defined as any IMC-CS4-related AE that occurs during Cycle 1, as follows and does 
not improve to Grade ≤2 (unless stated otherwise), despite medical management, including 
steroids (if applicable) within 7 days of documented occurrence.  The following are considered 
DLTs:

Grade 4 neutropenia lasting ≥7 days;

Grade 3 or 4 neutropenia complicated by fever ≥38.0°C or infection;

Grade 4 thrombocytopenia;

Grade 3 thrombocytopenia complicated by hemorrhage;

Grade 3 or 4 anemia;

Grade ≥3 AST/ALT elevation (exceptions mayor 4 nonhematologic toxicity.  Exceptions 
maybe be made for transient [that is, lasting <7 days] the following, if agreed upon by the 
Sponsor AND the Investigator:

Grade 3 elevations of AST/ALT ≥3 liver function test (LFT) abnormality, such as 
alkaline 
phosphatase, 
gamma 
glutamyl 
transferase 
(GGT), 
aspartate 
aminotransferase (AST), and alanine aminotransferase ALT, without evidence of 
hepatic injury

Transient Grade ≥2 bilirubin elevation in the presence of known liver metastases 
and without evidence of other hepatic injury, if agreed by the Investigator and 
ImClone CRP);lasting ≤7 days
•
Grade ≥2 AST/ALT elevation and Grade ≥2 bilirubin elevation (exceptions may be made 
for transient [that is, lasting < 7 days] elevations of AST/ALT and bilirubin in the 
presence of known liver metastases without evidence of other hepatic injury, if agreed by 
the Investigator and ImClone CRP); and/or
•
Grade 3 or 4 nonhematologic toxicity (excluding fatigue or anorexia lasting <7 days, or 
Grade 3 nausea and/or vomiting that persists for <2 days following appropriate 
supportive care).

Laboratory abnormalities that are reversible to Grade ≤2 or baseline levels within 
7 days after initial documentation or that are deemed not clinically significant

Grade 3 elevation of CK WITHOUT elevation in serum and urine myoglobin is 
NOT considered a DLT.
4.4  Extension Continued Access Period
All subjects remaining on study treatment without disease progression or unacceptable toxicity 
following the final analysis for RP2D will be able to enter the extension continued access period 

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of the study.  The extension continued access period begins after study completion and ends at 
the end of trial.  During the extension continued access period, subjects on study treatment who 
continue to experience clinical benefit may continue to receive study treatment until disease 
progression, death, unacceptable toxicity, or start of new anticancer treatment.  The extension
continued access period includes a Follow-up visit.  The Follow-up visit begins 1 day after the 
subject and the Investigator agree that the subject will no longer continue treatment in the 
extension continued access period and lasts approximately 30 days.  If it is deemed to be in the 
best interest of the subject to start a new anticancer treatment prior to the scheduled end of the 
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.
Subjects must sign a new ICF before entering the extension continued access period.  The 
Sponsor will notify investigators when the extension continued access period begins.
During the extension continued access period, all AEs, SAEs, study drug dosing, and dose 
reduction of treatment will be collected on the eCRF.
5.1.1.1
Part A Only
The dose of IMC-CS4 is based on the subject’s body weight in kilograms.  Subjects recruited in 
Cohort 1 have received IMC-CS4 infusions over a period of 90 minutes.  Because of a change in 
the dosing scheme in Protocol Amendment 3.0, subjects in Cohorts 2 through 6 will receive5 
received IMC-CS4 I.V. via infusion over a period of 30 minutes.  Subjects in Cohorts 7 and 8 
will receive IMC-CS4 I.V. via infusion over a period of 90 minutes.  Subjects in the RP2D 
expansion cohort will receive IMC-CS4 I.V. via infusion over a period of 90 minutes for the first 
infusion, 60 minutes for the second infusion, and 30 minutes for the remaining infusions.  The 
infusion rate should not exceed 25 mg/minute.
The first dose of IMC-CS4 is dependent upon the subject’s baseline body weight in kilograms.  
Subsequent doses of IMC-CS4 must be recalculated if there is a ≥10% change (increase or 
decrease) in body weight from baseline; subsequent doses may be recalculated if there is a <10% 
change (increase or decrease) in body weight from baseline.

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For subjects with fluid retention, the estimated dry weight, instead of the actual body weight, 
should be used for dose calculation or recalculation (in the setting of substantial fluid retention, 
the ImCloneSponsor CRP or designee should be consulted regarding optimal assessment of dry 
weight).
5.1.1.2
Part B Only
The dose of IMC-CS4 is non-weight based.  Subjects will receive IMC-CS4 I.V. via infusion 
over a period of 30 minutes.  The infusion rate should not exceed 25 mg/minute.
5.1.1.3
Both Parts A and B
5.1.1.1
Monitoring
6.2  Medical History
Concomitant medication assessment – To be performed and documented as outlined in Section 7 
(Study Activities).
6.3  Physical Examination
Complete physical examination – Evaluation by body system and height (at pretreatment only).
Weight measurement – Performed qw.
ECOG performance status– According to the ECOG PS criteria.
Concomitant medication assessment – To be performed and documented qw.
6.5  Clinical Laboratory Tests
Serum chemistry profile – Includes sodium, potassium, chloride, carbon dioxide, blood urea 
nitrogen, creatinine, glucose, total protein, albumin, AST, ALT, AP, total bilirubin, LDH, CK, 
lipase, amylase, calcium, magnesium, and phosphorus, and troponin T.  Serum myoglobin levels 
will be analyzed in case of CK elevation (for CK increases ≥2.5 × ULN).
Troponin (I or T or institutional standard) - Results are not needed prior to dosing, except for the 
Cycle 1, Day 1 dose.

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Hepatic monitoring – The following selected tests may be obtained in the event of a treatment-
emergent hepatic abnormality and may be required in follow up with subjects in consultation 
with the ImCloneSponsor CRP:
6.6  Efficacy Assessments

Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, 
abdomen, pelvis, and (if applicable) brain.  CT or MRI of the neck should be performed, 
if clinically indicated.  It is recommended that CT imaging of the abdomen/pelvis be 
performed with I.V. contrast, whenever possible.  For subjects with known serious 
allergic reactions to CT contrast material, a CT of the chest without contrast and contrast-
enhanced MRI of the abdomen/pelvis or a CT of the abdomen/pelvis with oral contrast 
should be performed, at the discretion of the Investigator.

Chest x-rays are not permitted for tumor response assessment in this trial.

Bone scans should be performed at baseline. as clinically indicated.  Routine bone scans 
during treatment must be performed only in the setting of bone-only disease (no lymph 
node, visceral, skin, or subcutaneous metastases), or as deemed appropriate by the 
Investigator.  In the event that a positron emission tomography (PET) scan is performed 
within 28 (calendar) days prior to first dose of study therapy that is negative for bone 
disease, then no baseline bone scan is required.

Imaging methods must be employed consistently during the course of each subject’s 
evaluation during the study (that is, subjects who have MRI as baseline examination 
continue to have MRI assessments as a means of determining response/progression).
6.7  Tissue Sampling
To assess the pharmacodynamic effect of IMC-CS4 administration on tumor-associated 
macrophages, all subjects enrolled in Cohort 2 and beyond will undergo tumor biopsies before 
study enrollment (unless medically contraindicated and if acceptable archived tumor material is 
available) and as specified in Table 6.
The.  For these cohorts, investigators will carry out a tumor (core needle or excisional) biopsy
(attempt to obtain at least 3 cores) before starting the treatment and at the end of Cycle 1 (to be 
done in the week prior to Cycle 2, at the same time as tumor evaluation), if the subject’s 
condition allows it.  If an enrolled subject undergoes a pretreatment tumor biopsy but is unable to 
tolerate a posttreatment tumor biopsy, then a skin punch biopsy will be acceptable.
At the time of disease progression, the Investigator will also perform a tumor biopsy if the 
subject consents to it and if the subject’s condition allows it.

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Previously archived tumor tissue from the primary tumor (paraffin block [whole or partial block] 
or 20 unstained slides), if available, will be collected (if possible) prior to receiving the first dose 
of study therapy if a tumor core biopsy cannot be performed before treatment, either because of 
the tumor location or because the subject’s condition does not permit it (that is, medically 
contraindicated).  If the subject’s condition allows it, the Investigator will also perform a tumor 
biopsy if disease progression is diagnosed.  If a tumor core biopsy is not possible, the 
Investigator may consult the ImClone CRP to evaluate the possibility of performing a tumor 
fine-needle aspiration (FNA).
Tissue will Previously archived and/or biopsied tissue may be used for analysis that may include, 
but would not be limited to immunohistochemistry for CD68 and CD163 and for potential 
pharmacogenomics analysis of, factors related to the CSF-1 pathways and analysis of 
macrophage-specific markers.1R pathway, macrophages, and immune microenvironment.  All 
tissue samples will be kept by the Sponsor for a total maximum of 15 years after the main study 
is completed; then all samples will be destroyed.
6.8.1 Pharmacokinetics
The analytical methods used to determine serum drug concentration will conform to the 
May 2001 United States Food and Drug Administration (FDA) Guidance for Industry: 
Bioanalytical Method Validation (FDA 2001).be validated at a laboratory determined by the 
sponsor.  Serum concentrations of IMC-CS4 will be determined using an enzyme-linked 
immunosorbent assay.
6.8.4 Other Analyses
Refer to Section 6.5 for details of blood samples drawn for other analyses, including flow-
cytometric analysis of peripheral leukocytes; isoenzymes of LDH, CK, and AP; troponin (I or 
T;); and bone metabolism markers CTX-I and P1NP.  These samples will be separate from those 
used for PK/immunogenicity and pharmacodynamic analyses, and drawn according to the 
schedule described in Sections 7.2.2.2, 7.2.2.3, 7.2.2.4, and 7.2.2.5.

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6.9.1 Triplicate ECG (Part A Only)
Triplicate ECG consisting of 3 individual ECGs performed consecutively within a period of 
approximately 4 minutes will be obtained at the time points specified in Section 7.2.3.1 from the 
6 additional subjects enrolled at the RP2D.
6.10
Multigated Acquisition Scan or Echocardiogram
A multigated acquisition (MUGA) scan or an echocardiogram will be performed for all subjects 
during pretreatment evaluations (within 28 [calendar] days prior to first dose of study therapy), 
as an eligibility assessment of LVEF.  Refer to exclusion criterion #1211 (Section 3.3) for 
subject eligibility regarding LVEF.
6.11.1 Tumor Tissue Submission
If a core biopsy, surgical biopsy, or resection is performed in the course of the study as routine 
clinical care, the Sponsor requests a tissue block or unstained slides for analysis of potentially 
relevant surrogate biomarkers.  Tissue will be kept with the intention to perform tests as new 
techniques, research tools, and biomarkers become available.  All tissue samples will be kept by 
the Sponsor for a total maximum of 15 years after the main study is completed, then all samples 
will be destroyed.
7.1  Pretreatment Evaluations

Blood sample for troponin (I or T) assessment (prior to the first infusion of Cycle 1 so 
that results are obtained before dosing);

Bone scan, as clinically indicated (within 28 days prior to the first dose of study therapy; 
not required if PET is performed within 28 days prior to the first dose of study therapy 
that is negative for bone disease); and

Tumor (core needle or excisional) biopsy (mandatory) (within 7 days prior to the first 
dose of study therapy) for subjects in Cohort 2 and beyond (unless medically 
contraindicated and if acceptable archived tumor material is available)..
7.2  Treatment Period
A series of clinical tests and procedures will be performed at specified intervals throughout the 
study (see also Section 7.6).  If, at any time during the study, tumor tissue is obtained as routine 
clinical care or through a biopsy, fine-needle aspiration (FNA), or resection, the Sponsor requests 
a portion of the sample for exploratory analyses.

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IMC-CS4 is administered I.V. as shown in Section 4.1, Table 2, Table 3, Table 4, and Table 5.  
An observation period will occur, as needed, in Cycle 1 of Part A only, as described in 
Section 4.1.  Radiographic assessment of tumor response will be performed at the end of every 
treatment cycle (prior to the first dose of study therapy in the subsequent cycle, approximately 
every 6 weeks assuming no treatment delays); radiographic assessment should be performed 
prior to the start of a cycle so that results are available before the subject receives a new cycle of 
treatment.  However, if a subject experiences a DLT is observed in Cycle 1, and the subject’s in 
a subject who is benefitting from treatment, Cycle 2 dosing is may be initiated within 4 weeks of 
Cycle 1, Day 1, with Sponsor approval; in this case, no radiographic disease assessment is 
required prior to dosing in Cycle 2.  Routine bone scans during treatment must be performed 
only in the setting of bone-only disease (no lymph node, visceral, skin, or subcutaneous 
metastases), or as deemed appropriate by the Investigator.
7.2.1 Regular Assessments
Beginning with Week 1, Day 1, the following evaluations will be performed every week
(±2 days for subjects in the qw cohorts and Cohorts 7 6b, 7b, and 8b and ±3 days for subjects in 
the q2w cohorts) for the first 12 weeks on therapy (this includes nontreatment weeks for subjects 
enrolled in the q2w cohorts and Cohorts 4 and 6, as well as Cohorts 76b, 7b, and 8b), unless 
otherwise indicated:

ECOG PS assessment;

Vital sign measurements (vital signs to be checked and recorded prior to each infusion of 
IMC-CS4, midway through each infusion, at the end of each infusion, and every 
15 minutes for the first hour following each infusion, including Week 1, Day 1 [also to be 
checked and recorded at nontreatment visits during Cycle 1]);

Weight measurement;

Toxicity/AE evaluations;

Concomitant medication assessment;

Hematology profile (evaluations performed within 7 days prior to the first dose do not 
need to be repeated at Week 1, Day 1);

Serum chemistry profile (evaluations performed within 7 days prior to the first dose 
do not need to be repeated at Week 1, Day 1); 

C-reactive protein assessment;

Tumor biopsy – At the end of Cycle 1, if the subject’s condition allows it, a (mandatory) 
(core needle or excisional) biopsy of the tumor will be performed, regardless of whether 
the tumor progressed, stabilized, or regressed (refer to Section 7.2.1.1 for the timing of 
non-mandatory tumor biopsies);

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
Blood samples for PK, immunogenicity, and pharmacodynamic analyses, per Section 7.7 
(Table 7, Table 8, and Table 9); and

Blood samples for the following assessments, per Section 7.7 (Table 7, Table 8, and 
Table 9): flow cytometry of peripheral leukocytes; isoenzymes of LDH, CK, and AP; 
troponin (I or T); and bone metabolism markers CTX-I and P1NP.
After study Week 12 (that is, after Cycle 2), ECOG PS assessment, vital sign measurements, 
weight measurement, toxicity/AE evaluations, and concomitant medication assessment will 
continue to be performed every week, while C-reactive protein assessment will be performed 
q2w.  After Week 12, hematology and serum chemistry will be performed:  q2w for cohorts up 
to and including Cohorts 1, 2, 3, 4, 5, 6a, 6c, 7a, 7c, 8a, 8c, and every 3 weeks (q3w) for 
Cohorts 7 6b, 7b, and 8b (such that these hematology and serum chemistry assessments are done 
on rest Weeks 3 and 6).
7.2.1.1
Tumor Biopsy
Tumor (core needle or excisional) biopsy will be performed at the following time points:
Weekly Cohorts and Cohorts 7 6b, 7b, and 8b
Mandatory (unless medically contraindicated)

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days) (unless medically 
contraindicated and if acceptable archived tumor material is available)

At the end of Cycle 1, if the subject’s condition allows it, a (core needle or excisional) 
biopsy of the tumor will be performed, regardless of whether the tumor progressed, 
stabilized, or regressed.
Non-mandatory

In cases of tumor progression, if the subject’s condition allows it, a (core needle or 
excisional) biopsy will be performed.
Every-2-Week Cohorts
Mandatory (unless medically contraindicated)

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

At the end of Cycle 1, if the subject’s condition allows it, a (core needle or excisional)
biopsy of the tumor will be performed, regardless of whether the tumor progressed, 
stabilized, or regressed.

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Non-mandatory
•
Prior to the third IMC-CS4 infusion of Cycle 1, if the subject’s condition allows it
In cases of tumor progression, if the subject’s condition allows it, a (core needle or 
excisional) biopsy will be performed.
Every-2-Week Cohorts
Mandatory (unless medically contraindicated)
•
Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days) (unless medically 
contraindicated and if acceptable archived tumor material is available)
•
At the end of Cycle 1, if the subject’s condition allows it, a core biopsy of the tumor will 
be performed, regardless of whether the tumor progressed, stabilized, or regressed.
Non-mandatory
•
Prior to the second IMC-CS4 infusion of Cycle 1, if the subject’s condition allows it
•
In cases of tumor progression, if the subject’s condition allows it, a core biopsy will be 
performed.
7.2.2.2
Flow Cytometry Analysis
Weekly Cohorts and Cohorts 7 6b, 7b, and 8b

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

1 day (approximately 24 hours) after the first IMC-CS4 infusion in Cycle 1

2 days (approximately 48 hours) after the first IMC-CS4 infusion in Cycle 1

3 days (approximately 72 hours) after the first IMC-CS4 infusion in Cycle 1

Immediately prior to the second IMC-CS4 infusion of Cycle 1

Immediately prior to the third IMC-CS4 infusion of Cycle 1

Immediately prior to the fourth IMC-CS4 infusion of Cycle 1

Cohorts 7 6b, 7b, and 8b only:  1 day after the first IMC-CS4 infusion in Cycle 3 
(approximately 24 hours)

Immediately prior to the second IMC-CS4 infusion of Cycle 3.
7.2.2.3
LDH, CK, and AP Isoenzymes
Weekly Cohorts and Cohorts 6b, 7b, and 8b

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

Prior to the second IMC-CS4 infusion of Cycle 1 (≤3 days)

Prior to the third IMC-CS4 infusion of Cycle 1 (≤3 days)

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
On Week 1 of Cycle 2; collected only if serum enzymes are ≥2.5 × ULN at Week 5 of 
Cycle 1

Cohorts 7 6b, 7b, and 8b only:  Prior to the second IMC-CS4 infusion of Cycle 3 
(≤3 days); collected only if serum enzymes are ≥2.5 × ULN at Week 5 of Cycle 1.
7.2.2.4
Troponin T
Serum levels of troponin (I or T) will be assessed at the following time points:
Weekly Cohorts and Cohorts 7 6b, 7b, and 8b

Prior to the first IMC-CS4 infusion of Cycle 1 (sample to be collected prior to the first 
infusion of Cycle 1 so that results are obtained before dosing)

Prior to the second IMC-CS4 infusion of Cycle 1 (≤3 days)

Prior to the third IMC-CS4 infusion of Cycle 1 (≤3 days)

On Week 1 of Cycle 2; collected only if serum CK levels are ≥2.5 × ULN at Week 5 of 
Cycle 1

Cohorts 7 6b, 7b, and 8b only:  Prior to the second IMC-CS4 infusion of Cycle 3 
(≤3 days); collected only if serum CK levels are ≥2.5 × ULN at Week 5 of Cycle 1

When deemed appropriate by the Investigator.
In all cohorts, blood samples for troponin T analysis will be collected at the end of therapy and at 
the 30-Day Follow-up visit only if CK ≥2.5 × ULN at Week 5 of Cycle 1.
With the exception of the first IMC-CS4 infusion of Cycle 1, IMC-CS4 may be administered as 
planned while troponin T results are pending, provided no cardiac symptoms have been revealed 
upon ECG or physical examination.  For the first IMC-CS4 infusion of Cycle 1 (all cohorts), 
troponin T results should be obtained before dosing.
7.2.2.5
Bone Metabolism Markers CTX-I and P1NP
Weekly Cohorts and Cohorts 7 6b, 7b, and 8b

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

Prior to the second IMC-CS4 infusion of Cycle 1 (≤3 days)

Prior to the fourth IMC-CS4 infusion of Cycle 1 (≤3 days)

Prior to the second IMC-CS4 infusion of Cycle 3 (≤3 days).

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7.2.3.1
Triplicate ECG Schedule (Part A Only)
As described in Section 4.1.2, 6 additional subjects will may be enrolled at the RP2D for each 
dosing schedule.  These 6 subjects only will undergo triplicate ECG testing (see Section 6.9.1) at 
each of the following time points:

Prior to the first infusion of Cycle 1 and 1 hour (±30 minutes) following the completion 
of the first infusion of Cycle 1

Prior to the last infusion of Cycle 1 and 1 hour (±30 minutes) following the completion of 
the last infusion of Cycle 1 (qw cohorts and Cohorts 7 and 8 only)

Prior to the last infusion of Cycle 3 and 1 hour (±30 minutes) following the completion of 
the last infusion of Cycle 3 (q2w cohorts only)

Prior to the last infusion of all subsequent cycles and 1 hour (±30 minutes) following the 
completion of the last infusion of all subsequent cycles.
7.3  End-of-Therapy Evaluations
End-of-therapy evaluations will be assessed on subjects who are no longer receiving study 
therapy.  The end-of-therapy evaluations will include:

ECG (triplicate ECG for the 6 additional subjects in whichever cohort is expanded to 
12 subjects; refer also to Part A only, as described in Sections 6.9.1 and 7.2.3.1);

ECOG PS assessment;

Physical examination;

Vital signs (including temperature, pulse rate, respiration rate, and blood pressure);

Weight measurement;

Toxicity/AE evaluations;

Concomitant medication assessment;

Hematology profile;

Serum chemistry profile;

C-reactive protein assessment;

Troponin (I or T) analysis and isoenzyme assessment of LDH, CK, and AP only if serum 
enzymes are ≥2.5 × ULN at Week 5 of Cycle 1; and

Urinalysis.
In cases of tumor progression, if the subject’s condition allows it, a (core needle or excisional) 
biopsy of the tumor will be performed.  For subjects who discontinue study therapy for any 
reason other than PD, every effort will be made to obtain radiographic tumor assessments at 6 
and 12 weeks following the first dose of study therapy and/or until radiographic documentation 
of PD.

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7.4  30-Day Follow-up Evaluations

Troponin (I or T) analysis and isoenzyme assessment of LDH, CK, and AP only if serum 
enzymes are ≥2.5 × ULN at Week 5 of Cycle 1;

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7.6Study Events Table
Table 6.  Flow Chart for Protocol
Procedures
Pretreatment
(Prior to first dose)
Treatment Cyclesa
End of 
Therapy
30-Day 
Follow-
up
Extended 
Follow-
up
Within
28 Days
Within
14 Days
Within
7 Days
Every
Weekb
Every 2
Weeks
Every 3
Weeks
Every 6
Weeks
Every 12
Weeks
Eligibility Assessments
Informed consent
Xc
N/A
Medical history
X
N/A
β-hCG Pregnancy test
Xd
Xd
Xd
ECG
X
Xe
X
MUGA/echocardiogram
X
Triplicate ECG (Part A only)
Xe,f
Xf
ECOG PS assessment
X
X
X
X
Safety Assessments
Physical examination
Xg
Xh
Xh
X
X
Vital signs
Xi
Xi
Xi
X
Weight measurement
X
X
X
X
Toxicity/AE assessment
Xj
X
X
X
Xk
Concomitant medication assessment
Xl
X
X
X
Laboratory Tests
Hematology profile
X
Xm,n
Xm
Xm
X
X
Coagulation profile
X
Xo
Serum chemistry profile
X
Xm,n
Xm
Xm
X
X
C-reactive protein assessment
X
Xm,n
Xm
X
X

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Table 65.  Flow Chart for Protocol
Procedures
Pretreatment
(Prior to first dose)
Treatment Cyclesa
End of 
Therapy
30-Day 
Follow-
up
Extended 
Follow-
up
Within
28 Days
Within
14 Days 
Within
7 Days
Every
Weekb
Every 2
Weeks
Every 3
Weeks
Every 6
Weeks
Every 12
Weeks
Urinalysis
X
Xo
X
Blood Sampling
All blood sampling
Refer to Table 7 (qw cohorts), Table 8 (q2w cohorts), and Table 9 (Cohorts 6b, 7b, and 8b).
Efficacy Assessments
Imaging studies (CT/MRI)
X
Xp
Bone scan
Xq
Xr
Tumor assessments
X
Xp
Tumor (core needle or excisional)
biopsy
X
Xs
Xt
Tumor tissue submission
Xu
Study Therapy Administration
Administer IMC-CS4
N/A
Refer to Table 2 (Part A - qw cohorts), Table 3 (q2w 
cohorts), Table 4 (Part B – qw cohorts), and Table 5
(Cohorts 6b, 7b, and 8b), .
N/A
Abbreviations:  β-hCG = beta human chorionic gonadotropin; AE = adverse event; CK = creatine kinase; CT/MRI = computed tomography (scan)/magnetic resonance imaging; 
DLT = dose-limiting toxicity; ECOG PS = Eastern Cooperative Oncology Group performance status; ECG = electrocardiogram; FNA = fine-needle aspiration; MUGA = 
multigated acquisition; N/A = not applicable; NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PET = positron emission tomography; 
PK = pharmacokinetic(s); qw = weekly; q2w = every 2 weeks; q3w = every 3 weeks; RP2D = recommended Phase 2 dose; ULN = upper limit of normal; 
WOCBP = women of childbearing potential.
a
Visit windows will coincide with the study therapy administration windows; that is, ±2 days for subjects in the qw cohorts and Cohorts 6b, 7b, and 8b, and ±3 days for 
subjects in the q2w cohorts.
b
Evaluations performed as part of the pretreatment assessment do not need to be repeated on Day 1 of Week 1 unless required in the opinion of the Investigator.
c
Written permission will be given by each subject prior to undergoing any protocol-specific pretreatment evaluations and prior to receiving treatment.
d
At baseline, serum pregnancy test is required for WOCBP.  Thereafter, including at Week 13 (that is, 12 weeks after the first dose), every 12 weeks (or according to local 
regulations, whichever is more frequent), and at the 30-Day Follow-up visit, a serum or urine pregnancy test may be performed.
e
ECG assessment will be performed at the following time points:  Prior to the first infusion of Cycle 1 and 1 hour (±30 minutes) following the completion of the first infusion 
of Cycle 1; prior to the last infusion of Cycle 1 and 1 hour (±30 minutes) following the completion of the last infusion of Cycle 1; prior to the last infusion of all subsequent 
cycles and 1 hour (±30 minutes) following the completion of the last infusion of all subsequent cycles; and when deemed appropriate by the Investigator.  Note that in cases 
where ECG and blood sample collection are scheduled at the same time, all blood sampling should be performed prior to ECG assessment.

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Table 65.  Flow Chart for Protocol
f
For 6 additional subjects enrolled either:  (1) at the RP2D of Part A only; or (2) into a cohort below the RP2D rather than at the RP2D, if appropriate based on PK and/or 
safety findings from this study.  Tthey will undergo triplicate (instead of single) ECG testing, according to the following schedule:  Prior to the first infusion of Cycle 1 and 1 
hour (±30 minutes) following the completion of the first infusion of Cycle 1; prior to the last infusion of Cycle 1 and 1 hour (±30 minutes) following the completion of the last 
infusion of Cycle 1 (qw cohorts and Cohorts 7 and 8 only); prior to the last infusion of Cycle 3 and 1 hour (±30 minutes) following the completion of the last infusion of 
Cycle 3 (q2w cohorts only); and prior to the last infusion of all subsequent cycles and 1 hour (±30 minutes) following the completion of the last infusion of all subsequent 
cycles.
g
The complete physical examination includes height (at baseline only).
h
Every 2 weeks for the first 12 weeks of the study, and every 6 weeks thereafter.
i
Vital signs include temperature, pulse rate, respiration rate, and blood pressure.  Vital signs will be checked and recorded prior to each infusion of IMC-CS4, midway through 
each infusion, at the end of each infusion, and every 15 minutes for the first hour following each infusion, including Week 1, Day 1 (also to be checked and recorded at 
nontreatment visits during Cycle 1).
j
Any preexisting toxicity should be documented, recorded, and graded (NCI-CTCAE, Version 4.0 grade) as a part of the pretreatment medical history.
k
All SAEs and IMC-CS4-related AEs will be followed until the event is resolved, stabilized, returned to baseline, deemed irreversible, or otherwise explained (frequency of 
follow-up evaluations is left to the discretion of the Investigator).  Data on SAEs that occur before the end of the trial will be stored in the collection database and the Lilly 
Safety System.
l
Including those medications taken within 30 days prior to the first dose of study therapy.
m
Every week for the first 12 weeks on therapy.  After Week 12, C-reactive protein assessment will be performed q2w; hematology and serum chemistry will be performed q2w 
for Ccohorts 1, 2, 3, 4, 5, 6a, 6c, 7a, 7c, 8a, and 8cup to and including Cohort 6 and q3w for Cohorts 6b, 7b, and 8b (that is, on rest Weeks 3 and 6).
n
Hematology and serum chemistry evaluations performed within 7 days prior to the first dose do not need to be repeated at Week 1, Day 1.
o
Coagulation profile and urinalysis will be performed at the beginning of each cycle (that is, approximately every 6 weeks following the first dose of study therapy).
p
Radiographic assessment of tumor response should be performed prior to the start of a cycle so that results are available before the subject receives a new cycle of treatment.  
However, if a DLT is observed in Cycle 1 in a subject who is benefitting from treatment, and Cycle 2 dosing is may be initiated within 4 weeks of Cycle 1, Day 1, with 
Sponsor approval; in this case, no radiographic disease assessment is required prior to dosing in Cycle 2.
q
Not required if PET is performed within 28 days prior to the first dose of study therapy that is negative for bone disease.
r
Bone scan at baseline, as clinically indicated.  Routine bone scans during treatment must be performed only in the setting of bone-only disease (no lymph node, visceral, skin, 
or subcutaneous metastases), or as deemed appropriate by the Investigator.
s
At the end of Cycle 1, if the subject’s condition allows it, a biopsy of the tumor will be performed, regardless of whether the tumor progressed, stabilized, or regressed.  If the 
subjects’s condition does not safely permit a tumor biopsy, then a skin biopsy may be submitted.A non-mandatory biopsy may be performed, if the subject’s condition allows 
it:  prior to the third IMC-CS4 infusion of Cycle 1 (for qw cohorts and Cohorts 7 and 8) or prior to the second IMC-CS4 infusion of Cycle 1 (for q2w cohorts).
t
In cases of disease progression, if the subject’s condition allows it, a tumor biopsy will be performed.  If a tumor core biopsy is not possible, the investigators may consult the 
ImClone CRP to evaluate the possibility of performing a tumor FNA.
u
If, at any time during the study, tumor tissue is obtained through a core biopsy, surgical biopsy, or resection as routine clinical care, the Sponsor requests a tissue block or 
unstained slides for analysis of potentially relevant surrogate biomarkers.  Subjects must consent to these optional procedures.

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7.7  Pharmacokinetic and Other Sampling
Table 7, Table 8, and Table 9 summarize PK and other sampling scheduled to occur as part of 
Study IMCL CP24-1001.
Table 7.  Blood Collection Schedule (Parts A and B - Weekly Cohorts 1, 2, 3, 5, 6a, 
6c, 7a, 7c, 8a, and 8c)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
TropT
Bone
Pretreatment
Prior to the first infusion
Xc
Xd
Xd
Xd
Xd
Xd
Xd
Cycle 1 (Week 1)
Immediately after the end of the first infusion of 
Cycle 1
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
X
X
48 hr (Day 3) after the end of the first infusion
X
X
X
72 hr (Day 4) after the end of the first infusion
X
X
X
168 hr (Day 8) after the end of the first infusion 
immediately (unless otherwise footnoted) prior the 
second infusion of Cycle 1
X
X
X
X
Xe
Xe
Xe
Cycle 1 (Week 3)
Immediately (unless otherwise footnoted) prior to 
the third infusion of Cycle 1
X
Xe
Xe
Cycle 1 (Week 4)
Immediately (unless otherwise footnoted) prior to 
the fourth infusion of Cycle 1
X
X
X
X
Xe
Cycle 2 (Week 1)
Prior to the first infusion of Cycle 2
Xf
Xg
Cycle 2 (Week 6)
Immediately prior to the sixth infusion of Cycle 2
X
X
Cycle 3 (Week 1)
Immediately prior to the first infusion of Cycle 3
X
X
X
Immediately after the end of the first infusion
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
48 hr (Day 3) after the end of the first infusion
X
96 hr (Day 5) after the end of the first infusion
X
168 hr (Day 8) after the end of the first infusion, 
immediately (unless otherwise footnoted) prior to 
the second infusion of Cycle 3
X
X
X
Xe
Cycle 3 (Week 4)
Immediately prior to the fourth infusion of Cycle 
3
X
X
X
Cycles 4-6i h
Prior to the last infusion of each cycle
X
X
Table is continued on the next page.

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Table 76.  Blood Collection Schedule (Parts A and B - Weekly Cohorts 1, 2, 3, 5, 
6a, 6c, 7a, 7c, 8a, and 8c)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
TropT
Bone
Cycle 5
Immediately prior to the first infusion of Cycle 5 
(6 months after the first infusion of Cycle 1)
X
End of Therapy
At the End-of-Therapy visit
Xf
Xg
Follow-up
30-Day Follow-up visitj i
X
X
X
X
Xf
Xg
Abbreviations:  Bone = assessment of bone metabolism markers (CTX-I and P1NP); CK = creatine kinase; CTX-I = C-terminal 
cross-linking telopeptide of type I collagen; ECG = electrocardiogram; FC = flow cytometry analysis; IGx = immunogenicity; Iso 
= isoenzyme analysis; P1NP = procollagen type 1 N-terminal propeptide; PD = pharmacodynamic markers; PK = 
pharmacokinetic(s); TropT = troponin (I or T) assessment; ULN = upper limit of normal.
a
It is understood that it may not be feasible to collect samples at precise intervals following the end of the infusions.  Every 
attempt should be made to collect each of these samples as close to the time point as possible.  The date and time of all PK 
samplings must be clearly and accurately recorded.
b
PK samples will be collected from all subjects.  The date and time of all samplings must be clearly and accurately recorded. 
The blood samples collected for PK will also be used for immunogenicity analyses.  For each specified time point, 1 tube 
(approximately 7.5 mL/tube) of blood is required to be drawn for any combination of PK or immunogenicity analyses.  As 
an example, if the timing of a PK sample should coincide with that of an immunogenicity sample, the same sample will 
suffice for these studies and the same total amount of blood (1 tube, approximately 7.5 mL/tube) will be collected.
c
Pretreatment sampling should be collected on the day of and immediately prior to the first infusion.
d
IGx, PD, FC, isoenzyme analysis, and bone metabolism markers:  Sample to be collected ≤7 days prior to the first infusion 
of Cycle 1.  Troponin (I or T) analysis:  Sample to be collected prior to the first infusion of Cycle 1 so that results are 
obtained before dosing.
e
Sample to be collected at any time ≤3 days prior to the infusion.  IMC-CS4 may be administered as planned while troponin 
(I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or physical examination.
f
Analysis to be performed only if serum enzymes are ≥2.5 × ULN at Week 5 of Cycle 1.
g
Analysis to be performed only if serum CK levels are ≥2.5 × ULN at Week 5 of Cycle 1.  IMC-CS4 may be administered as 
planned while troponin (I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or 
physical examination.
h
For subjects who proceed to Cycles 24 to 6, blood samples will be collected prior to the last infusion of each cycle.  In the 
event that a subject does not proceed to these cycles, these samples will not be collected.
i
A sample will be collected 30 days after last dose of investigational agent, regardless of duration of therapy.
Note:  If at any time a subject experiences an infusion-related reaction to IMC-CS4, all attempts will be made to obtain a blood 
sample for immunogenicity analysis as close to the onset of the event as possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken for immunogenicity testing may be used for PK analysis, in the setting of 
infusion-related reactions.

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Table 8.  Blood Collection Schedule (Part A - Every-2-Week Cohorts 4)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
TropT
Bone
Pretreatment
Prior to the first infusion
Xc
Xd
Xd
Xd
Xd
Xd
Xd
Cycle 1 (Week 1)
Immediately after the end of the first infusion of 
Cycle 1
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
X
72 hr (Day 4) after the end of the first infusion
X
X
X
168 hr (Day 8) after the end of the first infusion
X
X
336 hr (Day 15) after the end of the first infusion, 
immediately (unless otherwise footnoted) prior to 
the second infusion of Cycle 1
X
X
X
Xe
Xe
Xe
Cycle 1 (Week 3)
Immediately after the end of the second infusion 
of Cycle 1
X
1 hr after the end of the second infusion
X
X
2 hr after the end of the second infusion
X
X
4 hr after the end of the second infusion
X
X
24 hr (Day 2) after the end of the second infusion
X
X
72 hr (Day 4) after the end of the second infusion
X
X
168 hr (Day 8) after the end of the second infusion
X
X
336 hr (Day 15) after the end of the second 
infusion (Week 5)
X
X
504 hr (Day 22) after the end of the second 
infusion (Week 6) of Cycle 1
X
X
Cycle 2 (Week 1)h
Prior to the first infusion of Cycle 2
Xf
Xg
Cycle 2 (Week 5)h
Immediately prior to the third infusion of Cycle 2
X
X
Cycle 3 (Week 1)h
Immediately prior to the first infusion of Cycle 3
X
X
X
Immediately after the end of the first infusion
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
72 hr (Day 4) after the end of the first infusion
X
168 hr (Day 8) after the end of the first infusion
X
336 hr (Day 15) after the end of the first infusion, 
immediately prior to the second infusion of Cycle 
3
X
X
X
Cycle 3 (Week 5)h
Immediately prior to the third infusion of Cycle 3
X
X
X
Cycles 4-6h
Prior to the last infusion of each cycle
X
X
Table is continued on the next page.

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Table 87.  Blood Collection Schedule (Part A - Every-2-Week Cohorts 4)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
TropT
Bone
Cycle 5
Immediately prior to the first infusion of Cycle 5 
(6 months after the first infusion of Cycle 1)
X
End of Therapy
At the End-of-Therapy visit
Xf
Xg
Follow-up
30-Day Follow-up visiti
X
X
X
X
Xf
Xg
Abbreviations:  Bone = assessment of bone metabolism markers (CTX-I and P1NP); CK = creatine kinase; CTX-I = C-terminal 
cross-linking telopeptide of type I collagen; ECG = electrocardiogram; FC = flow cytometry analysis; IGx = immunogenicity; Iso 
= 
isoenzyme 
analysis; 
P1NP 
= 
procollagen 
type 
1 N-terminal 
propeptide;
PD = pharmacodynamic 
markers; 
PK = pharmacokinetic(s); TropT = troponin (I or T) assessment; ULN = upper limit of normal.
a
It is understood that it may not be feasible to collect samples at precise intervals following the end of the infusions.  Every 
attempt should be made to collect each of these samples as close to the time point as possible.  The date and time of all PK 
samplings must be clearly and accurately recorded.
b
PK samples will be collected from all subjects.  The date and time of all samplings must be clearly and accurately recorded.  
The blood samples collected for PK will also be used for immunogenicity analyses.  For each specified time point, 1 tube 
(approximately 7.5 mL/tube) of blood is required to be drawn for any combination of PK or immunogenicity analyses.  As 
an example, if the timing of a PK sample should coincide with that of an immunogenicity sample, the same sample will 
suffice for these studies and the same total amount of blood (1 tube, approximately 7.5 mL/tube) will be collected.
c
Pretreatment sampling should be collected on the day of and immediately prior to the first infusion.
d
IGx, PD, FC, isoenzyme analysis, and bone metabolism markers:  Sample to be collected ≤7 days prior to the first infusion 
of Cycle 1.  Troponin (I or T) analysis:  Sample to be collected prior to the first infusion of Cycle 1 so that results are 
obtained before dosing.
e
Sample to be collected at any time ≤3 days prior to the second infusion of Cycle 1.  IMC-CS4 may be administered as 
planned while troponin (I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or 
physical examination.
f
Analysis to be performed only if serum enzymes are ≥2.5 × ULN at Week 5 of Cycle 1.
g
Analysis to be performed only if serum CK levels are ≥2.5 × ULN at Week 5 of Cycle 1.  IMC-CS4 may be administered as 
planned while troponin (I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or 
physical examination.
h
For subjects who proceed to Cycles 2 to 6, blood samples will be collected as shown in this table.  In the event that a subject 
does not proceed to these cycles, these samples will not be collected.
i
A sample will be collected 30 days after last dose of investigational agent, regardless of duration of therapy.
Note:  If at any time a subject experiences an infusion-related reaction to IMC-CS4, all attempts will be made to obtain a blood 
sample for immunogenicity analysis as close to the onset of the event as possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken for immunogenicity testing may be used for PK analysis, in the setting of
infusion-related reactions.

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Table 9.  Blood Collection Schedule (Part B - Cohorts 6b, 7b, and 8b)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
TropT
Bone
Pretreatment
Prior to the first infusion
Xc
Xd
Xd
Xd
Xd
Xd
Xd
Cycle 1 (Week 1)
Immediately after the end of the first infusion of 
Cycle 1
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
X
X
48 hr (Day 3) after the end of the first infusion
X
X
X
72 hr (Day 4) after the end of the first infusion
X
X
X
168 hr (Day 8) after the end of the first infusion 
immediately (unless otherwise footnoted) prior 
the second infusion of Cycle 1
X
X
X
X
Xe
Xe
Xe
Cycle 1 (Week 2)
1 hr after the end of the second  infusion of Cycle 
1
X
2 hr after the end of the second infusion
X
4 hr after the end of the second infusion
X
24 hr (Day 2) after the end of the second infusion
X
48 hr (Day 3) after the end of the second infusion
X
72 hr (Day 4) after the end of the second infusion
X
168 hr (Day 8) after the end of the second 
infusion of Cycle 1
X
Cycle 1 (Week 4)
Immediately (unless otherwise footnoted) prior to 
the third infusion of Cycle 1
X
X
Xe
Xe
Cycle 1 (Week 5)
Immediately (unless otherwise footnoted) prior to 
the fourth infusion of Cycle 1
X
X
X
X
Xe
Cycle 2 (Week 1)
Prior to the first infusion of Cycle 2
Xg
Xh
Cycle 2 (Week 4)
Immediately prior to the third infusion of Cycle 2
X
Cycle 3 (Week 1)
Immediately prior to the first infusion of Cycle 3
X
X
X
Immediately after the end of the first infusion
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
X
X
48 hr (Day 3) after the end of the first infusion
X
X
72 hr (Day 4) after the end of the first infusion
X
X
168 hr (Day 8) after the end of the first infusion 
immediately (unless otherwise footnoted) prior to 
the second infusion of Cycle 3
X
X
X
Xf
Xg
Xe
Table is continued on the next page.

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Table 98.  Blood Collection Schedule (Part B - Cohorts 6b, 7b, and 8b)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
TropT
Bone
Cycle 3 (Week 2)
1 hr after the end of the second infusion of 
Cycle 3
X
2 hr after the end of the second infusion
X
4 hr after the end of the second infusion
X
24 hr (Day 2) after the end of the second 
infusion
X
48 hr (Day 3) after the end of the second 
infusion
X
72 hr (Day 4) after the end of the second 
infusion
X
168 hr (Day 8) after the end of the second 
infusion
X
Cycle 3 (Week 4)
Immediately prior to the third infusion of Cycle 3
X
X
Cycles 4-6i h
Prior to the last infusion of each cycle
X
X
X
Cycle 5
Immediately prior to the first infusion of Cycle 
5 (6 months after the first infusion of Cycle 1)
X
End of Therapy
At the End-of-Therapy visit
Xf
Xg
Follow-up
30-Day Follow-up visitj i
X
X
X
X
Xf
Xg
Abbreviations:  Bone = assessment of bone metabolism markers (CTX-I and P1NP); CK = creatine kinase; CTX-I = C-terminal 
cross-linking telopeptide of type I collagen; ECG = electrocardiogram; FC = flow cytometry analysis; IGx = immunogenicity; 
Iso = isoenzyme analysis; P1NP = procollagen type 1 N-terminal propeptide;
PD = pharmacodynamic markers; 
PK = pharmacokinetic(s); TropT = troponin (I or T) assessment; ULN = upper limit of normal.
a
It is understood that it may not be feasible to collect samples at precise intervals following the end of the infusions.  Every 
attempt should be made to collect each of these samples as close to the time point as possible.  The date and time of all PK 
samplings must be clearly and accurately recorded.
b
PK samples will be collected from all subjects.  The date and time of all samplings must be clearly and accurately recorded. 
The blood samples collected for PK will also be used for immunogenicity analyses.  For each specified time point, 1 tube 
(approximately 7.5 mL/tube) of blood is required to be drawn for any combination of PK or immunogenicity analyses.  As 
an example, if the timing of a PK sample should coincide with that of an immunogenicity sample, the same sample will 
suffice for these studies and the same total amount of blood (1 tube, approximately 7.5 mL/tube) will be collected.
c
Pretreatment sampling should be collected on the day of and immediately prior to the first infusion.
d
IGx, PD, FC, isoenzyme analysis, and bone metabolism markers:  Sample to be collected ≤7 days prior to the first infusion 
of Cycle 1.  Troponin (I or T) analysis:  Sample to be collected prior to the first infusion of Cycle 1 so that results are 
obtained before dosing.
e
Sample to be collected at any time ≤3 days prior to the infusion.  IMC-CS4 may be administered as planned while troponin 
(I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or physical examination.
f
Analysis to be performed only if serum enzymes are ≥2.5 × ULN at Week 5 of previous Ccycle 1.
g
Analysis to be performed only if serum CK levels are ≥2.5 × ULN at Week 5 of previous Ccycle 1.  IMC-CS4 may be 
administered as planned while troponin (I or T) results are pending, provided no cardiac symptoms have been revealed upon 
ECG or physical examination.
h
For subjects who proceed to Cycles 42 to 6, blood samples will be collected prior to the last infusion of each cycle.  In the 
event that a subject does not proceed to these cycles, these samples will not be collected.
i
A sample will be collected 30 days after last dose of investigational agent, regardless of duration of therapy.
Note:  If at any time a subject experiences an infusion-related reaction to IMC-CS4, all attempts will be made to obtain a blood 
sample for immunogenicity analysis as close to the onset of the event as possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken for immunogenicity testing may be used for PK analysis, in the setting of 
infusion-related reactions.

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8.3.  Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the 
Development Core Safety Information (DCSI) or in the IB and that the Investigator identifies as 
related to study drug or procedure.  The United States 21 CFR 312.32, the European Union 
Clinical Trial Directive 2001/20/EC, 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 regulatory regulations and the associated detailed guidances.
8.3 8.4 Safety Monitoring
The ImClone Sponsor CRP or designee will monitor safety data throughout the course of the 
study.
The ImClone Sponsor CRP or designee will review SAEs within time frames mandated by 
company procedures.  The ImClone Sponsor CRP or designee, will, as is appropriate, consult 
with the functionally independent Global Patient Safety therapeutic area physician or clinical 
research scientist (CRS), and periodically review trends and laboratory analytes.
If a subject experiences elevated ALT ≥5 × ULN and elevated total bilirubin ≥2 × ULN, clinical 
and laboratory monitoring should be initiated by the Investigator.  For subjects entering the study 
with ALT ≥3 × ULN, monitoring should be triggered at ALT ≥2 × baseline.  Details for hepatic 
monitoring depend upon the severity and persistence of observed laboratory test abnormalities.  
To ensure subject safety and comply with regulatory guidance, the Investigator is to consult with 
the ImClone Sponsor CRP regarding collection of specific recommended clinical information 
and follow-up laboratory tests.  Refer to Section 6.5 for a list of the hepatic monitoring tests to be 
performed.
8.4 8.5 Complaint Handling
9  Treatment-Related Adverse Events
Subjects will be closely monitored for treatment-related AEs, especially infusion-related 
reactions, immune-related adverse events (irAE), periorbital edema, and signs indicative of 

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hepatic impairment, leukocyte alterations, and inflammation.  Subjects will be evaluated for AEs 
at each visit and will be instructed to call their study physician to report any AEs between visits.
Adverse event collection will include verbatim term, onset and resolution dates, action taken, 
outcome, severity (NCI-CTCAE, Version 4.0 grade), relationship to the study therapy, and, if the 
event is serious, a clear indication of the seriousness.
9.1 IMC-CS4
9.1.1 Immune-Related Adverse Events
Symptoms occurring during or following infusion of investigational therapy will be defined 
according to the NCI-CTCAE, Version 4.0.
In the setting of symptoms consistent with irAE occurring following infusion of investigational 
therapy, investigators are encouraged to refer to Table 10 as a guideline for the management of 
potential toxicities encountered with immuno-oncology agents.  Due to the potential of rapid and 
serious sequelae associated with irAEs, early intervention with immunomodulatory agents as 
indicated is encouraged, concurrent with further diagnostic medical evaluations for possible non-
immune-related causes of AEs.  Table 10 is a guideline for the management of irAEs; local 
standards may supersede recommendations when deemed appropriate by the Investigator.

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Table 10.  Guidelines for the Management of Potential Toxicities Encountered with Immuno-Oncology Agents
System Organ 
Class
Adverse Event
CTCAE, Version 4.0 Grade (if applicable) and/or Symptomsa
Treatment Planb
Grade
Symptoms
Endocrine
Thyroid issues
Asymptomatic, with TSH <0.5 × LLN or >2 × ULN
Continue drug.
Symptomatic
Continue drug.  Administer thyroid replacement.
Hypotension, altered mental 
status, headache, fatigue
Endocrine issues aside from thyroid (for example, 
hypophysitis)
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Resume drug when symptoms resolve and are 
stable on hormone replacement.  In case of adrenal crisis, 
administer stress-dose steroids.
Gastrointestinal
Diarrhea, abdominal pain, 
blood in stool
2
Withhold drug for 1 wk.  Administer antidiarrheal 
medication and check etiology.  Resume drug when 
symptoms resolve to Grade ≤1.
If >5 days’ duration despite antidiarrheals, begin steroids 
(0.5 mg/kg/d prednisone); can resume drug during taper 
when symptoms resolve to Grade ≤1.
Diarrhea, ileus, perforation
≥3
Permanently discontinue drug.  Administer steroids (1-2 
mg/kg/d prednisone), except if the possibility of perforation 
exists.
If >3 days’ duration despite steroids, also administer 
nonsteroidal immunosuppressive.
Pancreatitis
1-2
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Can resume drug during taper.
≥3
Permanently discontinue drug.

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Table 10.  Guidelines for the Management of Potential Toxicities Encountered with Immuno-Oncology Agents
System Organ 
Class
Adverse Event
CTCAE, Version 4.0 Grade (if applicable) and/or Symptomsa
Treatment Planb
Grade
Symptoms
Hepatobiliary
Transaminitis, elevated 
bilirubin
Subjects with baseline AST or ALT ≤2.5 × ULN:
AST or ALT >5 × ULN but ≤7.5 × ULN
and
total bilirubin ≤ULN
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Resume drug when AST or ALT ≤5 × ULN.
Subjects with baseline AST or ALT >2.5 × ULN 
and ≤5 × ULN:
AST or ALT >7.5 × but ≤10 × ULN
and
total bilirubin ≤ ULN
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Resume drug when AST or ALT ≤7.5 × ULN.
Subjects with baseline AST or ALT ≤2.5 × ULN:
AST or ALT >7.5 × ULN
or
total bilirubin > 3× ULN
Permanently discontinue drug.  Administer steroids (1-2 
mg/kg/d prednisone).
Subjects with baseline AST or ALT >2.5 × ULN 
and ≤5 × ULN:
AST or ALT >10 × ULN
or
total bilirubin >3× ULN
Permanently discontinue drug.  Administer steroids (1-2 
mg/kg/d prednisone).
Nervous
Weakness, paresthesia (for 
example, Guillain-Barré 
syndrome, myasthenia gravis)
No impact on activities of daily living (ADL).
Withhold drug.  Resume drug when symptoms resolve.
Impact on ADL.
Withhold drug.  Administer appropriate medical 
intervention and steroids (1-2 mg/kg/d prednisone).  Can 
resume drug during taper.
Respiratory
Dyspnea, hypoxia, 
pneumonitis
1
Consider to withhold drug.  Resume drug when stable.
2
mild to mild-to-moderate symptoms
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Can resume drug during taper.
≥3
Severe
Permanently discontinue drug.  Administer steroids (1-2 
mg/kg/d prednisone).

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Table 10.  Guidelines for the Management of Potential Toxicities Encountered with Immuno-Oncology Agents
System Organ 
Class
Adverse Event
CTCAE, Version 4.0 Grade (if applicable) and/or Symptomsa
Treatment Planb
Grade
Symptoms
Renal and 
urinary
Elevated creatinine, decreased 
urine output, blood in urine, 
edema
1
<1.5 × baseline
Continue drug.
2-3
>1.5 × ULN but <6 × ULN
or
>1.5 × baseline
Withhold drug.  Administer steroids (1- 2 mg/kg/d 
prednisone).
If symptoms resolve to Grade ≤1, taper steroids over 1 
month.  Can resume drug during taper.
4
>6 × ULN
Permanently discontinue drug.  Administer steroids (1-2 
mg/kg/d prednisone).
Skin
Rash, pruritus
≤50% skin affected
Withhold drug.  If symptoms persist or worsen after 1 wk, 
administer topical or systemic steroids.
Resume drug if rash improves to mild (localized) and 
steroid dose <7.5 mg.
Stevens-Johnson syndrome, toxic epidermal 
necrolysis, necrosis, bullous or hemorrhagic lesions
Permanently discontinue drug.  Begin steroids (1-2 mg/kg/d 
prednisone).
Abbreviations:  ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse 
Events; I.V. = intravenous(ly); LLN = lower limit of normal; TSH = thyroid-stimulating hormone; ULN = upper limit of normal.
a
If definition of grade not specified, use CTCAE, Version 4.0 definition.
b
Treatment plan should always include a thorough workup of the issue to rule out other potential etiologies.
Note regarding steroids:  Steroids should be tapered over 1 month after symptoms have resolved; if withheld drug may be resumed (that is, not permanently discontinued), it can be 
resumed only after taper has begun.  Other steroid options (besides those shown in this table) may be administered at equivalent doses.  For severe adverse events, administration 
of I.V. steroids is recommended.  In the case of adrenal crisis, mineralocorticoid should be administered in addition to steroids.

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9.1.1 9.1.2 IMC-CS4 Infusion-Related Reactions
In the setting of symptoms occurring during or following infusion of investigational therapy, 
Iinvestigators are encouraged to use the AE term “infusion-related reaction” and any additional 
terms (including those not listed here) that best describe the event.
Consistent with usual medical practice, selected parenteral medications may be utilized for 
Grade 2 allergic/hypersensitivity reaction as detailed below.  The SponsorImClone CRP should 
be contacted immediately if questions arise concerning the grade of the reaction.  The following 
are treatment guidelines for IMC-CS4 infusion-related reactions:
10.1.1 During Cycle 1
No IMC-CS4 dose reductions are were permitted for any subject (in Cohort 1 or 2) following a 
DLT.  If a subject (in Cohort 1 or 2) experienceds a DLT during Cycle 1, IMC-CS4 was must be
permanently discontinued.
If benefitting from treatment (that is, no disease progression or other withdrawal criteria), any 
subject in Cohort 3 and beyond who experiences a DLT may continue to receive IMC-CS4 upon 
agreement of the Sponsor and according to the dose reduction guidelines for this study 
(Table 12).
In the setting of non-life-threatening reversible Grade ≤3 IMC-CS4-related toxicities in Cycle 1 
that do not meet the definition of a DLT, IMC-CS4 may be held (if appropriate, in the opinion of 
the Investigator and upon agreement with the Sponsor) for a maximum of 3 weeks, until 
resolution to baseline or improvement to Grade ≤<2.  Upon resolution to baseline or 
improvement to Grade ≤<2, IMC-CS4 may be administered at a reduced dose (according to
Table 12) beginning with Cycle 2, if appropriate, in the opinion of the Investigator and upon 
agreement with the Sponsor (no dose reductions are permitted during Cycle 1 [for subjects in 
Cohort 1 or 2]; subjects [in Cohort 1 or 2] who would require dose reductions during Cycle 1 
must be discontinued).  If toxicity does not resolve to baseline or improve to Grade ≤<2 within 3 
weeks following the last administered dose, IMC-CS4 should be permanently discontinued.

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10.1.2 After Cycle 1
Dose reductions, if required during Cycle 2 or after, in the context of IMC-CS4-related toxicity, 
may be implemented according to the guidelines in Table 12.  Any individual subject (including 
those experiencing an event that occurred after the DLT assessment period that otherwise would 
have been considered a DLT) may be dose reduced a maximum of 2 times during the course of 
the study (except as noted in Table 12; for example, subjects in Cohort 3 are only permitted to 
have one dose reduction).  Once a subject has had a dose reduction (has started a new cycle at the 
reduced dose), all subsequent infusions will be at the reduced dose level; there will be no 
resumption to prior dose level(s).  Any subject experiencing toxicity that would necessitate more 
than 2 dose reductions must discontinue treatment.  Dose reductions must be confirmed by the 
Sponsor.
Any subject who experiences a Grade 4 toxicity after Cycle 1 may continue to receive study 
treatment only if agreed upon by the Investigator and the ImClone Sponsor CRP and according 
to the dose reduction guidelines for this study (Table 12).
Table 12.  General Dose Reduction Guidelines
Cohort
Starting Dose Level and 
Schedule
First Reduction
Second Reduction
Part A Only
1
2.5 mg/kg (qw)
Discontinue
Discontinue
2
0.3 mg/kg (qw)
Discontinue
Discontinue
3
0.6 mg/kg (qw)
0.3 mg/kg (qw)
Discontinue
4
1.25 mg/kg (q2w)
0.6 mg/kg (qw)
0.3 mg/kg (qw)
5
1.25 mg/kg (qw)
1.25 mg/kg (q2w)
0.6 mg/kg (qw)
Part B Only
6a
2.5 100 mg/kg (q2w)
1.25 75 mg/kg (qw)
1.25 50 mg/kg (q2w)
6b
100 mg (Weeks 1, 2, 4, and 5)
75 mg (Weeks 1, 2, 4, and 5)
50 mg (Weeks 1, 2, 4, and 5)
6c
75 mg (qw)
50 mg (qw)
40 mg (qw)
7a
2.5 150 mg/kg (Weeks 1, 2, 4, 
and 5qw)
2.5 125 mg/kg (q2w)
1.25 100 mg/kg (qw)
7b
150 mg (Weeks 1, 2, 4, and 5)
125 mg (Weeks 1, 2, 4, and 5)
100 mg (Weeks 1, 2, 4, and 5)
7c
125 mg (qw)
100 mg (qw)
75 mg (qw)
8a
3.75 200 mg/kg (Weeks 1, 2, 4, 
and 5qw)
2.5 175 mg/kg (Weeks 1, 2, 4, 
and 5qw)
2.5 150 mg/kg (q2w)
8b
200 mg (Weeks 1, 2, 4, and 5)
175 mg (Weeks 1, 2, 4, and 5)
150 mg (Weeks 1, 2, 4, and 5)
8c
175 mg (qw)
150 mg (qw)
125 mg (qw)
Abbreviations:  qw = weekly; q2w = every 2 weeks.

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10.6.1 Granulocyte Colony-Stimulating Factors
Although neutropenia is not an expected side effect of IMC-CS4, the use of granulocyte colony-
stimulating factors (G-CSFs) is permitted during investigational therapy, based on American 
Society of Clinical Oncology (ASCO) guidelines (Smith et al. 20062015).  G-CSF or similar 
agents are strongly recommended following Grade 3 or 4 neutropenia lasting more than 5 days 
duration or following any incidence of febrile neutropenia (ANC <1000/µL with temperature 
≥38.5°C, which would constitute a DLT in the present study [see Section 4.1.4]).
10.6.5 Premedication for IMC-CS4
Premedication such as antihistamines or steroids for the prophylaxis of hypersensitivity is not 
recommended to be administered prior to the first infusion of IMC-CS4 administration.  
Premedication must be implemented in the setting of a prior Grade 1-2 IMC-CS4-related 
infusion-related reaction and is detailed in Section 9.1.2.
11 Criteria for Tumor Response Evaluation
Study evaluations will take place in accordance with the flow chart in Section 7.6.
Subjects will be evaluated for response according to RECIST 1.1 guidelines (Eisenhauer et al. 
2009).  Radiographic assessment of tumor response will be performed at the end of the initial 
6-week cycle, and the end of every subsequent cycle.  However, if a DLT is observed in Cycle 1
in a subject who is benefitting from treatment, and Cycle 2 dosing is may be initiated within 4 
weeks of Cycle 1, Day 1, with Sponsor approval; in this case, no radiographic disease assessment 
is required prior to dosing in Cycle 2.
12.1 General Considerations
Statistical analysis of this study will be the responsibility of the Sponsor.
The interpretation of the study results will be the responsibility of the investigators with the Lilly 
CRP or CRS, pharmacokineticist, and statistician.  The CRP or CRS and statistician will also be 
responsible for the appropriate conduct of an internal review for both the final study report and 
any study-related material to be authorized by Lilly for publication.
The analyses for this study will be descriptive, except for possible exploratory analyses as 
deemed appropriate.  Data analyses will be provided by dose levels and for all subjects 

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combined, wherever appropriate.  For continuous variables, summary statistics will include 
number of subjects (N), mean, median, standard deviation, minimum, and maximum.  
Categorical endpoints will be summarized using N, frequency, and percentages.  Missing data 
will not be imputed.  Exploratory analyses of the data that are not described in the protocol will 
be conducted as deemed appropriate.  A detailed description of data analyses will be provided in 
a separate statistical analysis plan document for this study.
This is a Phase 1 study with an open-label, dose-escalation design.  Subjects will be enrolled into 
cohorts sequentially without randomization to dose level.  During dose escalation, the total 
sample size per cohort will be guided by the standard oncology 3+3 method and determined by 
the occurrences of DLTs for the treated subjects.  The total sample size for Parts A and B is 
estimated to be approximately 72 treated subjects.  In Part A, the sample size is estimated to be 
approximately 30 subjects.  In Part B, the sample size is estimated to be approximately 9 to 42 
subjects.
12.3 Subject Disposition
Additional summary of subject participation flow will be performed for the purpose of fulfilling 
the Clinical Trial Registry (CTR) requirements.  A participant flow will describe how many 
enrolled subjects completed the study, and for those who did not, the frequency of each reason 
for not completing.
12.6 Analyses of Antitumor Response
Radiographic assessment of tumor response will be performed at the end of the initial 6-week 
cycle and the end of every subsequent cycle.  However, if a DLT is observed in Cycle 1 in a 
subject who is benefitting from treatment, and Cycle 2 dosing is may be initiated within 4 weeks 
of Cycle 1, Day 1, with Sponsor approval; in this case, no radiographic disease assessment is 
required prior to dosing in Cycle 2.  Overall response rate (number of subjects who achieve a 
best response of CR or PR during therapy divided by the total number of subjects treated) and 
disease control rate (number of subjects who achieve a best response of CR or PR or SD during 
therapy divided by the total number of subjects treated) will be presented for each cohort of 
subjects.  Tumor response data will be summarized, if appropriate.

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12.7.2 Pharmacodynamic Assessments
Pharmacodynamic analyses will be descriptive, and correlations to safety and/or efficacy will be 
performed as appropriate.  Those biomarkers collected from different types of tissues or assays 
will be analyzed separately.  Whether a subject is available or willing to provide tissue samples 
may be considered as a potential confounding variable for exploratory pharmacodynamic 
analysis.
12.8 Data Safety Monitoring Plan
In order to track and clearly document/record the occurrence of DLTs and identify the decisions 
made regarding dose escalation, the study investigators, the ImClone Sponsor CRP, and other 
members of the study team, as appropriate, will meet at specific times throughout this clinical 
study to review subject safety data.  They will make the determination regarding dose escalation 
based upon their review of the safety/tolerability data and upon availability the PK data from the 
previous cohorts.  At a minimum, they will meet:

If there are 2 subjects with DLTs within a single cohort during the DLT assessment 
period;

At the completion of each dose cohort, in order to determine if dose escalation will 
proceed (as described in Section 4.1).  This review will include safety data collected to 
date, across all dose cohorts;

After the RP2D is determined, to determine whether dose escalation should proceed; and

At least quarterly.
The aforementioned team will determine if the number of subjects experiencing DLTs, as well as 
any events that occurred after the DLT assessment period that otherwise would have been 
considered DLTs, exceeds that expected with IMC-CS4 and recommend action, if necessary.  
The recommended actions may include protocol modification, termination, or additional safety 
review at specified time points.  The ImClone Sponsor CRP may perform additional periodic 
reviews of relevant safety data (such as a review of Council for International Organizations of 
Medical Sciences [CIOMS] reports); these evaluations will be documented according to the trial-
level safety review plan (a separate, study-specific document that will further detail the process).

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13.1 Organizational Structure of the Study
The study sponsor, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, may 
delegate certain tasks to designees, including a contract research organization or other third-party 
vendor.
13.4 Compliance with the Protocol and Protocol Revisions
The Investigator must comply with all requirements of the protocol.  If a situation occurs that 
requires a temporary departure from the protocol, the Investigator or other physician in 
attendance must contact the ImClone Sponsor CRP as soon as possible to discuss the situation 
and agree on an appropriate course of action.  The Investigator will describe the departure from 
the protocol and the circumstances requiring it on the applicable subjects’ eCRFs and will notify 
the IRB/aEC as appropriate.
13.11 Publication and Disclosure Policy
Lilly’s authorship criteria are based on the International Committee of Medical Journal Editors 
(ICMJE) Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical Journals (www.ICMJE.org, updated August 2013):
1. Substantial contributions to conception and design of the work, or the acquisition, analysis, or 
interpretation of data for the work
2. Drafting the article or revising it critically for important intellectual content
3. Final approval of the version to be published 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
NOTE:  Authors must meet conditions 1, 2, 3, and 4.
The Sponsor’s authorship criteria are based on the International Committee of Medical Journal 
Editors (ICMJE) Uniform Requirements for Manuscripts Submitted to Biomedical Journals
(ICMJE 2010):
Substantial contributions to conception and design, or to acquisition of data, or to analysis and 
interpretation of data;

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Drafting the article or revising it critically for important intellectual content;
Final approval of the version to be published.
Note:  Authors must meet conditions 1, 2, and 3.
14 References
[FDA] United States Food and Drug Administration. Guidance for Industry: Bioanalytical 
Methods Validation. May 2001. Available at: http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM070107.pdf.  Accessed August 
28, 2013.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 update of 
recommendations for the use of white blood cell growth factors: an evidence-based clinical 
practice guideline. J Clin Oncol. 2006;24:3187-3205.
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO. 
Recommendations for the use of WBC growth factors: American Society of Clinical Oncology 
Clinical Practice Guideline Update. J Clin Oncol. 2015 Jul 13. pii: JCO.2015.62.3488. [Epub 
ahead of print].

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SYNOPSIS
Sponsor:
Eli Lilly and Company
Name of Finished Product:
IMC-CS4 (LY3022855)
Name of Active Ingredient:
IMC-CS4, a recombinant human immunoglobulin G, subclass 1 (IgG1) monoclonal antibody targeted to 
the colony-stimulating factor-1 receptor (CSF-1R).
Study Title:
Phase 1 Study of IMC-CS4, a Monoclonal Antibody Targeted to the CSF-1 Receptor (CSF-1R) in 
Subjects With Advanced Solid Tumors Refractory to Standard Therapy or for Which No Standard 
Therapy Is Available
Study Number:
IMCL CP24-1001 (I5F-IE-JSCA)
Study Phase:
Phase 1
Primary Objectives:
The primary objectives of this study are to establish the safety profile and characterize the 
pharmacokinetic (PK) profile of IMC-CS4 in the treatment of subjects with advanced solid tumors
refractory to standard therapy or for which no standard therapy is available.
Secondary Objectives:
The secondary objectives of this study are:

Part A only:  To define the recommended Phase 2 dose (RP2D) using weight-based dosing;

Part B only:  To define the RP2D using non-weight-based dosing;

To characterize the pharmacodynamic profile of IMC-CS4 on circulating levels of CSF-1; and

To assess the development of antibodies against IMC-CS4 (immunogenicity).
Exploratory Objectives:
The exploratory objectives of this study are:

To assess pharmacodynamic response markers including, but not limited to, interleukin-34 
(IL-34) and MCP-1;

To assess the impact of IMC-CS4 monotherapy on lactate dehydrogenase (LDH), creatine kinase 
(CK), and alkaline phosphatase (AP) isoenzymes;

To assess the pharmacodynamic impact of IMC-CS4 on selected cellular and molecular markers 
to establish a potential correlation with safety and antitumor activity;

To assess the pharmacodynamic impact of IMC-CS4 on various components of the monocyte-
macrophage system in hematologic or tissue specimens;

To assess the impact of IMC-CS4 monotherapy on bone metabolism; and

To assess the antitumor activity of IMC-CS4 as monotherapy in the treatment of advanced solid 
tumors.

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Study Design:
This open-label, dose-escalation, Phase 1 study will enroll (that is, assign to a dose cohort) approximately 
72 subjects to 2 parts – Parts A and B.  Part A consisted of dose escalation of IMC-CS4 using weight-
based dosing; Part B will consist of dose escalation of IMC-CS4 using non-weight-based dosing.  The 
actual enrollment will depend on the number of dose-limiting toxicities (DLTs) observed and the resultant 
size of each cohort.
Dose cohorts, including dose and dosing schedule, are summarized in the table below.  For each cohort, 
one cycle is 6 weeks.  In each cohort, subjects will receive IMC-CS4 by intravenous (I.V.) infusion (with 
an observation period for weekly [qw] and every-2-week [q2w] cohorts in Cycle 1 only, as described in 
the following table).
Dose Cohort Assignment
Cohort
Dose Level
Dosing Schedulea
Cycle 1
Observation Periodb
Number of Infusions
Part A (weight-based dosing)
1
2.5 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
2
0.3 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
3
0.6 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
4
1.25 mg/kg
q2w
3 weeks (Weeks 4-6)
Cycle 1:  2
Subsequent cycles:  3
5
1.25 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
Part B (non-weight-based dosing)
6a
100 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
6bc,d
100 mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4
6cc
75 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
7a
150 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
7bc,d
150 mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4
7cc
125 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
8a
200 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
8bc,d
200 mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4
8cc
175 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
Abbreviations:  aEC = approving Ethics Committee; DLT = dose-limiting toxicity; IRB = Institutional Review Board; 
PK = pharmacokinetic(s); qw = weekly; q2w = every 2 weeks.
a – At the highest dose level where major toxicity is observed and that requires a longer recovery period between infusions, 
a change in the periodicity of dosing (that is, other dosing schedules based on safety and PK considerations) will be agreed 
upon with the Investigator and communicated to IRBs/aECs.

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b – Observation following the fourth infusion in Cohorts 1, 2, 3, and 5 (qw dosing) and the second infusion in Cohort 4 (q2w 
dosing) in Cycle 1 only.  No Cycle 1 observation period for Cohorts 6a, 6c, 7a, 7c, 8a, or 8c.  Weeks 3 and 6 of all cycles are 
rest weeks in Cohorts 6b, 7b, and 8b (qw dosing on Weeks 1, 2, 4, and 5).
c – Concurrently enroll to Cohorts 6b/7b/8b and 6c/7c/8c, should ≥2 subjects in Cohort 6a/7a/8a experience DLT events.
d – For all cycles:  Infusions on Weeks 1, 2, 4, and 5, and rest on Weeks 3 and 6.
Following the first cycle of therapy (Cycle 1), subjects may continue to receive IMC-CS4 at the same 
dose and schedule until there is unequivocal evidence of disease progression or other withdrawal criteria 
are met.  Radiographically confirmed disease progression (that is, numerical disease progression, per 
Response Evaluation Criteria in Solid Tumors [RECIST]) only is not sufficient to discontinue treatment
(refer to “Duration of Treatment” section in this Synopsis for further details).  Radiographic assessment of 
tumor response will be performed at the end of the initial cycle (that is, prior to administration of any 
study therapy in Cycle 2) and the end of every subsequent cycle; radiographic assessment should be 
performed prior to the start of a cycle so that results are available before the subject receives a new cycle 
of treatment.  However, if a DLT is observed in Cycle 1 in a subject who is benefitting from treatment, 
Cycle 2 dosing may be initiated within 4 weeks of Cycle 1, Day 1, with Sponsor approval; in this case, no 
radiographic disease assessment is required prior to dosing in Cycle 2.
Each cohort will initially enroll at least 3 subjects.
For all cohorts, all subjects who complete the first treatment cycle (that is, receive all scheduled 
treatments for Cycle 1 and complete the observation period, as needed) or discontinue therapy due to a 
DLT will be considered evaluable subjects and will be included in the DLT analyses.  Subjects who do 
not complete Cycle 1 for reasons other than a DLT will be replaced for the analysis until the cohort 
includes 3 evaluable subjects (or 6 evaluable subjects in case of one DLT in the first 3 subjects); however,
if benefitting from treatment (that is, no disease progression or other withdrawal criteria), any subject in 
Cohort 3 and beyond who experiences a DLT may continue to receive IMC-CS4 upon agreement of the 
Sponsor and according to the dose reduction guidelines for this study.
If the first 3 evaluable subjects in a cohort complete Cycle 1 of therapy with no DLT, dose escalation to 
the next cohort may proceed.  If 1 of the first 3 evaluable subjects in a cohort experiences a DLT, 
enrollment will proceed until there are at least 6 evaluable subjects in that cohort.  If no additional subject
experiences a DLT, dose escalation may proceed.  If 2 or more subjects experience a DLT in a cohort 
(whether in the initial 3-subject cohort or following expansion to 6 subjects), dose escalation will not 
occur and the recommended Phase 2 dose (RP2D) will be determined according to the instructions that 
follow.
Each subsequent cohort will be opened upon completion of the previous cohort.  A safety review meeting 
will be held prior to each dose escalation.
The provisional RP2D will be defined as the dose level at which pharmacodynamic effects are observed 
in the absence of clinically relevant toxic effects (that is, measurable pharmacodynamic effects with no 
DLT in the first 3 subjects or ≤1 DLT in the first 6 subjects enrolled at that dose level).  After discussion 
with the Investigator, the Sponsor may choose to enroll additional subjects at the RP2D.
A DLT is defined as any IMC-CS4-related adverse event (AE) that occurs during Cycle 1 and does not 
improve to Grade ≤2 (unless stated otherwise), despite medical management, including steroids (if 
applicable) within 7 days of documented occurrence.  The following are considered DLTs:

Grade 4 neutropenia lasting ≥7 days;

Grade 3 or 4 neutropenia complicated by fever ≥38.0°C or infection;

Grade 4 thrombocytopenia;

Grade 3 thrombocytopenia complicated by hemorrhage;

Grade 3 or 4 anemia;

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
Grade 3 or 4 nonhematologic toxicity.  Exceptions maybe be made for the following, if agreed 
upon by the Sponsor AND the Investigator:
o
Grade ≥3 liver function test (LFT) abnormality, such as alkaline phosphatase, gamma 
glutamyl transferase (GGT), aspartate aminotransferase (AST), and alanine 
aminotransferase (ALT), without evidence of hepatic injury
o
Transient Grade ≥2 bilirubin elevation in the presence of known liver metastases lasting 
≤7 days
o
Laboratory abnormalities that are reversible to Grade ≤2 or baseline levels within 7 days 
after initial documentation or that are deemed not clinically significant
o
Grade 3 elevation of CK WITHOUT elevation in serum and urine myoglobin is NOT
considered a DLT.
Throughout this protocol, “days” refers to calendar days, unless otherwise indicated.
Study Population:
It is anticipated that approximately 72 subjects will be enrolled in approximately 6 study sites in the 
United States.
Inclusion/Exclusion Criteria:
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study:
1. The subject has a histologic or cytologic confirmation of advanced solid tumors that are 
refractory to standard therapy or for which no standard therapy is available.
2.
The subject has measurable or nonmeasurable disease according to the Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST 1.1).
3.
The subject has resolution to Grade ≤1 by the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE), Version 4.03, of all clinically significant toxic effects 
of prior chemotherapy, surgery, radiotherapy, or hormonal therapy (with the exception of 
alopecia).
4.
The subject has an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 
0-2.
5.
The subject has adequate hematologic function, as defined by:

Absolute neutrophil count (ANC) ≥1500/L;

Hemoglobin ≥9 g/dL (5.58 mmol/L); and

Platelets ≥100,000/L.
6.
The subject has adequate hepatic function, as defined by:

Bilirubin ≤1.5 times the upper limit of normal (× ULN); and

AST and ALT ≤2.5 × ULN (or ≤5 × ULN in the presence of known liver metastases).
7.
The subject has adequate renal function as defined by creatinine clearance ≥50 mL/min measured 
either by 24-hour urine collection or calculated using the Cockcroft-Gault formula.
8.
The subject must have adequate coagulation function as defined by:

International Normalized Ratio (INR) ≤1.5; and

Prothrombin time (PT) and partial thromboplastin time (PTT) or activated PTT ≤1.5 × ULN.
9.
The subject has CK ≤ULN.
10. The subject has a life expectancy >3 months.
11. The subject is 18 years of age or older.
12. The subject (women of childbearing potential [WOCBP] or fertile men with partners of 
childbearing potential) agrees to use adequate contraception during the study period and for 
12 weeks after the last dose of study therapy.
13. The subject has provided signed informed consent.

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14. The subject is accessible for treatment and follow-up; subjects enrolled in this trial must be 
treated at the study center.
15. The subject must undergo mandatory biopsies, including one pretreatment and one posttreatment 
tumor biopsy procedure.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. The subject has experienced acute pathologic fracture or spinal cord compression within 28 days 
prior to first dose of study therapy.
2.
The subject has a known hypersensitivity to monoclonal antibodies or to agents of similar 
biologic composition as IMC-CS4.
3.
The subject has received treatment with any monoclonal antibodies within 4 weeks prior to first
dose of study therapy.
4.
The subject has undergone a major surgical procedure, open biopsy, radiofrequency ablation, or 
has experienced a significant traumatic injury within 28 days prior to enrollment.
5.
The subject has a history of another primary cancer, with the exception of: a) curatively resected 
non-melanomatous skin cancer; b) curatively treated cervical carcinoma in situ; or c) other 
primary solid tumor treated with curative intent, no known active disease present, and no 
treatment administered during the last 3 years prior to study entry.
6.
The subject is receiving concurrent treatment with other anticancer therapy, including other 
chemotherapy, immunotherapy, chemoembolization, targeted therapy, or any investigational 
agent within 4 weeks prior to study entry, or radiotherapy within 2 weeks prior to study entry.  An 
exception is that subjects with metastatic breast or prostate cancer who have been on a stable dose 
(≥28 days) of an approved hormonal agent will not be excluded (ie, they will be eligible).  
Subjects with breast cancer may also continue with concurrent human epidermal growth factor 
receptor 2 (HER2)-directed therapy.
7.
The subject has known muscle damage due to a primary, traumatic, or other muscle disease.
8.
The subject is known to be human immunodeficiency virus (HIV) seropositive.
9.
The subject has a known and uncontrolled infection.
10. The subject is known to have active tuberculosis, leishmaniasis, or listeriosis.
11. The subject has a history of and/or current: symptomatic coronary artery disease, confirmed left 
ventricular ejection fraction (LVEF) ≤50% or any cardiac insufficiency > New York Heart 
Association (NYHA) class II,* uncontrolled hypertension, or serious cardiac arrhythmia (well-
controlled atrial fibrillation is permitted).
12. Subjects with known history or clinical or laboratory evidence of liver disease.  Notably, subjects
with any of the following liver function abnormalities will be excluded:
a
Cirrhosis with evidence of portal hypertension or bridging fibrosis
b
Alcoholic hepatitis
c
Esophageal varices
d
A history of bleeding esophageal varices
e
Hepatic encephalopathy
f
Ascites related to portal hypertension
g
Chronic viral hepatitis with total serum bilirubin >3 mg/dL
13. The subject has active bleeding.
14. The subject has leukemia or lymphoma.
15. The subject has a known psychiatric illness/social situation (including alcohol and/or drug 
dependency) that would, in the Investigator’s opinion, limit compliance with study requirements.
16. The subject has known or suspected primary brain or leptomeningeal tumors or metastases 

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(subjects with a history of brain metastases must have received definitive surgery or radiotherapy, 
be clinically stable, and may not be taking steroids; subjects receiving anticonvulsants are 
eligible).
17. The subject is pregnant (confirmed by serum beta human chorionic gonadotropin [β-hCG] test 
performed within 7 days prior to first dose of study therapy) or breastfeeding.
18. The subject has received a solid organ transplant.
19. The subject has any other serious uncontrolled medical disorders, which, in the opinion of the 
Investigator, would compromise the subject’s safety or the ability of the subject to participate in 
the study.
*NYHA Congestive Heart Failure Classification (NYHA 1994):
Class I – Patients with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II – Patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion.
Class III – Patients with marked limitation of activity; they are comfortable only at rest.
Class IV – Patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and 
symptoms occur at rest.
Test Product, Dose, and Mode of Administration:
IMC-CS4 drug product (DP) is a sterile, preservative-free injection for I.V. use of IMC-CS4 drug 
substance (DS) formulated in a histidine buffer at a concentration of 5 mg/mL (100 mg/20-mL vial), 
administered as a weekly (qw) or every-2-week (q2w) I.V. infusion at the dose specified for each cohort.  
IMC-CS4 will be infused over a period of 30 minutes at infusion rates that will not exceed 25 mg/minute.
Reference Therapy, Dose, and Mode of Administration:
Not applicable.
Duration of Treatment:
All subjects should continue to receive treatment until there is unequivocal evidence of progressive 
disease (PD) (per immune-related response criteria), toxicity requiring cessation, protocol noncompliance
(in the opinion of the Investigator or Sponsor), withdrawal of consent by the subject, or until other 
withdrawal criteria are met.  Radiographically confirmed disease progression (that is, numerical disease 
progression, per RECIST) only is not sufficient to discontinue treatment.  Subjects with disease 
progression (per RECIST) but without clinical deterioration at Week 6 (the first response assessment) 
may continue to receive IMC-CS4, at the discretion of the Investigator; study treatment will be 
discontinued if, at the next disease assessment (performed at least 4 weeks later), disease progression is 
unequivocal (that is, radiographically confirmed disease progression alone is sufficient).  On the other 
hand, subjects with disease progression (per RECIST) and with clinical deterioration (unequivocal) at 
Week 6 (the first response assessment) will be discontinued from study treatment.
Safety Assessments:
The safety and tolerability of study drug will be assessed based on reported AEs (including any DLTs), 
serious adverse events (SAEs), and laboratory tests.  Adverse events will be summarized using the 
Medical Dictionary for Regulatory Activities (MedDRA®) dictionary and graded using NCI-CTCAE, 
Version 4.0.  Clinical laboratory values will be classified using NCI-CTCAE, Version 4.0 criteria.
Efficacy Assessments:
Radiographic assessment of disease response and tumor assessments, according to RECIST 1.1, will be 
performed at baseline and at the end of every cycle.  Radiographic assessment should be performed prior 
to the start of a cycle so that results are available before the subject receives a new cycle of treatment.  
However, if a DLT is observed in Cycle 1 in a subject who is benefitting from treatment, Cycle 2 dosing 
may be initiated within 4 weeks of Cycle 1, Day 1, with Sponsor approval; in this case, no radiographic 
disease assessment is required prior to dosing in Cycle 2.
Pharmacokinetic Assessments:
Pharmacokinetic assessments will be performed in order to assess the levels of IMC-CS4 in serum.  
Parameters to be reported may include, but not be limited to, maximum serum concentration (Cmax), 

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trough serum concentration (Cmin), area under the serum concentration versus time curve (AUC), half-life 
(t1/2), clearance (Cl), and volume at steady state (Vss) of IMC-CS4.
Pharmacodynamic Assessments:
Blood and tissue samples will be taken.  Pharmacodynamic analyses may include, but are not limited to,
the following parameters:

Levels of potential circulating and tissue pharmacodynamic markers, including but not limited to,
CSF-1, IL-34, MCP-1, and macrophage-specific markers (for example, CD68 and CD163);

Characterization of blood monocyte subsets by flow cytometry (CD14, CD16, and HLA/DR); and

Serum markers of bone metabolism (C-terminal cross-linking telopeptide of type I collagen 
[CTX-I] and procollagen type 1 N-terminal propeptide [P1NP]).
Immunogenicity Assessments:
Blood samples for the assessment of antibodies against IMC-CS4 will be collected for all study subjects
at specified time points throughout the study.
Other Serum Assessments:
Blood samples may also be drawn for analyses of LDH, CK, and AP isoenzymes.
Tissue Assessments:
To assess the pharmacodynamic effect of IMC-CS4 administration on tumor-associated myeloid cells, 
including macrophages, all subjects enrolled in Cohort 2 and beyond will undergo tumor biopsies before 
study enrollment.  For these cohorts, investigators will carry out a tumor (core needle or excisional) 
biopsy (attempt to obtain at least 3 cores) before starting the treatment and at the end of Cycle 1 (to be 
done in the week prior to Cycle 2, at the same time as tumor evaluation), if the subject’s condition allows 
it. If an enrolled subject undergoes a pretreatment tumor biopsy but is unable to tolerate a posttreatment 
tumor biopsy, then a skin punch biopsy will be acceptable.  At the time of disease progression, the 
Investigator will also perform a tumor biopsy if the subject consents to it and if the subject’s condition 
allows it.
Statistical Methods:
All enrolled subjects who received at least one dose of IMC-CS4 will be included in the safety 
population.  Subjects who complete the initial cycle of therapy or experience a DLT will be included in 
the DLT population.  The DLT population will be used for the determination of the RP2D, including 
evaluation of DLTs.  All other variables (including demographic and baseline subject characteristics, 
efficacy and safety variables) will be analyzed using the safety population.
Demographic and baseline subject characteristics will be summarized using descriptive statistics.
The number of subjects who experience any DLT will be presented based on all DLT-evaluable subjects
(DLT population).
Adverse events will be summarized by MedDRA System Organ Class and Preferred Term, classified 
from verbatim terms.  The incidence and percentage of subjects with at least one occurrence of a 
Preferred Term will be included, according to the most severe NCI-CTCAE, Version 4.0 grade.  Causality 
(relationship to study drug) will be summarized separately.  Duration of AE will be determined and 
included in listings along with action taken and outcome.
Laboratory results will be classified according to NCI-CTCAE, Version 4.0.  Laboratory results not 
corresponding to an NCI-CTCAE, Version 4.0 term will not be graded.  Laboratory toxicity shifts from 
baseline to worst grade will be provided.  The results from physical examination, vital sign measurement, 
and other assessments will be tabulated.
Tumor response data will be summarized, if appropriate.

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Version History:
Date of Original Approved Protocol: 14 December 2010
Version 2.0: 01 March 2011
Version 3.0: 28 March 2012
Version 4.0:  08 January 2013
Version 5.0:  02 May 2013
Version 6.0:  31 March 2014

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TABLE OF CONTENTS
Protocol Changes from Version 6.0 to Version 7.0......................................................................2
Synopsis....................................................................................................................................57
Table of Contents......................................................................................................................65
List of In-Text Tables................................................................................................................70
List of In-Text Figures ..............................................................................................................71
List of Abbreviations and Definitions........................................................................................72
1
Introduction ......................................................................................................................75
1.1
The CSF-1 Receptor and the Treatment of Cancer........................................................75
1.2
IMC-CS4 .....................................................................................................................75
1.3
Nonclinical Studies ......................................................................................................76
1.3.1
Pharmacokinetics .................................................................................................77
1.3.2
Target IMC-CS4 Blood Level for Nonclinical Efficacy........................................78
1.3.3
Toxicology...........................................................................................................79
1.3.3.1
Tissue Cross Reactivity ..................................................................................80
1.3.3.2
Single-Dose Toxicity......................................................................................80
1.3.3.3
Repeat-Dose Toxicity.....................................................................................81
1.4
Dose Rationale.............................................................................................................84
1.4.1
Rationale for Starting Dose ..................................................................................84
1.4.2
Clinical Experience from Cohort 1.......................................................................85
1.4.3
Clinical Experience from Cohorts 2 through 5......................................................87
1.4.4
Exploring Non-Weight-Based Dosing (Cohorts 6a through 
8c)........................................................................................................................87
1.5
Human Experience.......................................................................................................89
2
Study Objectives...............................................................................................................91
2.1
Primary Objectives.......................................................................................................91
2.2
Secondary Objectives...................................................................................................91
2.3
Exploratory Objectives.................................................................................................91
3
Study Population Selection................................................................................................92
3.1
Study Population..........................................................................................................92
3.2
Inclusion Criteria..........................................................................................................92
3.3
Exclusion Criteria ........................................................................................................93
3.4
Subject Enrollment.......................................................................................................94
3.5
Method of Assigning Subjects to Treatment .................................................................95
3.6
Blinding .......................................................................................................................95
4
Investigational Plan...........................................................................................................96

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4.1
Overall Study Design and Plan.....................................................................................96
4.1.1
Cohort Enrollment and Dose Escalation .............................................................100
4.1.2
Determination of the Recommended Dose for Phase 2 .......................................101
4.1.3
Continuation of Therapy ....................................................................................101
4.1.4
Dose-Limiting Toxicity Definition.....................................................................102
4.2
Study Duration...........................................................................................................102
4.3
Study Completion and End of Trial ............................................................................103
4.4
Continued Access Period............................................................................................104
4.5
Discontinuation of Study Sites and Discontinuation of the Study................................104
5
Study Treatment..............................................................................................................106
5.1
Treatment Administered.............................................................................................106
5.1.1
IMC-CS4 Drug Product......................................................................................106
5.1.1.1
Part A Only ..................................................................................................106
5.1.1.2
Part B Only...................................................................................................106
5.1.1.3
Both Parts A and B.......................................................................................106
5.1.2
Premedication ....................................................................................................107
5.2
Treatment Compliance ...............................................................................................107
5.3
Packaging and Labeling .............................................................................................108
5.3.1
IMC-CS4 Drug Product......................................................................................108
5.4
Storage.......................................................................................................................108
5.4.1
IMC-CS4 ...........................................................................................................108
5.5
Accountability............................................................................................................109
5.6
Return of Investigational Product ...............................................................................109
5.7
Investigational Product Retention at Study Site ..........................................................110
6
Study Procedures ............................................................................................................111
6.1
Informed Consent.......................................................................................................111
6.2
Medical History .........................................................................................................111
6.3
Physical Examination.................................................................................................111
6.4
Vital Signs .................................................................................................................111
6.5
Clinical Laboratory Tests ...........................................................................................111
6.6
Efficacy Assessments.................................................................................................113
6.7
Tissue Sampling.........................................................................................................114
6.8
Blood Sampling .........................................................................................................114
6.8.1
Pharmacokinetics ...............................................................................................114
6.8.2
Immunogenicity Testing (Anti-IMC-CS4 Antibodies)........................................115
6.8.3
Pharmacodynamics ............................................................................................115
6.8.4
Other Analyses...................................................................................................116
6.9
Electrocardiogram......................................................................................................116

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6.9.1
Triplicate ECG (Part A Only).............................................................................116
6.10
Multigated Acquisition Scan or Echocardiogram........................................................116
6.11
Optional Study Procedures.........................................................................................117
6.11.1
Tumor Tissue Submission..................................................................................117
6.12
Appropriateness of Measurements..............................................................................117
7
Study Activities ..............................................................................................................118
7.1
Pretreatment Evaluations............................................................................................118
7.2
Treatment Period........................................................................................................119
7.2.1
Regular Assessments..........................................................................................120
7.2.1.1
Tumor Biopsy...............................................................................................121
7.2.2
Blood Sampling .................................................................................................122
7.2.2.1
Pharmacokinetic, Pharmacodynamic, Immunogenicity 
Sampling ......................................................................................................122
7.2.2.2
Flow Cytometry Analysis .............................................................................122
7.2.2.3
LDH, CK, and AP Isoenzymes .....................................................................122
7.2.2.4
Troponin.......................................................................................................123
7.2.2.5
Bone Metabolism Markers CTX-I and P1NP................................................124
7.2.3
ECG Assessment................................................................................................124
7.2.3.1
Triplicate ECG Schedule (Part A Only) ........................................................125
7.3
End-of-Therapy Evaluations.......................................................................................125
7.4
30-Day Follow-up Evaluations...................................................................................126
7.5
Extended Follow-up Evaluations................................................................................126
7.6
Study Events Table ....................................................................................................127
7.7
Pharmacokinetic and Other Sampling.........................................................................130
8
Adverse Events Assessments...........................................................................................136
8.1
Adverse Events ..........................................................................................................136
8.2
Serious Adverse Events..............................................................................................138
8.3
Suspected Unexpected Serious Adverse Reactions .....................................................139
8.4
Safety Monitoring ......................................................................................................139
8.5
Complaint Handling...................................................................................................140
9
Treatment-Related Adverse Events .................................................................................141
9.1
IMC-CS4 ...................................................................................................................141
9.1.1
Immune-Related Adverse Events .......................................................................141
9.1.2
IMC-CS4 Infusion-Related Reactions ................................................................145
9.1.3
Other Adverse Events.........................................................................................148
10
Dose Modifications.........................................................................................................149
10.1
General Dose Modifications – IMC-CS4....................................................................149
10.1.1
During Cycle 1...................................................................................................149

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10.1.2
After Cycle 1......................................................................................................149
10.1.3
Infusion-Related Reactions ................................................................................150
10.2
Removal of Subjects from Therapy ............................................................................151
10.3
Concomitant Therapy.................................................................................................152
10.4
Prohibited and Restricted Therapies during the Study.................................................152
10.4.1
Prohibited Therapies ..........................................................................................152
10.4.2
Restricted Therapies...........................................................................................152
10.4.3
Precautions.........................................................................................................153
10.5
Nontherapy Precautions and Restrictions....................................................................153
10.6
Supportive Care Guidelines........................................................................................153
10.6.1
Granulocyte Colony-Stimulating Factors............................................................153
10.6.2
Erythroid Growth Factors...................................................................................153
10.6.3
Transfusion of Blood Products...........................................................................153
10.6.4
Antiemetic Therapy............................................................................................153
10.6.5
Premedication for IMC-CS4...............................................................................153
11
Criteria for Tumor Response Evaluation .........................................................................154
11.1
Baseline Tumor Assessments .....................................................................................154
11.2
Method of Tumor Response Assessment ....................................................................154
11.3
Definitions .................................................................................................................155
11.3.1
Measurable.........................................................................................................155
11.3.2
Nonmeasurable ..................................................................................................155
11.4
Definitions of Response .............................................................................................156
11.4.1
Target Lesions....................................................................................................156
11.4.1.1
Lesions Too Small to Measure......................................................................157
11.4.1.2
Lesions That Split or Coalesce......................................................................157
11.4.2
Nontarget Lesions ..............................................................................................158
11.4.3
New Lesions ......................................................................................................159
11.5
Determination of Overall Response............................................................................159
12
Planned Statistical Methods ............................................................................................161
12.1
General Considerations ..............................................................................................161
12.2
Analysis Populations..................................................................................................162
12.3
Subject Disposition ....................................................................................................162
12.4
Demographics and Baseline Characteristics................................................................162
12.5
Analyses of Safety Data .............................................................................................162
12.5.1
Extent of Exposure.............................................................................................162
12.5.2
Safety Analysis ..................................................................................................163
12.6
Analyses of Antitumor Response................................................................................164
12.7
Other Assessments or Analyses..................................................................................164

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12.7.1
Pharmacokinetic Assessments............................................................................164
12.7.2
Pharmacodynamic Assessments .........................................................................164
12.8
Data Safety Monitoring Plan ......................................................................................164
13
Administrative Considerations ........................................................................................166
13.1
Organizational Structure of the Study.........................................................................166
13.2
Institutional Review Board/Approving Ethics Committee 
Approval....................................................................................................................166
13.3
Ethical Conduct of the Study......................................................................................166
13.4
Compliance with the Protocol and Protocol Revisions................................................167
13.5
Subject Information and Consent................................................................................167
13.5.1
Informed Consent Procedures.............................................................................168
13.5.2
Update of the Informed Consent.........................................................................168
13.6
Study Monitoring .......................................................................................................169
13.7
Case Report Forms and Study Records.......................................................................169
13.8
Access to Source Documentation ...............................................................................170
13.9
Retention of Data .......................................................................................................171
13.10 Financial Disclosure...................................................................................................171
13.11 Publication and Disclosure Policy ..............................................................................171
14
References ......................................................................................................................173

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LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1.  Dose Cohort Assignment ................................................................................................97 
Table 2.  Treatment Schedule (Part A - Weekly Dosing – Cohorts 1, 2, 3, and 5) ........................99 
Table 3.  Treatment Schedule (Part A - Every-2-Week Dosing – Cohort 4) .................................99 
Table 4.  Treatment Schedule (Part B - Weekly Dosing – Cohorts 6a, 6c, 7a, 7c, 8a, and 8c) .....99 
Table 5.  Treatment Schedule (Part B - Weekly Dosing on Weeks 1, 2, 4, and 5 – Cohorts 6b, 
7b, and 8b) 
..............................................................................................................99 
Table 6.  Flow Chart for Protocol ................................................................................................127 
Table 7.  Blood Collection Schedule (Parts A and B - Weekly Cohorts 1, 2, 3, 5, 6a, 6c, 7a, 
7c, 8a, and 8c) 
............................................................................................................130 
Table 8.  Blood Collection Schedule (Part A - Every-2-Week Cohort 4) ...................................132 
Table 9.  Blood Collection Schedule (Part B - Cohorts 6b, 7b, and 8b) ......................................134 
Table 10.  Guidelines for the Management of Potential Toxicities Encountered with Immuno-
Oncology Agents ............................................................................................................142 
Table 11.  NCI-CTCAE, Version 4.0, Infusion-Related Reactions .............................................146 
Table 12.  General Dose Reduction Guidelines ...........................................................................150 
Table 13.  Overall Response ........................................................................................................160 
 

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LIST OF IN-TEXT FIGURES 
Figure 
Page 
Figure 1.   Reported body weight versus LY3022855 drug clearance (as determined using 
non-compartmental analysis) for eligible subject data from Study JSCA (IMCL 
CP24-1001.) 
..............................................................................................................88 
Figure 2.   Profile review of CD14DIM CD16BR MONO (cells/µL). ...............................................89 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS
ADA
anti-drug antibody
AE
adverse event:  Any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product that does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of medicinal 
(investigational) product, whether or not related to the medicinal (investigational) 
product.
aEC
approving Ethics Committee
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AP
alkaline phosphatase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the serum concentration versus time curve
β-hCG
beta human chorionic gonadotropin
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
Cl
clearance
Cmax
maximum serum concentration
Cmin
trough serum concentration
collection 
database
A computer database where clinical trial data are entered and validated.
complaint
Any written, electronic, or oral communication that alleges deficiencies related to the 
identity, quality, purity, durability, reliability, safety, effectiveness, or performance 
of a drug or drug delivery system.
CR
complete response
CRS
clinical research scientist
CS7
A recombinant rat IgG1 antibody specific for murine CSF-1R, used as a surrogate 
antibody to evaluate the effects of targeting CSF-1R on macrophages in murine 
models of cancer.
CSF-1
colony-stimulating factor-1
CSF-1R
colony-stimulating factor-1 receptor (also known as CSF-1 receptor)
CT
computed tomography (scan)
CTX-I
C-terminal cross-linking telopeptide of type I collagen
DLT
dose-limiting toxicity
DP
drug product
DS
drug substance
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group performance status
eCRF
electronic case report form
EDC
electronic data capture
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last subject.
enroll
Subjects who are enrolled in the trial are those who have been assigned to a dose 
cohort.
enter
Subjects who are entered in the trial are those who have signed the informed consent 
form directly or through their legally acceptable representatives.
FDA
United States Food and Drug Administration

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FDG
fluorodeoxyglucose
FITC
fluorescein isothiocyanate
FNA
fine-needle aspiration
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GGT
gamma glutamyl transferase
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
identification
IgG1
immunoglobulin G, subclass 1
IL-34
interleukin-34
INR
International Normalized Ratio
irAE
immune-related adverse event
IRB
Institutional Review Board
I.V.
intravenous(ly)
Kd
dissociation constant
LDH
lactate dehydrogenase
LFT
liver function test
Lilly Safety 
System
Global safety database that tracks and reports serious adverse and spontaneous 
events occurring while using a drug/drug delivery system.
LVEF
left ventricular ejection fraction
MedDRA®
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition (scan)
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NE
non-evaluable
NK
natural killer
NOAEL
no-observed-adverse-effect level
NYHA
New York Heart Association
P1NP
procollagen type 1 N-terminal propeptide
PD
progressive disease; also, pharmacodynamic markers (in tables only)
PET
positron emission tomography
PK
pharmacokinetic(s)
PK/PD
pharmacokinetic/pharmacodynamic
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
QTc
corrected QT (interval)
qw
weekly
q2w
every 2 weeks
q3w
every 3 weeks
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
reporting database
A point-in-time copy of the collection database.  The final reporting database is used 
to produce the analyses and output reports for interim or final analyses of data.
RP2D
recommended Phase 2 dose

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SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part 
of a pool of potential candidates for participation in a clinical trial.
screen failure
A subject who does not meet one or more criteria required for participation in a trial.
SD
stable disease
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TK
toxicokinetic(s)
TNM
tumor, nodes, and metastases
TRAP-5b
tartrate-resistant acid phosphatase 5b
ULN
upper limit of normal
Vd
volume of distribution
Vss
volume at steady state
WOCBP
women of childbearing potential

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1 INTRODUCTION
1.1
The CSF-1 Receptor and the Treatment of Cancer
Colony-stimulating factor-1 receptor (CSF-1R) is a tyrosine kinase receptor expressed 
selectively on macrophage and granulocyte celllineages in normal individuals and on tumor 
cells in cancer(Kacinski 1995; Sasmono et al. 2003).  Upon colony-stimulating factor-1 (CSF-1) 
or interleukin-34 (IL-34) binding to CSF-1R, CSF-1R and downstream signaling molecules are 
phosphorylated and activated, resulting in the regulation of proliferation, differentiation, survival 
and migration of monocytes/macrophages(Bourette and Rohrschneider 2000; Pixley and Stanley 
2004; Lin et al. 2008).  In cancer, increased infiltration of macrophages within and surrounding 
the tumor mass correlates with increased tumor invasiveness and growth(Nowicki et al. 1996; 
Lewis and Pollard 2006), and depleting these tumor associated macrophages results in decreased 
growth of experimental tumors in mice (Lin et al. 2001; Lin et al. 2006).  In addition to the 
effects of CSF-1R on macrophages, there are reports of CSF-1R expression on cancer cells, 
particularlyleukemias of myeloid origin,whichproliferate in response to CSF-1(Dubreuil et al. 
1988; Tang et al. 1992; Kacinski 1995). Furthermore, CSF-1 and CSF-1R are required for 
osteoclast formation and activityin bone metastases, osteoclasts being amajor component 
leading to bone erosion and pain in cancer patients(Ross 2006). Inhibition of CSF-1R signaling 
results in lessening of osteolytic bone destruction in mouse modelsof bone metastasis(Ohno 
etal. 2006; Manthey et al. 2009).  While CSF-1R levels are infrequently increased in tumors 
compared to analogous normal tissues, increased CSF-1 in sera of cancer patients is more 
frequently observed, and is associated with poor prognosis and severity of disease in multiple 
cancers(Lawicki et al. 2006; Mroczko et al. 2007; Zhu et al. 2008).  These data suggest that 
targeting CSF-1R has potential to limit cancer progression.
1.2
IMC-CS4
CCI
IMC-CS4 is a recombinant human monoclonal antibody of the immunoglobulin G, subclass1 
(IgG1) targeting CSF-1R.  
 
 
  
 
  IMC-CS4
was selected for having high affinity binding to CSF-1R and its ability to blockthe binding of 

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CSF-1 and IL-34 to CSF-1R.  The IMC-CS4 heavy and light chain antibody genes were then 
engineered into a suitable vector for expression in Chinese hamster ovary cells.  Subcloning 
techniques were utilized to generate a stable clone expressing high levels of IMC-CS4 for 
manufacturing purposes.
1.3
Nonclinical Studies
CCI
Detailed results from all relevant studies conducted to assess the nonclinical pharmacology, 
pharmacokinetics(PK), and toxicology of IMC-CS4 are provided in the current Investigator’s 
Brochure(IB).
IMC-CS4 prevents the ligands CSF-1 and IL-34 from binding to CSF-1R with 
 
 respectively, and in this way inhibits CSF-1R activation.  CSF-1R activation is 
required for proper functioning and survival of tumor-associated macrophages.  Thus, by 
blocking CSF-1R activation, 
 
 
Because IMC-CS4 does not recognize the mouse CSF-1R, the use of a mouse surrogate 
antibody, CS7, was required to target macrophages in proof of principle preclinical 
pharmacology studies.  The effects of CS7 in several tumor models of breast,prostate,and 
endometrialcancer established in mice with human and murine tumor cells were evaluated.  CS7 
was efficacious in decreasing tumor size in 3xenograft breast cancer models and 2syngeneic 
mammary cancer models in mice.  Additionally, CS7 inhibited tumor growth in a prostate and 
endometrial tumor model. Utilizing data from testing CS7 in a panel of models, antitumor 
efficacy was found to be significantly better against tumors established with cell lines that 
produce CSF-1.  CS7 effectively depleted tumor macrophages in all tumor models evaluated.  
However, CS7 was particularlyefficaciousin those models in which tumor cellsexpressed high 
levels of CSF-1.  These data suggest that tumors secreting CSF-1 may be most responsive to 
therapy with IMC-CS4.  In line with the potential utility of IMC-CS4 as a combination therapy, 
CS7 increased the antitumor effects of targeted agents such as trastuzumab, doxorubicin, 
paclitaxel, and docetaxel in preclinical models. In addition to antitumor effects,antibodies to 
CSF-1R decrease osteolytic activity by osteoclasts in the bone. In a bone metastasis model 
where breast cancer cells were injected into the mouse tibia, treatment with CS7 not only 
decreased tumor burden but alsominimized bone erosion.
CCI

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As stated above, the antitumor effects of IMC-CS4mediated by targeting macrophagescould not 
be evaluated in murine models.  However, 
 
 
 
 
 
 
1.3.1 Pharmacokinetics
IMC-CS4 was administered to mice at 20 mg/kg and to cynomolgus monkeys at dose levels that 
ranged from 10 to 180 mg/kg.  The PK of IMC-CS4 in cynomolgus monkeys were characterized 
by a relatively long serum half-life (t
1/2
CCI
) after single (183-275 hours) or multiple doses (158-
470hours), which were substantially longer than observed in CD-1 mice (110 hours).  
Accumulation (approximately 2-fold) of IMC-CS4 was evident after repeated once weekly (qw) 
dosing, suggesting that accumulation may similarly occur in humans depending on the frequency 
of dosing.  The estimated 
 
In the 
cynomolgus monkey studies, IMC-CS4 serumexposures were generally proportional to the 
increases in dose from 10 to 180 mg/kg and no sexdifferences were observed.
The concentration of serum CSF-1 increased in cynomolgus monkeys that were treated with 
IMC-CS4, suggesting that CSF-1 is a pharmacodynamic marker of IMC-CS4 exposure.  
However, in contrast to the IMC-CS4 levels, CSF-1 levels did not increase proportionally to the 
increase in IMC-CS4 dose.  The concentration of CSF-1 reached apparent maximal levels in all 
dose groups after the first dose, typically between 24 and 168 hours following administration of 
IMC-CS4.  This observation suggests that the 
 
 
  
 
 
CCI
CCI

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In the repeat-dose cynomolgus monkey toxicity study, 
 
 
 
 
 
  ADA in the other animals did not appear to impact the IMC-CS4 
concentrations.
1.3.2
Target IMC-CS4 Blood Level for Nonclinical Efficacy
One of the main pharmacological effectsof IMC-CS4 proposed to underlie the inhibition of 
cancer progression is the depletion of tumor-associated macrophages.  To model this effect and 
estimate the minimum effective blood level required to achieve significant antitumor effects, 
cancer models established in mice were utilized.  However, since IMC-CS4 does not bind to 
murine CSF-1R, a surrogate antibody, CS7, was developed and utilized in order to examine 
pharmacokinetic/pharmacodynamic (PK/PD) relationships.  The binding affinity of CS7 to 
murine CSF-1R (K
d= 0.13nM) is 6-fold greater than that of IMC-CS4 to human CSF-1R 
(K
d
CCI
=0.8nM).  However, comparable potencies of the antibodies were observed in cell-based 
assays of inhibition of CSF-1 induced phosphorylation (
), 
monocyte differentiation (
), and 
inhibition of monocyte proliferation (
 
).  Therefore, CS7 and IMC-CS4 were anticipated to have similar pharmacological 
effects in vivo at similar concentrations.  Hence, CS7 was utilized in animal models to directly 
predict the trough serumIMC-CS4 levels necessary to achieve relevant efficacy in human 
subjects.
Based on theseassumptions, to estimate target serum concentrations for efficacy in initial 
clinical investigations, trough concentrations associated with efficacy were determined in human 
breast cancer (HCC-1954) and human leukemia (NKM-1) models established in mice.  IMC-CS4 
was evaluated in the leukemia model established following I.V.injection of CSF-1R-expressing 
NKM-1 cells.  The rat surrogate, CS7, was used in the breast cancer model established following 
subcutaneous injection of CSF-1R-negative HCC-1954 cells.  The results from the 2studies 
identified markedly different efficacious concentrations for the antibodies in the different 
CCI
CCI
CCI

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models.  The human NKM-1 model appeared very sensitive to the antitumor effect of IMC-CS4, 
as efficacy was achieved at mean trough concentrations down to 0.2 µg/mL. For CS7, notably 
higher doses and concentrations were required to inhibit human HCC-1954 breast cancer tumor 
growth, as a mean trough concentration of 425 µg/mL was associated with efficacy.  Because the 
clinical investigation is conducted in solid tumors, this concentration was initially regarded as a 
conservative target concentration for efficacy.
1.3.3 Toxicology
A standard nonclinical toxicology program for advancement of a monoclonal antibody into 
clinical trials in oncology indications was conducted to assess the safety and toxicity of 
IMC-CS4.  The nonclinical safety assessment of IMC-CS4 was conducted in cynomolgus 
monkeys, which was considered a relevant model for the nonclinical safety evaluation of 
IMC-CS4 based on a preliminary cross-species evaluation of tissue/receptor binding and/or 
functional in vitro pharmacological activity in human and cynomolgus monkey test systems, and 
in a subsequent comprehensive tissue cross-reactivity study using full panels of monkey and 
human tissues.  The toxicology studies conducted with IMC-CS4 included an exploratory 
single-dose toxicity and toxicokinetic (TK) dose range-finding study, and a pivotal 4-week 
repeat-dose good laboratory practice toxicity, TK, and immunogenicity study with a 6-week 
recovery period.  Animals were administered IMC-CS4 by I.V. infusion, the intended clinical 
method of administration, using the most aggressive dosing schedule (qw) in the planned clinical 
investigations of IMC-CS4.  The pivotal study included evaluations of relevant safety 
pharmacology parameters.  Because of an anticipated effect of IMC-CS4 on circulating levels of
the target ligand, CSF-1, the levels of CSF-1 were also measured in the study animals as a 
potential marker of the pharmacodynamic activity of the antibody.  A thorough assessment of 
peripheral blood and spleen mononuclear cell subsets, and an immunohistochemical analysis of 
CD68+ macrophages in liver and spleen was also included to determine the effects that blockade 
of the CSF-1 receptor might have on these endpoints.
Assessment of the genotoxicity potential of monoclonal antibodies is not relevant, and was 
therefore not studied.  Based on the early stage of clinical development and the oncology 
indication, reproductive toxicity studies of IMC-CS4 have not been conducted.

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1.3.3.1
Tissue Cross Reactivity
A comprehensive tissue cross-reactivity study was conducted in cryosections of normal human 
and cynomolgus monkey tissues using a fluorescein isothiocyanate (FITC)-labeled form of 
IMC-CS4, designated IMC-CS4-FITC, applied to cryosections of normal human and 
cynomolgus monkey tissues at 2concentrations (5 µg/mL and0.5 µg/mL).
The tissue binding and distribution profile of IMC-CS4-FITC staining observed in the human 
and cynomolgus monkey tissue panels was generally consistent with reported sites of CSF-1R 
expression, and no important,unexpected (that is,off-target) binding was observed. 
 
 
 
 
 
 
  
 
  
Although CSF-1R is expressed mainly by cells of myeloid and mononuclear phagocytic lineage 
(for example,macrophages and monocytes, and glomerular mesangial cells), expression has also 
been reported inthe trophoblasts(Mori et al. 1990; Pampfer et al. 1992; Jokhi et al. 1993; 
Watanabe et al. 2001; Hume 2006; Guo and Cantley 2010).
1.3.3.2
Single-Dose Toxicity
Single-dose I.V.administration of IMC-CS4 at dose levels of 10, 40, and 140 mg/kg 
administered by I.V.infusion over a 15-minute period was well tolerated incynomolgus 
monkeys (2 monkeys/sex/group).  Sustained, dose-proportional exposure to IMC-CS4 was 
generally observed throughout a 14-day observation period at all dose levels following 
administration with no apparent sexdifferences.  A relatively long t1/2 
CCI
was observed for 
IMC-CS4, ranging from approximately 183 to 275hours.
The key toxicological findings after a single administration of IMC-CS4 were elevations in 
serum transaminases (alanine aminotransferase [ALT]andaspartate aminotransferase [AST]) 
and lactate dehydrogenase (LDH) on Days 2, 7and 15 after dosing. Elevations in ALT were 

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generally minimal at the lowest dose level (10 mg/kg), whereas generally minimal to moderate 
elevations were observed in ALT at 40 and 140mg/kg and in AST and LDHacross all dose 
groups. The elevations in ALT, AST, and LDHobserved on Day 7 declined towards baseline 
levels in most animals by the end of the observation period, suggesting reversibility of these 
effects. No histological changes in the liver were noted to correlate with the increases in ALT, 
AST, and LDH, nor were any changes noted inliver functional parameters (that is,alkaline 
phosphatase[AP], bilirubin, coagulation). Therefore, based on the small magnitude of the 
elevations, and the absence of histological or functional changes, the increases in ALT, AST,and 
LDHwere not considered adverse.
No other adverse clinical signsoreffects on food consumption, body weight, hematology,and 
organ weights were associated with administration of IMC-CS4.
The no-observed-adverse-effect level(NOAEL)in this study was considered to be the highest 
dose tested of 140 mg/kg. This dose corresponded to Day1 mean C168hrof 1097μg/mL, mean 
maximum serum concentration (Cmax)of 4010 μg/mL,and mean area under the serum 
concentration versus time curve (AUC)
0-168hrof 303127μg•hr/mL for males and females.
1.3.3.3
Repeat-Dose Toxicity
In the pivotal repeat-dose toxicity, TK, and immunogenicity study of IMC-CS4, doses of 0, 20, 
60, and 180 mg/kg/dose IMC-CS4 were administered by I.V.infusion qwto cynomolgus 
monkeys (5/sex/group)for 4 weeks followed by a 6-week recovery period.  Standard 
toxicological and relevant safety pharmacology (cardiovascular, central nervous, and respiratory 
systems) endpoints were assessed. As in the single-dose study, circulating levels of CSF-1 were 
measured. A thorough assessment of peripheral blood and spleen mononuclear cell subsets, and 
an immunohistochemical analysis of CD68+
CCI
cells in liver and spleen was also conducted.

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CCI
Intravenous infusion of IMC-CS4 was generally welltolerated at all dose levels. Sustained, 
dose-proportional to slightly-greater-than-dose-proportional increases in exposure to IMC-CS4 
were generally observed, and no sexdifferences in exposure were apparent. Moderate 
accumulation (approximately 2-fold) of IMC-CS4 occurred after repeated administration.  
 
 
 
 
As noted in the single-dose exploratory study, 
 
 
 
 
The key toxicological findings attributed to IMC-CS4 administration in this study were 
periorbital swelling, increases in serum transaminases as noted in the exploratory study, changes 
in leukocyte populations (monocytes, neutrophils, CD68+ mononuclear cells, natural killer 
[NK]cells),and target organ effects in liver (Kupffer cell hypertrophy/hyperplasia), spleen 
(follicular hypertrophy/dendritic cell hyperplasia), and bone marrow (hypercellularity). 
Theimmunomodulatory effects on leukocytes, Kupffer cells, spleen,and bone marrow likely 
reflect an exaggerated pharmacological response to IMC-CS4, possibly due to elevations in 
circulating CSF-1 levels noted during the study.
Elevations in ALT after the last dosing of IMC-CS4were generally minimal in the lowest dose 
group (20 mg/kg), and minimal to moderate at the 60 and 180 mg/kg dose levels.  AST levels 
were minimally to moderately increased at all dose levels.  ALT and AST returned to baseline in 
the 20 mg/kg group, and trended towards baseline in the 60 and 180 mg/kg groups during the 
recovery period, but remained increased in some individual animals compared to baseline. 
Nohistological changes in the liver were noted to correlate with the transaminases increases, nor 
CCI

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were any changes in liver functional parameters (that is,AP, bilirubin, coagulation).  Therefore, 
based on the small magnitude of the elevations, and the absence of histological or functional 
changes, the increases in ALT and AST were not considered adverse. Similar elevations in 
serum enzyme levelshavealso been observedwhen treating with other pharmacological agents 
targeting CSF-1R(MacDonald et al. 2010)or CSF-1(Radi et al. 2011).
Increases in circulating white blood cells, due to increases in neutrophils and monocytes, were 
observed in both sexesat 60 and 180 mg/kg. Flow cytometry analysis of spleen and peripheral 
blood revealed increases in monocytes in spleen and blood at 60 and 180 mg/kg, and reductions 
in splenic NK cells in all IMC-CS4 treated groups. Variability in NK cell numbers in the 
peripheral blood of animals in all dose groups (including control) precluded any definitive 
relationship with IMC-CS4 treatment. These changes inwhite blood cellcounts, in conjunction 
with minimal, reversible increases in serum globulin concentrations with a corresponding 
decrease in A:G ratio, areconsistentwiththe presence of an inflammatory response. However, 
no histopathologicevidence of inflammation was observed. Themonocyte, neutrophil, and 
globulinchanges were reversible by the end of the recovery period, while the splenic NK cell 
reductions were still apparent in some animals. These changes were not considered adverse 
because of the small magnitude of changes.
Anatomic pathology changes attributed to the administration of IMC-CS4 at the end of the 
dosing period included increased spleen weights in females (all dose groups), which generally 
correlated with splenic follicular hypertrophy (males at 60 and 180 mg/kg; females at 20 and 
180mg/kg), bone marrow hypercellularity (all female dose groups, one 60 mg/kg male), bone 
marrow lymphoid aggregates (one male, one female at 180 mg/kg),and Kupffer cell 
hypertrophy/hyperplasia (primarily minimal, all male dose groups, one 60 mg/kg female). 
Immunohistochemical analyses confirmed the presence of increased size or number of CD68+
Kupffer cells in the liver, and increased numbers of CD68+
CCI
mononuclear cells in the spleen at all 
dose levels. 
 
 
 
 
 
These changes were not considered adverse because of the small magnitude of changes.

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Slight to moderate periorbital swelling was observed primarily during the recovery phase in all 
IMC-CS4-treated groups.  This clinical sign has been reported to occur in humans with another 
antibody to CSF-1 (Sadis et al. 2009), and may thus represent a delayed response to IMC-CS4 in 
the treated monkeys.  Watery feces was observed only in the 60-mg/kg/dose animals, but is 
considered possibly related to the administration of IMC-CS4.  These clinical signs were not 
considered adverse based on their limited impact to the overall health of the animal.
Based on the absence of any definitive IMC-CS4-related adverse findings, the NOAEL for 
IMC-CS4 administered via 15-minute I.V. infusion qw on 4 occasions was considered to be 
180 mg/kg/dose (Day 22 mean Cmax of 7985 µg/mL, C168hr of 2945 µg/mL, and mean AUC0-168hr
of 711340 µg•hr/mL).
1.4
Dose Rationale
1.4.1
Rationale for Starting Dose
The optimal dose and regimen of IMC-CS4 in humans are not known.  The proposed starting 
dose and regimen of IMC-CS4 was 2.5 mg/kg administered qw by I.V. infusion.  This starting 
dose was based on the following rationale:

IMC-CS4 was well tolerated in cynomolgus monkeys when administered qw at 20, 60, or 
180 mg/kg by I.V. infusion for 4 weeks.  The key toxicological findings included 
periorbital swelling, increased serum transaminases, and immunomodulatory effects on 
monocytes, neutrophils, spleen, Kupffer cells, and bone marrow.  As none of the 
observed effects were considered adverse, the NOAEL was identified as 180 mg/kg.

Most antibodies and other large proteins scale best between species when doses are 
compared directly in mg/kg (FDA 2005).  Given the similar binding affinities of 
IMC-CS4 to human and monkey CSF-1R, this approach predicts that 20 mg/kg in 
humans will have similar findings as in the monkey at the same dose, and that a dose 
equal to one-eighth of this (2.5 mg/kg), would be an acceptable and safe starting dose for 
this first-in-human study in oncologic indications.  This starting dose is 72-fold lower 
than the NOAEL (180 mg/kg).

A noncompartmental PK analysis of IMC-CS4 in cynomolgus monkeys of serum 
sampled following the fourth infusion, where the drug is at or approaching steady state, 
indicated a mean (sex-combined) elimination half-life of 158, 243, and 470 hours 
(approximately 7 to 20 days) for the 20, 60, and 180 mg/kg doses, respectively, and is 
supportive of a dosing interval of equal to or greater than qw.

The target serum trough concentration for IMC-CS4 based on antitumor activity of the 
surrogate antibody CS7 in a murine model of breast cancer is approximately 425 µg/mL.

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To further support identification of the appropriate IMC-CS4 dose and regimen to attain these 
serum concentrations, simulations based on the mathematical modeling of serum concentration 
data of IMC-CS4 derived from the cynomolgus monkey PK study were used.  A one-
compartment model best fit the data.  The simulations were based on the following assumptions:
1. The one-compartmental model was applicable to the simulated doses.
2. PK parameters obtained from the 20-mg/kg dose monkey PK study and elimination 
half-life values were applicable to human PK dosing and regimens.
3. IMC-CS4 drug levels following the fourth infusion were at or near steady state.
4. No inter-subject or intra-subject variability was accounted for.
The simulations suggest that doses of 20 mg/kg IMC-CS4 every week achieve target minimum 
trough levels of 480 µg/mL IMC-CS4, which approximates the trough level associated with 
antitumor activity in nonclinical tumor xenograft models (425 µg/mL).
Based on the above, subjects in the first cohort were administered a dose of 2.5 mg/kg qw.
1.4.2
Clinical Experience from Cohort 1
IMC-CS4 was administered to 6 subjects at the starting dose of 2.5 mg/kg qw.  Two of the first 
3 subjects experienced Grade 2 creatine kinase (CK) serum level elevations, associated with 
elevated levels of AST (Grade 1-2), LDH, and CSF-1.  A muscle biopsy was performed, 
independently of the protocol, in one of the subjects with elevated CK values and did not reveal 
any signs of rhabdomyolysis, nor of muscle damage of inflammatory or non-inflammatory 
origin.  However, because of the serum enzyme elevation and subjects’ general conditions, 
Cycle 1 was not completed as per protocol in 2 of the 3 subjects.
Therefore, 3 additional subjects were ultimately recruited (a total of 3 of 6 subjects completed 
Cycle 1).  These subjects also exhibited elevated levels of CK, AST, and LDH, in agreement 
with data obtained in various experimental models of CSF-1R blockade (Mori et al. 1990) and 
with nonclinical observations (in cynomolgus monkeys).  In one subject, the serum levels of CK 
and AST reached Grade 3; however, this event was not classified as a dose-limiting toxicity 
(DLT) because of the lack of clinical signs and symptoms of organ toxicity upon comprehensive 
clinical evaluation of the subject.  Enzyme levels decreased upon discontinuation of IMC-CS4, 
indicating that this effect was temporary and reversible.

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Overall, in the cohort of 6 subjects treated with IMC-CS4 administered at an I.V. dose of 
2.5 mg/kg every week, the following laboratory findings were consistently reported:

Elevation of CK ranging from Grade 1-3;

Elevation of AST ranging from Grade 1-3, in the absence of a significant increase in ALT 
(except in 1 of 6 subjects) and an increase in bilirubin;

Elevated levels of LDH ranging from 3- to 7-fold above the upper limit of normal (ULN);

Elevation of CSF-1 levels above normal values.
The concomitant elevation in CSF-1 serum levels and the increase in the serum levels of CK, 
LDH, and AST suggest pharmacodynamic activity of IMC-CS4.  Since preclinical studies with 
IMC-CS4 in monkeys demonstrated a dose-response correlation between the dose of IMC-CS4 
and the increase in serum enzyme levels, a dose escalation was considered likely to result in a 
DLT. Therefore, it was considered medically prudent not to dose escalate further as initially 
planned.
In order to better characterize the IMC-CS4 dose-response effect on the monocyte / macrophage 
system and on various serologic and hematologic parameters, the dosing scheme and schedule 
was amended in Protocol Amendment Version 3.0 to reflect dose reductions and prolonged 
administration intervals as follows:  Under Version 2.0 of the protocol, dose escalation was to 
begin at 2.5 mg/kg in Cohort 1 and proceed to 5, 10, 20, and 30 mg/kg (all qw) in Cohorts 2 to 5, 
respectively.  Following completion of Cohort 1 (2.5 mg/kg), the dose-escalation scheme was 
revised to 0.3 mg/kg qw in Cohort 2, 0.6 mg/kg qw in Cohort 3, 1.25 mg/kg every 2 weeks (q2w)
in Cohort 4, 1.25 mg/kg qw in Cohort 5, and 2.5 mg/kg q2w in Cohort 6 (a newly added cohort).  
The addition of q2w dosing was deemed reasonable based on the relatively long half-life
observed in cynomolgus monkeys.
Further rationale for the revised dose-escalation scheme was as follows.  The second cohort 
started at approximately an 8-fold lower dose level (0.3 mg/kg administered qw) than the study 
starting dose (2.5 mg/kg qw in Cohort 1).  Additionally, certain doses (1.25 and 2.5 mg/kg) were
to be administered on both qw and q2w regimens to facilitate PK/PD characterization.  Upon 
completion of all 6 planned cohorts, the PK/PD and safety profiles were to be evaluated to assess 
if further dose escalation and/or regimens were warranted to determine the recommended 
Phase 2 dose (RP2D).

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1.4.3
Clinical Experience from Cohorts 2 through 5
This section describes the clinical experience after the revised dose-escalation scheme was 
implemented in Protocol Amendment Version 3.0, specifically, the clinical observations for 
Cohorts 2, 3, 4, and 5.  No DLTs were observed in Cohorts 2 and 3.  The clinical data generated 
for subjects treated in Cohorts 2 and 3 indicate that IMC-CS4 is safe and well tolerated when 
administered as 4 qw doses (0.3 or 0.6 mg/kg) followed by 2 weeks of recovery.
In Cohort 4 (1.25 mg/kg q2w), one subject with a history of cardiac dysfunction developed a 
Grade 3 left ventricular systolic dysfunction (verbatim) after one dose of IMC-CS4; the event 
was considered by the Investigator to be related to IMC-CS4.  Because DLT could not be ruled 
out for this event, 2 additional subjects were enrolled into Cohort 4 and completed protocol-
defined therapy without experiencing DLT events.
In Cohort 5 (1.25 mg/kg qw), 2 subjects experienced DLT events: 1 subject was diagnosed with 
rhabdomyolysis complicated by acute renal failure following 1 dose of IMC-CS4, and the second 
subject was diagnosed with pancreatitis after receiving 3 doses of IMC-CS4.  The subject 
diagnosed with pancreatitis slowly developed symptoms in conjunction with rising amylase and 
lipase levels during the course of treatment; these signs and symptoms, which were consistent 
with pancreatitis, resolved upon discontinuation of IMC-CS4 and initiation of systemic steroids.  
As a result of these 2 DLT events, the RP2D was determined to be 1.25 mg/kg every 2 weeks.
1.4.4
Exploring Non-Weight-Based Dosing (Cohorts 6a through 8c)
Exploratory graphical analysis of the pharmacokinetics of IMC-CS4 in Cohorts 1 to 5 indicates 
no clear relationship between body weight and drug clearance (Figure 1). Furthermore, weekly 
dosing results in sustained elevation of CSF-1, an indicator of target engagement, for the 
duration of the dosing period (Figure 2). In contrast, dosing every 2 weeks allows CSF-1 levels 
to return to baseline, indicating reduced target engagement with a more intermittent dosing 
schedule.  Therefore, additional cohorts are being added in this protocol amendment, 
Version 7.0, to evaluate safety, pharmacokinetics, and pharmacodynamics of non-weight-based 
dosing of IMC-CS4 administered on a weekly schedule. As was done for weight-based dosing 
cohorts, doses for non-weight-based dosing cohorts will be escalated to identify RP2D.  To 
accommodate these new non-weight-based dosing cohorts, the definition of DLT has been 

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revised and an algorithm added to initiate steroid therapy early during the course of an immune-
related adverse event (irAE) (refer to Section 9.1.1 for additional details).
Abbreviations:  QW = weekly; Q2W = every 2 weeks.
Figure 1.
Reported body weight versus LY3022855 drug clearance (as 
determined using non-compartmental analysis) for eligible 
subject data from Study JSCA (IMCL CP24-1001.)

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Profile plot of CD14DIM CD16BR MONO (CELLS/uL) 
Program Location: F:/lillyce/prd/ly3022855/i5f_ie_jsca/misc1/programs_nonsdd/CS4_jsca_CD14dimCD16br_C4-C5.r 
Data Location: F:/lillyce/prd/ly3022855/i5f_ie_jsca/misc1/data/shared/custom/dm.csv  
Data Location: F:/lillyce/prd/ly3022855/i5f_ie_jsca/misc1/data/shared/custom/lb.csv 
Output Location: F:/lillyce/prd/ly3022855/i5f_ie_jsca/misc1/programs_nonsdd/tfl_output/CS4_JSCA_CD14dimCD16br_C4-C5.rtf
Figure 2.
Profile review of CD14DIM CD16BR MONO (cells/µL).
1.5
Human Experience
This is the first study of IMC-CS4 in humans.  Limited data are available from this study to date, 
and are described in Sections 1.4.2 and 1.4.3.
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) may be found in the IB.  Information on AEs expected to be related to the 
investigational product may be found in Section 7 (Development Core Safety Information) of the 
IB.  Information on serious adverse events (SAEs) expected in the study population independent 
of drug exposure and that will be assessed by the Sponsor in aggregate, periodically during the 
course of the study, may be found in Section 6 (Effects in Humans) of the IB.

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NOTE:
Protocol Amendment Version 7.0 describes additional cohorts for non-weight-based dosing of 
IMC-CS4, which will be referred to as Part B of the study.  Cohorts described in the protocol 
prior to Protocol Amendment Version 7.0 (that is, for weight-based dosing of IMC-CS4) will 
now be referred to as Part A of the study.  Refer to Section 4.1 for details of the dose 
assignments for Parts A and B.
Throughout the protocol, information relevant only to Part A (weight-based dosing) or only to 
Part B (non-weight-based dosing) is indicated as such.  Any information not indicated as “Part A 
only” or “Part B only” is relevant to both parts.

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2
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objectives of this study are to establish the safety profile and characterize the 
pharmacokinetic (PK) profile of IMC-CS4 in the treatment of subjects with advanced solid 
tumors refractory to standard therapy or for which no standard therapy is available.
2.2
Secondary Objectives
The secondary objectives of this study are:

Part A only – To define the recommended Phase 2 dose (RP2D) using weight-based 
dosing;

Part B only – To define the RP2D using non-weight-based dosing;

To characterize the pharmacodynamic profile of IMC-CS4 on circulating levels of 
CSF-1; and

To assess the development of antibodies against IMC-CS4 (immunogenicity).
2.3
Exploratory Objectives
The exploratory objectives of this study are:

To assess pharmacodynamic response markers including, but not limited to, interleukin-34 
(IL-34) and MCP-1;

To assess the impact of IMC-CS4 monotherapy on LDH, CK, and AP isoenzymes;

To assess the pharmacodynamic impact of IMC-CS4 on selected cellular and molecular 
markers to establish a potential correlation with safety and antitumor activity;

To assess the pharmacodynamic impact of IMC-CS4 on various components of the 
monocyte-macrophage system in hematologic or tissue specimens;

To assess the impact of IMC-CS4 monotherapy on bone metabolism; and

To assess the antitumor activity of IMC-CS4 as monotherapy in the treatment of 
advanced solid tumors.

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3
STUDY POPULATION SELECTION
3.1
Study Population
Subjects will be recruited from a population of cancer subjects treated at the investigational 
centers.  A record of the most recent pretreatment evaluations will be reviewed to determine the 
eligibility of a subject for this study.
3.2
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study:
1. The subject has a histologic or cytologic confirmation of advanced solid tumors that are
refractory to standard therapy or for which no standard therapy is available.
2. The subject has measurable or nonmeasurable disease according to the Response 
Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1; see Section 11).
3. The subject has resolution to Grade ≤1 by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03, of all clinically 
significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal 
therapy (with the exception of alopecia).
4. The subject has an Eastern Cooperative Oncology Group performance status (ECOG PS) 
score of 0-2.
5. The subject has adequate hematologic function, as defined by:

Absolute neutrophil count (ANC) 1500/L;

Hemoglobin 9 g/dL (5.58 mmol/L); and

Platelets 100,000/L.
6. The subject has adequate hepatic function, as defined by:

Bilirubin ≤1.5 times the upper limit of normal (× ULN); and

AST and ALT ≤2.5 × ULN (≤5 × ULN in the presence of known liver metastases).
7. The subject has adequate renal function as defined by creatinine clearance ≥50 mL/min 
measured either by 24-hour urine collection or calculated using the Cockcroft-Gault 
formula.
8. The subject must have adequate coagulation function as defined by:

International Normalized Ratio (INR) ≤1.5; and

Prothrombin time (PT) and partial thromboplastin time (PTT) or activated PTT ≤1.5 
× ULN.
9. The subject has CK ≤ULN.
10. The subject has a life expectancy >3 months.
11. The subject is 18 years of age or older.
12. The subject (women of childbearing potential [WOCBP] or fertile men with partners of 
childbearing potential) agrees to use adequate contraception during the study period and 
for 12 weeks after the last dose of study therapy.
13. The subject has provided signed informed consent.

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14. The subject is accessible for treatment and follow-up; subjects enrolled in this trial must 
be treated at the study center.
15. The subject must undergo mandatory biopsies, including one pretreatment and one 
posttreatment tumor biopsy procedure (refer to tumor biopsy Section 7.2.1.1).
3.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. The subject has experienced acute pathologic fracture or spinal cord compression within 
28 days prior to first dose of study therapy.
2. The subject has a known hypersensitivity to monoclonal antibodies or to agents of similar 
biologic composition as IMC-CS4.
3. The subject has received treatment with any monoclonal antibodies within 4 weeks prior 
to first dose of study therapy.
4. The subject has undergone a major surgical procedure, open biopsy, radiofrequency 
ablation, or has experienced a significant traumatic injury within 28 days prior to 
enrollment.
5. The subject has a history of another primary cancer, with the exception of a) curatively 
resected non-melanomatous skin cancer; b) curatively treated cervical carcinoma in situ; 
or c) other primary solid tumor treated with curative intent, no known active disease 
present, and no treatment administered during the last 3 years prior to study entry.
6. The subject is receiving concurrent treatment with other anticancer therapy, including 
other chemotherapy, immunotherapy, chemoembolization, targeted therapy, or any 
investigational agent within 4 weeks prior to study entry, or radiotherapy within 2 weeks 
prior to study entry.  An exception is that subjects with metastatic breast or prostate 
cancer who have been on a stable dose (≥28 days) of an approved hormonal agent will 
not be excluded (ie, they will be eligible).  Subjects with breast cancer may also continue 
with concurrent human epidermal growth factor receptor 2 (HER2)-directed therapy.
7. The subject has known muscle damage due to a primary, traumatic, or other muscle 
disease.
8. The subject is known to be human immunodeficiency virus (HIV) seropositive.
9. The subject has a known and uncontrolled infection.
10. The subject is known to have active tuberculosis, leishmaniasis, or listeriosis.
11. The subject has a history of and/or current:  symptomatic coronary artery disease, 
confirmed left ventricular ejection fraction (LVEF) ≤50% or any cardiac insufficiency 
> New York Heart Association (NYHA) class II,* uncontrolled hypertension, or serious 
cardiac arrhythmia (well-controlled atrial fibrillation is permitted).
12. Subjects with known history, or clinical or laboratory evidence of, liver disease. Notably, 
subjects with any of the following liver function abnormalities will be excluded:
a
Cirrhosis with evidence of portal hypertension or bridging fibrosis
b
Alcoholic hepatitis
c
Esophageal varices
d
A history of bleeding esophageal varices
e
Hepatic encephalopathy
f
Ascites related to portal hypertension

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g
Chronic viral hepatitis with total serum bilirubin >3 mg/dL.
13. The subject has active bleeding.
14. The subject has leukemia or lymphoma.
15. The subject has a known psychiatric illness/social situation (including alcohol and/or 
drug dependency) that, in the Investigator’s opinion, would limit compliance with study 
requirements.
16. The subject has known or suspected primary brain or leptomeningeal tumors or 
metastases (subjects with a history of brain metastases must have received definitive 
surgery or radiotherapy, be clinically stable, and may not be taking steroids; subjects
receiving anticonvulsants are eligible).
17. The subject is pregnant (confirmed by serum beta human chorionic gonadotropin 
[β-hCG] test performed within 7 days prior to first dose of study therapy) or 
breastfeeding.
18. The subject has received a solid organ transplant.
19. The subject has any other serious uncontrolled medical disorders that, in the opinion of 
the Investigator, would compromise the subject’s safety or the ability of the subject to 
participate in the study.
*NYHA Congestive Heart Failure Classification (NYHA 1994):
Class I – Patients with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II – Patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion.
Class III – Patients with marked limitation of activity; they are comfortable only at rest.
Class IV – Patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and 
symptoms occur at rest.
Throughout this protocol, “days” refers to calendar days, unless otherwise indicated.
3.4
Subject Enrollment
All subjects meeting the eligibility requirements will be considered for enrollment regardless of 
race, religion, or sex.  Subjects will be recruited from a population of subjects with advanced 
solid tumors who have been previously evaluated at the participating institution or have been 
referred from other institutions.  The Investigator will review the subject’s medical record to 
determine his or her eligibility for the study.  The criteria for enrollment must be followed 
explicitly.  Exceptions to the eligibility criteria may not be granted by the Investigator or the 
Sponsor.  If a subject who does not meet enrollment criteria is unintentionally enrolled, the 
Investigator informs the subject of the inadvertent enrollment, and the Sponsor or its designee 
must be contacted.  In these rare cases, the Investigator must obtain documented approval from 
the Sponsor to allow the subject to continue in the study.

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Subjects will be made aware of the protocol, its specific aims and objectives, and the potential 
risks and benefits the subject may incur.  Each subject will be required to read, agree to, and sign 
a current Institutional Review Board (IRB)/approving Ethics Committee (aEC)-approved ICF 
prior to being enrolled and before any study-related procedure is performed.  There will be no 
financial compensation for subjects enrolling on this protocol.
Individuals who do not meet the criteria for participation in this study (screen failure) within 
14 days after study entry may be rescreened once.  Sites are responsible for determining if the 
subject must sign a new ICF, based on regulatory and institutional or central IRB/aEC 
guidelines.  All subjects who have signed an informed consent form will be assigned a study 
identification (ID) number.
Screening and other pretreatment evaluations will be performed as described in Section 7.1.
3.5
Method of Assigning Subjects to Treatment
Sites will enroll subjects into the study via facsimile and/or e-mail to the Sponsor.  Each subject
will be assigned a unique study ID number.  The study ID number is to be recorded on all 
electronic case report forms (eCRFs) and correspondence regarding the subject, and will be used 
in lieu of the subject’s name to protect the subject’s identity when reporting AEs and/or other 
study-related data.  Once the study ID number is obtained, the Investigator must administer the 
first dose of investigational agent to the subject within 7 days.  Specific instructions regarding 
the enrollment and registration process will be provided in a separate procedure manual.
3.6
Blinding
This is an open-label Phase 1 dose-escalation study; no blinding will be utilized.

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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This open-label, dose-escalation, Phase 1 study will enroll a total of approximately 72 subjects to 
2 parts - Parts A and B, in approximately 6 study sites in the United States.  Part A consists of 
dose escalation of IMC-CS4 using weight-based dosing (Part A enrollment is planned to be 
discontinued as of 30 September 2015); Part B will consist of dose escalation of IMC-CS4 using 
non-weight-based dosing; the actual enrollment will depend on the number of DLTs observed 
and the resultant size of each cohort.  Throughout this protocol, any information not indicated as 
“Part A only” or “Part B only” is relevant to both parts.  In Part A, additional subjects were 
enrolled to the maximum tolerated dose (MTD) of 1.25 mg/kg q2w, in order to help establish the 
safety profile of IMC-CS4.  In Part B, the cohort associated with the dose identified as the MTD
may be expanded (up to a maximum of 12 evaluable subjects) in order to help establish the 
safety profile of IMC-CS4.  Enrollment to the MTD expansion cohort may cease if the Sponsor 
(after conferring with the investigators) deems the toxicity profile precludes further enrollment.  
Refer also to Section 4.1.2.
Dose cohorts, including dose and dosing schedule, are summarized in Table 1.  For each cohort, 
one cycle is 6 weeks.  In each cohort, subjects will receive IMC-CS4 by I.V. infusion (with an 
observation period, in Part A only, for weekly [qw] and every-2-week [q2w] cohorts, in Cycle 1 
only, as described in Table 1).  Beginning with Protocol Amendment Version 7.0, enrollment to 
Part B of the study will start with Cohort 6a, then escalate to Cohorts 7a and 8a.  In the event 2 or 
more subjects on Cohort 6a experience a DLT event, concurrent enrollment of 3 to 6 subjects to 
each of Cohorts 6b and 6c will start and further dose escalation (that is, to Cohort 7a) will cease.  
Likewise, the same algorithm will apply for Cohorts 7a and 8a if enrollment to those cohorts 
occurs.  Subjects will be assigned to “b” and “c” cohorts by the Sponsor.  Note that there will be 
no Cycle 1 observation period for Part B cohorts.  No intra-subject dose-escalation is permitted 
for any subject.  Dose escalation may be reduced or ceased at any time based on safety and PK 
behavior.

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Table 1.  Dose Cohort Assignment
Cohort
Dose Level
Dosing Schedulea
Cycle 1
Observation Periodb
Number of Infusions
Part A (weight-based dosing)
1
2.5 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
2
0.3 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
3
0.6 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
4
1.25 mg/kg
q2w
3 weeks (Weeks 4-6)
Cycle 1:  2
Subsequent cycles:  3
5
1.25 mg/kg
qw
2 weeks (Weeks 5-6)
Cycle 1:  4
Subsequent cycles:  6
Part B (non-weight-based dosing)
6a
100 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
6bc,d
100 mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4
6cc
75 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
7a
150 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
7bc,d
150 mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4
7cc
125 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
8a
200 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
8bc,d
200 mg
qw on Weeks 1, 2, 4, and 5
None (Weeks 3 and 6 are 
rest)
Cycle 1:  4
Subsequent cycles:  4
8cc
175 mg
qw
None
Cycle 1:  6
Subsequent cycles:  6
Abbreviations:  aEC = approving Ethics Committee; DLT = dose-limiting toxicity; 
IRB = Institutional Review Board; PK = pharmacokinetic(s); qw = weekly; q2w = every 2 weeks.
a – At the highest dose level where major toxicity is observed and that requires a longer recovery period between infusions, a 
change in the periodicity of dosing (that is, other dosing schedules based on safety and PK considerations) will be agreed upon 
with the Investigator and communicated to IRBs/aECs.
b – Observation following the fourth infusion in Cohorts 1, 2, 3, and 5 (qw dosing) and the second infusion in Cohort 4  (q2w 
dosing) in Cycle 1 only.  No Cycle 1 observation period for Cohorts 6a, 6c, 7a, 7c, 8a, or 8c. Weeks 3 and 6 of all cycles are rest 
weeks in Cohorts 6b, 7b, and 8b (qw dosing on Weeks 1, 2, 4, and 5).
c – Concurrently enroll to Cohorts 6b/7b/8b and 6c/7c/8c, should ≥2 subjects in Cohort 6a/7a/8a experience DLT events.
d – For all cycles:  Infusions on Weeks 1, 2, 4, and 5, and rest on Weeks 3 and 6.
It is recognized that in the course of clinical cancer care, it is not always possible to schedule 
therapeutic infusions at precise intervals (because of holidays, travel difficulties, or other 
circumstances).  Accordingly, infusions administered within 2 days (all cohorts other than q2w 

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dosing) or 3 days (q2w dosing) before or after the planned infusion time point will be considered 
acceptable.  Deviations beyond this window are not permitted in Cycle 1 and will be allowed 
thereafter only if medically indicated or if the subject cannot be treated on the scheduled day.
Following the first cycle of therapy (Cycle 1), subjects should continue to receive IMC-CS4 at 
the same dose and schedule until there is unequivocal evidence of disease progression 
(per immune-related response criteria [Wolchok et al. 2009]) or other withdrawal criteria are 
met.  Radiographically confirmed disease progression (that is, numerical disease progression, per 
RECIST) only is not sufficient to discontinue treatment.*  Radiographic assessment of tumor 
response will be performed at the end of the initial 6-week cycle and at the end of every 
subsequent cycle; radiographic assessment should be performed prior to the start of a cycle so 
that results are available before the subject receives a new cycle of treatment.  However, if a 
DLT is observed in Cycle 1 in a subject who is benefitting from treatment, Cycle 2 dosing may 
be initiated within 4 weeks of Cycle 1, Day 1, with Sponsor approval; in this case, no 
radiographic disease assessment is required prior to dosing in Cycle 2.
*Note:  Subjects with disease progression (per RECIST) but without clinical deterioration at 
Week 6 (the first response assessment) may continue to receive IMC-CS4, at the discretion of the 
Investigator; study treatment will be discontinued if, at the next disease assessment (performed at 
least 4 weeks later), disease progression is unequivocal (that is, radiographically confirmed
disease progression alone is sufficient).  On the other hand, subjects with disease progression 
(per RECIST) and with clinical deterioration (unequivocal) at Week 6 (the first response 
assessment) will be discontinued from study treatment.
The treatment schedule, radiographic tumor assessment schedule, and observation period for 
each dosing schedule are summarized in Table 2, Table 3, Table 4, and Table 5.

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Table 2.  Treatment Schedule (Part A - Weekly Dosing – Cohorts 1, 2, 3, and 5)
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Txa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
O.P.b
X
X
Tumor
evalc
Xd
X
X
X
X
Abbreviations:  eval = evaluation; O.P. = observation period; Tx = treatment.
a – Administer IMC-CS4; b – Observation period; c – Radiographic assessment of tumor status; d – Baseline assessment, within 28 days prior to 
the first dose of study therapy; subsequent assessment should be performed in the week prior to the onset of the new cycle.
Table 3.  Treatment Schedule (Part A - Every-2-Week Dosing – Cohort 4)
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Txa
X
X
X
X
X
X
X
X
X
X
X
O.P.b
X
X
X
Tumor
evalc
Xd
X
X
X
X
Abbreviations:  eval = evaluation; O.P. = observation period; Tx = treatment.
a – Administer IMC-CS4; b – Observation period; c – Radiographic assessment of tumor status; d – Baseline assessment, within 28 days prior to 
the first dose of study therapy; subsequent assessment should be performed in the week prior to the onset of the new cycle.
Table 4.  Treatment Schedule (Part B - Weekly Dosing – Cohorts 6a, 6c, 7a, 7c, 8a, 
and 8c)
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Txa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
O.P.b
Tumor
evalc
Xd
X
X
X
X
Abbreviations:  eval = evaluation; O.P. = observation period; Tx = treatment.
a – Administer IMC-CS4; b – Observation period; c – Radiographic assessment of tumor status; d – Baseline assessment, within 28 days prior to 
the first dose of study therapy; subsequent assessment should be performed in the week prior to the onset of the new cycle.
Table 5.  Treatment Schedule (Part B - Weekly Dosing on Weeks 1, 2, 4, and 5 –
Cohorts 6b, 7b, and 8b)
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Txa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
O.P.b
Tumor
evalc
Xd
X
X
X
X
Abbreviations:  eval = evaluation; O.P. = observation period; Tx = treatment.
a – Administer IMC-CS4; b – Observation period; c – Radiographic assessment of tumor status; d – Baseline assessment, within 28 days prior to 
the first dose of study therapy; subsequent assessment to be performed in the week prior to the onset of the new cycle.

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4.1.1
Cohort Enrollment and Dose Escalation
Each cohort will initially enroll at least 3 subjects.  In the first cohort (Cohort 1), subjects were to
be enrolled sequentially.  That is, there was to be a minimum of a 7-day waiting period between 
the time a subject receives the first dose of IMC-CS4 and when the next subject in Cohort 1 
receives his or her first dose.
For all subsequent cohorts, no 7-day waiting period is required.
Beginning with Cohort 2 and provided safety is acceptable, concomitant enrollment of subjects
at different sites will be permitted, in order to ensure that at least 3 subjects will be treated for at 
least 1 cycle.  In a case where consent is obtained simultaneously for 2 subjects at 2 different 
sites, this may result in enrollment of 4 subjects rather than 3 in a cohort; however, no more than 
4 subjects should be enrolled in a cohort before safety data from Cycle 1 are available for review.
For all cohorts, all subjects who complete the first treatment cycle (that is, receive all scheduled 
treatments for Cycle 1 and complete the observation period, as needed) or discontinue therapy 
due to a DLT will be considered evaluable subjects and will be included in the DLT analyses.
Subjects who do not complete Cycle 1 for reasons other than a DLT will be replaced for the 
analysis until the cohort includes 3 evaluable subjects (or 6 evaluable subjects in case of one 
DLT in the first 3 subjects); however, if benefitting from treatment (that is, no disease 
progression or other withdrawal criteria), any subject in Cohort 3 and beyond who experiences a 
DLT may continue to receive IMC-CS4 upon agreement of the Sponsor and according to the 
dose reduction guidelines for this study.  Refer to Section 10.1 for details of general dose 
modifications for IMC-CS4.
If the first 3 subjects in a cohort complete Cycle 1 of therapy with no DLT (defined in 
Section 4.1.4), dose escalation to the next cohort may proceed.  If one of the first 3 subjects in a 
cohort experiences a DLT, enrollment will proceed until there are at least 6 evaluable subjects in 
that cohort.  If no additional subject experiences a DLT, dose escalation may proceed.  If 2 or 
more subjects experience a DLT in a cohort (whether in the initial 3-subject cohort or following 
expansion to 6 subjects), dose escalation will not occur and the RP2D will be determined 
according to the instructions in Section 4.1.2.

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In all cases, dose escalation will occur only if the criteria described in this section (Section 4.1.1)
are met.  Each subsequent cohort will be opened upon completion of the previous cohort.  
A safety review meeting will be held prior to each dose escalation.
4.1.2
Determination of the Recommended Dose for Phase 2
The provisional RP2D will be defined as the dose level at which pharmacodynamic effects are 
observed in the absence of clinically relevant toxic effects (that is, measurable pharmacodynamic 
effects with no DLT in the first 3 subjects or ≤1 DLT in the first 6 subjects enrolled at that dose 
level).  After discussion with the Investigator, the Sponsor may choose to enroll additional 
subjects at or below the RP2D.
4.1.3
Continuation of Therapy
Planned duration of therapy is not fixed.  After one cycle, subjects who are benefitting from 
treatment may continue to receive IMC-CS4 at the same dose and schedule until there is 
unequivocal
evidence of disease progression or other withdrawal criteria are met.  
Radiographically confirmed disease progression (that is, numerical progression, per RECIST) 
only is not sufficient to discontinue treatment (refer to Note in Section 4.1).  Permitted dose 
modifications are described in Section 10.1.  Subjects who do not meet any withdrawal criteria 
are eligible to continue receiving study therapy in a subsequent cycle even if one or more doses 
have been missed during the prior cycle.

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4.1.4
Dose-Limiting Toxicity Definition
A DLT is defined as any IMC-CS4-related AE that occurs during Cycle 1 and does not improve 
to Grade ≤2 (unless stated otherwise), despite medical management, including steroids (if 
applicable) within 7 days of documented occurrence.  The following are considered DLTs :

Grade 4 neutropenia lasting ≥7 days;

Grade 3 or 4 neutropenia complicated by fever ≥38.0°C or infection;

Grade 4 thrombocytopenia;

Grade 3 thrombocytopenia complicated by hemorrhage;

Grade 3 or 4 anemia;

Grade 3 or 4 nonhematologic toxicity.  Exceptions maybe be made for the following, if 
agreed upon by the Sponsor AND the Investigator:

Grade ≥3 liver function test (LFT) abnormality, such as alkaline phosphatase, 
gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), and 
alanine aminotransferase (ALT), without evidence of hepatic injury

Transient Grade ≥2 bilirubin elevation in the presence of known liver metastases 
lasting ≤7 days

Laboratory abnormalities that are reversible to Grade ≤2 or baseline levels within 
7 days after initial documentation or that are deemed not clinically significant

Grade 3 elevation of CK WITHOUT elevation in serum and urine myoglobin is 
NOT considered a DLT.
If benefitting from treatment (that is, no disease progression or other withdrawal criteria), any 
subject in Cohort 3 and beyond who experiences a DLT may continue to receive IMC-CS4 upon 
agreement of the Sponsor and according to the dose reduction guidelines for this study 
(Section 10.1).
4.2
Study Duration
All subjects should continue to receive treatment until there is unequivocal evidence of 
progressive disease (PD) (radiographically confirmed disease progression [that is, numerical 
disease progression, per RECIST, Section 11] only is not sufficient to discontinue treatment
[refer to Note in Section 4.1]), toxicity requiring cessation, protocol noncompliance (in the 
opinion of the Investigator or Sponsor), withdrawal of consent by the subject, or until other 
withdrawal criteria are met (see Section 10.2).

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4.3
Study Completion and End of Trial
The study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) after the last subject has completed the DLT assessment period (that is, has 
received all scheduled treatments for Cycle 1 and completed the observation period, as needed)
OR has discontinued therapy due to a DLT.
IMC-CS4 may be made available after completion of the study to subjects who are still receiving 
and benefitting from study treatment.
“End of trial” refers to the date of the last visit or last scheduled procedure for the last subject.

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4.4
Continued Access Period
All subjects remaining on study treatment without disease progression or unacceptable toxicity 
following the final analysis for RP2D will be able to 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, subjects on study treatment who continue to experience 
clinical benefit may continue to receive study treatment until disease progression, death, 
unacceptable toxicity, or start of new anticancer treatment.  The continued access period includes 
a Follow-up visit.  The Follow-up visit begins 1 day after the subject and the Investigator agree 
that the subject will no longer continue treatment in the continued access period and lasts 
approximately 30 days.  If it is deemed to be in the best interest of the subject to start a new 
anticancer treatment prior to the scheduled end of the 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.
Subjects must sign a new ICF before entering the continued access period.  The Sponsor will 
notify investigators when the continued access period begins.
During the continued access period, all AEs, SAEs, study drug dosing, and dose reduction of 
treatment will be collected on the eCRF.
Serious adverse events will also be reported to Lilly Global Patient Safety and collected in the
Lilly Safety System.  In the event that an SAE occurs, additional information (such as local 
laboratory results, concomitant medications, and hospitalizations) may be requested by the 
Sponsor in order to evaluate the reported SAE.
Investigators may perform other standard procedures and tests needed to treat and evaluate 
subjects; however, the Sponsor will not routinely collect the results of these assessments.
4.5
Discontinuation of Study Sites and Discontinuation of the Study
Individual study site participation may be discontinued if the Sponsor, the Investigator, the 
IRB/aEC, or the regulatory authority deems it necessary for any scientific, medical, or ethical 
reason.

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The study will be discontinued if the IRB/aEC or the Sponsor, while considering the rights, 
safety, and well-being of the subject(s), judges it necessary for any scientific, medical, safety, 
regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
Good Clinical Practice (GCP).

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5
STUDY TREATMENT
5.1
Treatment Administered
5.1.1
IMC-CS4 Drug Product
5.1.1.1
Part A Only
The dose of IMC-CS4 is based on the subject’s body weight in kilograms.  Subjects recruited in 
Cohort 1 have received IMC-CS4 infusions over a period of 90 minutes.  Because of a change in 
the dosing scheme in Protocol Amendment 3.0, subjects in Cohorts 2 through 5 received IMC-
CS4 I.V. via infusion over a period of 30 minutes.  Subjects in the RP2D expansion cohort will 
receive IMC-CS4 I.V. via infusion over a period of 90 minutes for the first infusion, 60 minutes 
for the second infusion, and 30 minutes for the remaining infusions.  The infusion rate should not 
exceed 25 mg/minute.
The first dose of IMC-CS4 is dependent upon the subject’s baseline body weight in kilograms.  
Subsequent doses of IMC-CS4 must be recalculated if there is a ≥10% change (increase or 
decrease) in body weight from baseline; subsequent doses may be recalculated if there is a <10% 
change (increase or decrease) in body weight from baseline.
For subjects with fluid retention, the estimated dry weight, instead of the actual body weight, 
should be used for dose calculation or recalculation (in the setting of substantial fluid retention, 
the Sponsor CRP or designee should be consulted regarding optimal assessment of dry weight).
5.1.1.2
Part B Only
The dose of IMC-CS4 is non-weight based.  Subjects will receive IMC-CS4 I.V. via infusion 
over a period of 30 minutes.  The infusion rate should not exceed 25 mg/minute.
5.1.1.3
Both Parts A and B
Aseptic technique is to be used when preparing and handling IMC-CS4.  Different drug product 
lots must not be mixed in a single infusion.
IMC-CS4 is compatible with commonly used infusion containers.  Refer to the IB for detailed 
information on acceptable infusion containers and infusion sets for administration of IMC-CS4.

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Subjects recruited in Cohort 1 have been administered IMC-CS4 in a total volume of 250 mL.  
Because of the dose reduction, subjects in Cohort 2 and beyond will receive IMC-CS4 doses in a 
total volume of at least 100 mL.  To this end, add (or remove from AVIVA I.V. bag which 
comes prefilled with 0.9% normal saline) a sufficient quantity of sterile normal saline (0.9% 
weight/volume) to the container to make the total volume 100 mL.  For dose volumes greater 
than 100 mL, the addition of sterile normal saline is not required.  The container should be gently 
inverted to ensure adequate mixing.
The infusion set must be flushed post infusion with sterile 0.9% normal saline equal to or 
exceeding the infusion line hold-up volume to ensure delivery of the calculated dose.
Subjects are to be observed closely from the start of the infusion until at least 1 hour after the end 
of the infusion of IMC-CS4 for any potential AEs in an area with resuscitation equipment and 
medications necessary for advanced life support and cardiopulmonary resuscitation, such as 
bronchodilators, vasopressor agents (for example, epinephrine), oxygen, glucocorticoids, 
antihistamines, and I.V. fluids, etc.
CAUTION:  Infusion-related reactions may occur during or following IMC-CS4 administration 
(see Section 9.1.2 for a definition of infusion-related reactions).
5.1.2
Premedication
Premedication is not recommended to be administered prior to the first infusion of IMC-CS4.  If 
the subject experiences a Grade 1 or 2 infusion-related reaction (as detailed in Section 9.1.2), 
premedication must be provided prior to any subsequent doses of IMC-CS4.  Any premedication 
administered should be documented in the eCRF, including dose and route of administration.
5.2
Treatment Compliance
Trained medical personnel will administer IMC-CS4.  Treatment compliance will be monitored 
by drug accountability records (Section 5.5), and treatment administration data are recorded in 
the subject’s medical record and subsequently transcribed in the eCRF.
The Investigator or his/her designee is responsible for the following:

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
Explaining the correct use of the drug(s) and planned duration of each subject’s treatment 
to the site personnel;

Verifying that instructions are followed properly;

Maintaining accurate records of study drug dispensing and collection (see Section 5.5); 
and

Disposing of all unused medication as described in Sections 5.6 and 5.7.
Subjects will be instructed to contact the Investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.
5.3
Packaging and Labeling
5.3.1
IMC-CS4 Drug Product
IMC-CS4 drug product (DP) is a sterile, preservative-free injection for I.V. use formulated in 
histidine buffer at an IMC-CS4 drug substance (DS) concentration of 5 mg/mL (100 mg/20-mL 
vial).  The buffer contains 10mM histidine, 100mM glycine, 100mM arginine, and 
0.01% polysorbate 80.  The pH is 6.0.
All excipients used for the manufacture of IMC-CS4 DP are of pharmacopeial grade.  
No animal-derived components are used in the manufacture of IMC-CS4 DP excipients.
IMC-CS4 DP is supplied in single-use, 20-mL nominal volume, United States Pharmacopeia 
Type I glass vials. Each vial contains 100 mg of IMC-CS4 at a concentration of 5 mg/mL 
(100 mg/20 mL) in a sterile, preservative-free solution. Each vial is stoppered with a chlorobutyl 
rubber stopper and sealed with an aluminum flip-off cap.
Each vial of IMC-CS4 is packaged in a single carton, and several cartons are contained in each 
shipment box. Each vial and each box contains a single-panel open label, including at a 
minimum, the following information:
product description, strength, lot number, storage 
conditions, and cautionary statement.
5.4
Storage
5.4.1
IMC-CS4
Refer to the IB and Pharmacy Manual for detailed storage information for IMC-CS4 DP and 
prepared IMC-CS4 for infusion.

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5.5
Accountability
It is the responsibility of the Investigator to ensure that a current record of investigational 
product disposition is maintained at each study site where investigational products are 
inventoried and disposed.  Records or logs must comply with applicable regulations and 
guidelines, and should include:

The amount received and placed in the storage area;

The amount currently in the storage area;

The label ID number or batch number;

The dates and initials of the person responsible for each investigational product inventory 
entry/movement;

The amount dispensed to each subject, including unique subject identifiers;

The amount transferred to another area for dispensing or storage;

Nonstudy disposition (for example, lost, wasted, broken);

The amount returned to the Sponsor and its representative(s)/delegate(s);

The amount destroyed at the study site, if applicable; and

Retained samples sent to a third party for bioavailability/bioequivalence, if applicable.
The Sponsor and its representative(s)/delegate(s) will provide forms to facilitate inventory 
control if the staff at the investigational site does not have an established system that meets these 
requirements.
5.6
Return of Investigational Product
At the end of the study, all unused and/or partially used investigational products must be returned 
to the Sponsor or its representative/delegate, if not authorized by the Sponsor or its 
representative/delegate to be destroyed at the site.
All investigational products returned to the Sponsor or its representative/delegate must be 
accompanied by the appropriate documentation and be clearly identified by protocol number and 
study site number on the outermost shipping container.  Returned supplies should be in the 
original containers.  Empty containers should not be returned to the Sponsor or its 
representative/delegate.  It is the Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established according to 
applicable federal, state, local, and institutional guidelines and procedures, and provided that 

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appropriate records of disposal are kept.  The return of unused investigational products should be 
arranged by the responsible study monitor.
5.7
Investigational Product Retention at Study Site
Opened vials may be disposed of at the investigation center as chemotherapy or biohazardous 
waste provided documented procedures for destruction have been provided to and approved by 
the Sponsor or its representative(s)/delegate(s).  Otherwise, opened vials must be returned to the 
Sponsor or its representative(s)/delegate(s) for disposal.  If IMC-CS4 is destroyed at the site, it is 
the Investigator’s responsibility to ensure that procedures for proper disposal have been 
established according to applicable regulations and guidelines and institutional procedures, 
including that:

Written authorization for disposal/destruction has been granted by the Sponsor or its 
representative/delegate;

Arrangements have been made for the disposal; and

Appropriate records of the disposal have been documented.

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6
STUDY PROCEDURES
6.1
Informed Consent
Informed consent – Written permission will be given by each subject prior to undergoing any 
protocol-specific evaluations and prior to receiving treatment.
6.2
Medical History
Medical history – Past and current medical conditions (for example, LVEF assessment) and 
treatments, current medications, medications taken within 30 (calendar) days prior to first dose 
of study therapy, date of initial diagnosis, pathological confirmation of malignancy, prior cancer 
therapy and surgery, current TNM (tumor, nodes, and metastases) staging and TNM staging at 
the time of initial diagnosis (refer to American Joint Committee on Cancer Staging Manual, 
7th edition [Edge et al. 2009] or higher).  Any preexisting toxicity (for example, Grade 1 fatigue) 
should be documented, recorded, and graded (NCI-CTCAE, Version 4.0 grade) at this time.
Concomitant medication assessment – To be performed and documented as outlined in Section 7
(Study Activities).
6.3
Physical Examination
Complete physical examination – Evaluation by body system and height (at pretreatment only).
Weight measurement
ECOG performance status – According to the ECOG PS criteria.
6.4
Vital Signs
Vital signs measurements – Includes temperature, pulse rate, respiration rate, and blood pressure.
6.5
Clinical Laboratory Tests
Investigators must document their review of each laboratory report.
Samples collected for specified laboratory tests will be destroyed within 60 (calendar) days of 
receipt of confirmed test results.  Tests are run and confirmed promptly whenever medically or 
scientifically appropriate.  When medical and scientific circumstances warrant, however, it is 

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acceptable to retain samples to batch the tests run.  Certain samples may be retained for a longer 
period, if necessary, to comply with applicable laws, regulations, or laboratory certification 
standards.
Hematology profile – Includes a complete blood count with differential and platelet count, 
surface staining and flow cytometric analysis of peripheral leukocytes.
Coagulation profile – Includes INR, PT if available, and PTT.
Serum chemistry profile – Includes sodium, potassium, chloride, carbon dioxide, blood urea 
nitrogen, creatinine, glucose, total protein, albumin, AST, ALT, AP, total bilirubin, LDH, CK, 
lipase, amylase, calcium, magnesium, and phosphorus.  Serum myoglobin levels will be 
analyzed in case of CK elevation (for CK increases ≥2.5 × ULN).
Isoenzymes of LDH, CK, and AP will be analyzed per Table 7, Table 8, and Table 9.  In 
addition, isoenzymes (such as CK isoenzymes MB, MM, and BB) will be quantified on Week 1 
of Cycle 2 and beyond only if that particular serum enzyme is ≥2.5 × ULN at Week 5 of Cycle 1.
Troponin (I or T or institutional standard) - Results are not needed prior to dosing, except for the 
Cycle 1, Day 1 dose.
C-reactive protein
Bone metabolism markers – Includes C-terminal cross-linking telopeptide of type I collagen 
(CTX-I) and procollagen type 1 N-terminal propeptide (P1NP).
Hepatic monitoring – The following selected tests may be obtained in the event of a treatment-
emergent hepatic abnormality and may be required in follow up with subjects in consultation 
with the Sponsor CRP:

Hematology profile – See above;

Hepatic chemistry – Includes total bilirubin, direct bilirubin, AST, ALT, AP, CK, and 
gamma-glutamyl transpeptidase;

Haptoglobin;

Coagulation profile – See above;

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
Hepatic serology – Includes hepatitis A antibody, total; hepatitis A antibody, IgM; 
hepatitis B surface antigen; hepatitis B surface antibody; hepatitis B core antibody; 
hepatitis C antibody; hepatitis E antibody, IgG; hepatitis E antibody, IgM;

Anti-nuclear antibody;

Anti-smooth muscle antibody.
Urinalysis – Routine dipstick measurements and, if clinically indicated, microscopic analysis.  
Myoglobin levels in the urine will be analyzed in case of serum CK elevation ≥2.5 × ULN.
Beta human chorionic gonadotropin (β-hCG) pregnancy test – Within 7 (calendar) days prior to 
the first dose of study therapy for WOCBP and every 12 weeks following the first dose thereafter 
(or according to local regulations, whichever is more frequent).  Serum pregnancy test required 
at pretreatment; serum or urine pregnancy test may be performed thereafter.
6.6
Efficacy Assessments
Imaging studies

Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, 
abdomen, pelvis, and (if applicable) brain.  CT or MRI of the neck should be performed, 
if clinically indicated.  It is recommended that CT imaging of the abdomen/pelvis be 
performed with I.V. contrast, whenever possible.  For subjects with known serious 
allergic reactions to CT contrast material, a CT of the chest without contrast and contrast-
enhanced MRI of the abdomen/pelvis or a CT of the abdomen/pelvis with oral contrast 
should be performed, at the discretion of the Investigator.

Chest x-rays are not permitted for tumor response assessment in this trial.

Bone scans should be performed at baseline as clinically indicated.  Routine bone scans
during treatment must be performed only in the setting of bone-only disease (no lymph 
node, visceral, skin, or subcutaneous metastases), or as deemed appropriate by the 
Investigator.  In the event that a positron emission tomography (PET) scan is performed 
within 28 (calendar) days prior to first dose of study therapy that is negative for bone 
disease, then no baseline bone scan is required.

Imaging methods must be employed consistently during the course of each subject’s 
evaluation during the study (that is, subjects who have MRI as baseline examination
continue to have MRI assessments as a means of determining response/progression).
Tumor measurements/disease response assessment – The determination of unidimensional 
measurements and disease response as defined in Section 11.

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6.7
Tissue Sampling
To assess the pharmacodynamic effect of IMC-CS4 administration on tumor-associated 
macrophages, all subjects enrolled in Cohort 2 and beyond will undergo tumor biopsies before 
study enrollment and as specified in Table 6.  For these cohorts, investigators will carry out a 
tumor (core needle or excisional) biopsy (attempt to obtain at least 3 cores) before starting the 
treatment and at the end of Cycle 1 (to be done in the week prior to Cycle 2, at the same time as 
tumor evaluation), if the subject’s condition allows it.  If an enrolled subject undergoes a 
pretreatment tumor biopsy but is unable to tolerate a posttreatment tumor biopsy, then a skin 
punch biopsy will be acceptable.
At the time of disease progression, the Investigator will also perform a tumor biopsy if the 
subject consents to it and if the subject’s condition allows it.
Previously archived tumor tissue from the primary tumor (paraffin block [whole or partial block] 
or 20 unstained slides), if available, will be collected (if possible) prior to receiving the first dose 
of study therapy.
Previously archived and/or biopsied tissue may be used for analysis that may include, but would 
not be limited to, factors related to the CSF-1R pathway, macrophages, and immune 
microenvironment.  All tissue samples will be kept by the Sponsor for a maximum of 15 years 
after the main study is completed; then all samples will be destroyed.
6.8
Blood Sampling
Blood will be collected from all subjects for PK, pharmacodynamic, immunogenicity, and other
analyses as described in Sections 6.8.1, 6.8.2, 6.8.3, and 6.8.4.  Samples collected will be 
retained for a maximum of 15 years (pharmacodynamics, immunogenicity) or 1 year (PK)
following the last subject visit for the study, or as previously described in Section 6.5.
6.8.1
Pharmacokinetics
The analytical methods used to determine serum drug concentration will be validated at a 
laboratory determined by the Sponsor.  Serum concentrations of IMC-CS4 will be determined 
using an enzyme-linked immunosorbent assay.

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Blood samples will be drawn in order to perform assessment of levels of IMC-CS4 in serum.  
Parameters to be reported may include, but not be limited to, Cmax, trough serum concentration
(Cmin), AUC, t1/2, clearance (Cl), and volume at steady state (Vss) of IMC-CS4.  Detailed 
instructions for collecting, processing, storing, and shipping of samples will be provided by the 
Sponsor or its representative(s)/delegate(s) in a separate procedural manual.  Refer to Section 7.7
for a detailed schedule of collection time points.  For each specified time point, one tube 
(approximately 7.5 mL/tube) of blood is required; if the timing of a PK sample should coincide 
with that of an immunogenicity sample, the same sample will suffice for both studies.
6.8.2
Immunogenicity Testing (Anti-IMC-CS4 Antibodies)
Blood samples for the assessment of antibodies against IMC-CS4 (immunogenicity) will be 
collected for all study subjects at specified time points throughout the study (Section 7.7).  
In addition, if a subject should have an infusion-related reaction to IMC-CS4, all attempts will be 
made to obtain a blood sample for immunogenicity analysis as close to the onset of the event as 
possible, at the resolution of the event, and 30 (calendar) days following the event.  For each 
specified time point, one tube (approximately 7.5 mL/tube) of blood is required; if the timing of 
a PK sample should coincide with that of an immunogenicity sample, the same sample will 
suffice for both studies.
In certain circumstances, including if antibodies against IMC-CS4 are detected, the subject’s 
serum IMC-CS4 concentration will be analyzed using the same sample, in order to determine if 
there is any alteration of IMC-CS4 PK.  Detailed instructions for collecting, processing, storing, 
and shipping of samples will be provided by the Sponsor and its representative(s)/delegate(s) in a 
separate procedure manual.  Refer to Section 7.7 for a detailed schedule of collection time points.
6.8.3
Pharmacodynamics
Blood and tissue samples will be taken.  Analyses may include, but are not limited to, the 
following parameters:

Levels of potential circulating and tissue pharmacodynamic markers, including but not 
limited to CSF-1, IL-34, MCP-1, and macrophage-specific markers (for example, CD68 
and CD163);

Characterization of blood monocyte subsets by flow cytometry (CD14, CD16, and 
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
Serum markers of bone metabolism (CTX-I and P1NP).
Samples drawn for pharmacodynamic analyses will be separate from those collected for PK and 
immunogenicity analyses as described in Sections 6.8.1 and 6.8.2, respectively.  Detailed 
instructions for collecting, processing, storing, and shipping of samples will be provided by the 
Sponsor or its representative(s)/delegate(s) in a separate procedural manual.  Refer to Section 7.7
for a detailed schedule of collection time points.
6.8.4
Other Analyses
Refer to Section 6.5 for details of blood samples drawn for other analyses, including flow-
cytometric analysis of peripheral leukocytes; isoenzymes of LDH, CK, and AP; troponin (I or T); 
and bone metabolism markers CTX-I and P1NP.  These samples will be separate from those used 
for PK/immunogenicity and pharmacodynamic analyses, and drawn according to the schedule 
described in Sections 7.2.2.2, 7.2.2.3, 7.2.2.4, and 7.2.2.5.
6.9
Electrocardiogram
An electrocardiogram (ECG) including measurement of QT/corrected QT (QTc) interval will be 
obtained pretreatment (within 14 [calendar] days prior to first dose of study therapy), on study, 
and at the end of therapy according to the schedule in Section 7.2.
6.9.1
Triplicate ECG (Part A Only)
Triplicate ECG consisting of 3 individual ECGs performed consecutively within a period of 
approximately 4 minutes will be obtained at the time points specified in Section 7.2.3.1 from 
additional subjects enrolled at the RP2D.
6.10
Multigated Acquisition Scan or Echocardiogram
A multigated acquisition (MUGA) scan or an echocardiogram will be performed for all subjects 
during pretreatment evaluations (within 28 [calendar] days prior to first dose of study therapy), 
as an eligibility assessment of LVEF.  Refer to exclusion criterion #11 (Section 3.3) for subject 
eligibility regarding LVEF.

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6.11
Optional Study Procedures
6.11.1
Tumor Tissue Submission
In addition to the mandatory collections described in Section 6.7, specimens will be collected 
when available as described below from subjects who consent to these optional procedures.
If a core biopsy, surgical biopsy, or resection is performed in the course of the study as routine 
clinical care, the Sponsor requests a tissue block or unstained slides for analysis of potentially 
relevant surrogate biomarkers.  Tissue will be kept with the intention to perform tests as new 
techniques, research tools, and biomarkers become available.  All tissue samples will be kept by 
the Sponsor for a maximum of 15 years after the main study is completed, then all samples will 
be destroyed.
Detailed instructions for collecting, processing, storing, and shipping of samples will be provided 
by the Sponsor or its representative(s)/delegate(s) in a separate procedural manual.
6.12
Appropriateness of Measurements
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional Phase 1 oncology trials.

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7
STUDY ACTIVITIES
Throughout this protocol, “days” refers to calendar days, unless otherwise indicated.
7.1
Pretreatment Evaluations
Pretreatment evaluations are used to determine the subject’s study eligibility and must be 
completed within 14 days prior to the first dose of study medication unless otherwise specified.  
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.  
All subjects must undergo the following pretreatment evaluations:

Medical history (any preexisting toxicity should be documented, recorded, and graded 
[NCI-CTCAE, Version 4.0 grade] as a part of the pretreatment history);

Serum β-hCG pregnancy test in WOCBP (within 7 days prior to the first dose of study 
therapy);

Baseline ECG;

Baseline MUGA or echocardiogram for LVEF assessment (within 28 days prior to the 
first dose of study therapy);

ECOG PS assessment;

Complete physical examination (including height measurement);

Vital signs (including temperature, pulse rate, respiration rate, and blood pressure);

Weight measurement;

Baseline toxicity/AE assessment;

Concomitant medication assessment (including those medications taken 30 days prior to 
the first dose of study therapy);

Hematology profile;

Coagulation profile;

Serum chemistry profile, including myoglobin;

C-reactive protein assessment;

Urinalysis;

Blood samples for baseline PK analysis (on the day of and immediately prior to the first 
dose of study therapy), and immunogenicity and pharmacodynamic analyses (within 
7 days prior to the first dose of study therapy);

Blood samples for flow cytometry assessment and isoenzyme assessment of LDH, CK, 
and AP (within 7 days prior to the first dose of study therapy) for subjects in Cohort 2
and beyond;

Blood sample for troponin (I or T) assessment (prior to the first infusion of Cycle 1 so 
that results are obtained before dosing);

Blood sample for bone metabolism marker assessment (within 7 days prior to the first 
dose of study therapy);

Imaging studies including a CT scan or MRI as described in Section 6.6 (performed and 
documented within 28 days prior to the first dose of study therapy); 

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
Bone scan, as clinically indicated (within 28 days prior to the first dose of study therapy; 
not required if PET is performed within 28 days prior to the first dose of study therapy 
that is negative for bone disease); and

Tumor (core needle or excisional) biopsy (mandatory) (within 7 days prior to the first 
dose of study therapy) for subjects in Cohort 2 and beyond.
7.2
Treatment Period
In all cohorts, WOCBP or fertile men with partners of childbearing potential must be using an 
adequate method of contraception to avoid pregnancy throughout the study and for up to 
12 weeks after the study.
A series of clinical tests and procedures will be performed at specified intervals throughout the 
study (see also Section 7.6).  If, at any time during the study, tumor tissue is obtained as routine 
clinical care or through a biopsy, fine-needle aspiration (FNA), or resection, the Sponsor requests 
a portion of the sample for exploratory analyses.
IMC-CS4 is administered I.V. as shown in Section 4.1, Table 2, Table 3, Table 4, and Table 5.  
An observation period will occur, as needed, in Cycle 1 of Part A only, as described in 
Section 4.1.  Radiographic assessment of tumor response will be performed at the end of every 
treatment cycle (prior to the first dose of study therapy in the subsequent cycle, approximately 
every 6 weeks assuming no treatment delays); radiographic assessment should be performed 
prior to the start of a cycle so that results are available before the subject receives a new cycle of 
treatment.  However, if a DLT is observed in Cycle 1 in a subject who is benefitting from 
treatment, Cycle 2 dosing may be initiated within 4 weeks of Cycle 1, Day 1, with Sponsor 
approval; in this case, no radiographic disease assessment is required prior to dosing in Cycle 2.  
Routine bone scans during treatment must be performed only in the setting of bone-only disease 
(no lymph node, visceral, skin, or subcutaneous metastases), or as deemed appropriate by the 
Investigator.
Other assessments and evaluations will be performed as described in the following sections.  
Note that evaluations will be performed according to the same schedule in all cohorts, unless 
otherwise specified.

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7.2.1
Regular Assessments
A serum or urine pregnancy test will be performed for WOCBP at Week 13 (that is, 12 weeks 
after the first dose), and every 12 weeks thereafter (or according to local regulations, whichever 
is more frequent).
Beginning with Week 1, Day 1, the following evaluations will be performed every week
(±2 days for subjects in the qw cohorts and Cohorts 6b, 7b, and 8b and ±3 days for subjects in 
the q2w cohorts) for the first 12 weeks on therapy (this includes nontreatment weeks for subjects
enrolled in the q2w cohorts and Cohorts 6b, 7b, and 8b), unless otherwise indicated:

ECOG PS assessment;

Vital sign measurements (vital signs to be checked and recorded prior to each infusion of 
IMC-CS4, midway through each infusion, at the end of each infusion, and every 
15 minutes for the first hour following each infusion, including Week 1, Day 1 [also to be 
checked and recorded at nontreatment visits during Cycle 1]);

Weight measurement;

Toxicity/AE evaluations;

Concomitant medication assessment;

Hematology profile (evaluations performed within 7 days prior to the first dose do not 
need to be repeated at Week 1, Day 1);

Serum chemistry profile (evaluations performed within 7 days prior to the first dose 
do not need to be repeated at Week 1, Day 1); 

C-reactive protein assessment;

Tumor biopsy – At the end of Cycle 1, if the subject’s condition allows it, a (mandatory) 
(core needle or excisional) biopsy of the tumor will be performed, regardless of whether 
the tumor progressed, stabilized, or regressed (refer to Section 7.2.1.1 for the timing of 
non-mandatory tumor biopsies);

Blood samples for PK, immunogenicity, and pharmacodynamic analyses, per Section 7.7
(Table 7, Table 8, and Table 9); and

Blood samples for the following assessments, per Section 7.7 (Table 7, Table 8, and 
Table 9):  flow cytometry of peripheral leukocytes; isoenzymes of LDH, CK, and AP; 
troponin (I or T); and bone metabolism markers CTX-I and P1NP.
After study Week 12 (that is, after Cycle 2), ECOG PS assessment, vital sign measurements, 
weight measurement, toxicity/AE evaluations, and concomitant medication assessment will 
continue to be performed every week, while C-reactive protein assessment will be performed 
q2w.  After Week 12, hematology and serum chemistry will be performed: q2w for Cohorts 1, 2, 
3, 4, 5, 6a, 6c, 7a, 7c, 8a, and 8c, and every 3 weeks (q3w) for Cohorts 6b, 7b, and 8b (such that 
these hematology and serum chemistry assessments are done on rest Weeks 3 and 6).

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A physical examination will be performed q2w for the first 12 weeks of the study, and every 
6 weeks thereafter.
Coagulation profile and urinalysis will be performed at the beginning of each cycle (that is, 
approximately every 6 weeks following the first dose of study therapy).
7.2.1.1
Tumor Biopsy
Tumor (core needle or excisional) biopsy will be performed at the following time points:
Weekly Cohorts and Cohorts 6b, 7b, and 8b
Mandatory (unless medically contraindicated)

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

At the end of Cycle 1, if the subject’s condition allows it, a (core needle or excisional) 
biopsy of the tumor will be performed, regardless of whether the tumor progressed, 
stabilized, or regressed.
Non-mandatory

In cases of tumor progression, if the subject’s condition allows it, a (core needle or 
excisional) biopsy will be performed.
Every-2-Week Cohorts
Mandatory (unless medically contraindicated)

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

At the end of Cycle 1, if the subject’s condition allows it, a (core needle or excisional)
biopsy of the tumor will be performed, regardless of whether the tumor progressed, 
stabilized, or regressed.

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Non-mandatory

In cases of tumor progression, if the subject’s condition allows it, a (core needle or 
excisional) biopsy will be performed.
7.2.2
Blood Sampling
7.2.2.1
Pharmacokinetic, Pharmacodynamic, Immunogenicity Sampling
Blood samples will be collected from all enrolled subjects according to the detailed schedule in 
Section 7.7, and used for PK, pharmacodynamic, and immunogenicity analyses.
7.2.2.2
Flow Cytometry Analysis
Blood samples for flow cytometric analysis of peripheral leukocytes will be collected at the 
following time points:
Weekly Cohorts and Cohorts 6b, 7b, and 8b

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

1 day (approximately 24 hours) after the first IMC-CS4 infusion in Cycle 1

2 days (approximately 48 hours) after the first IMC-CS4 infusion in Cycle 1

3 days (approximately 72 hours) after the first IMC-CS4 infusion in Cycle 1

Immediately prior to the second IMC-CS4 infusion of Cycle 1

Immediately prior to the third IMC-CS4 infusion of Cycle 1

Immediately prior to the fourth IMC-CS4 infusion of Cycle 1

Cohorts 6b, 7b, and 8b only:  1 day after the first IMC-CS4 infusion in Cycle 3 
(approximately 24 hours)

Immediately prior to the second IMC-CS4 infusion of Cycle 3.
Every-2-Week Cohorts

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

3 days (approximately 72 hours) after the first IMC-CS4 infusion in Cycle 1

Immediately prior to the second IMC-CS4 infusion of Cycle 1

Immediately prior to the second IMC-CS4 infusion of Cycle 3.
In all cohorts, blood samples for flow cytometric analysis will be collected at the 30-Day 
Follow-up visit.
7.2.2.3
LDH, CK, and AP Isoenzymes

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A sample for analysis of LDH, CK, and AP isoenzymes will be collected at the following 
time points:
Weekly Cohorts and Cohorts 6b, 7b, and 8b

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

Prior to the second IMC-CS4 infusion of Cycle 1 (≤3 days)

Prior to the third IMC-CS4 infusion of Cycle 1 (≤3 days)

On Week 1 of Cycle 2; collected only if serum enzymes are ≥2.5 × ULN at Week 5 of 
Cycle 1

Cohorts 6b, 7b, and 8b only:  Prior to the second IMC-CS4 infusion of Cycle 3 (≤3 days); 
collected only if serum enzymes are ≥2.5 × ULN at Week 5 of Cycle 1.
Every-2-Week Cohorts

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

Prior to the second IMC-CS4 infusion of Cycle 1 (≤3 days)

On Week 1 of Cycle 2; collected only if serum enzymes are ≥2.5 × ULN at Week 5 of 
Cycle 1.
In all cohorts, blood samples for isoenzyme analysis will be collected at the end of therapy and at 
the 30-Day Follow-up visit only if that particular serum enzyme is ≥2.5 × ULN at Week 5 of 
Cycle 1.
7.2.2.4
Troponin
Serum levels of troponin (I or T) will be assessed at the following time points:
Weekly Cohorts and Cohorts 6b, 7b, and 8b

Prior to the first IMC-CS4 infusion of Cycle 1 (sample to be collected prior to the first 
infusion of Cycle 1 so that results are obtained before dosing)

Prior to the second IMC-CS4 infusion of Cycle 1 (≤3 days)

Prior to the third IMC-CS4 infusion of Cycle 1 (≤3 days)

On Week 1 of Cycle 2; collected only if serum CK levels are ≥2.5 × ULN at Week 5 of 
Cycle 1

Cohorts 6b, 7b, and 8b only:  Prior to the second IMC-CS4 infusion of Cycle 3 (≤3 days); 
collected only if serum CK levels are ≥2.5 × ULN at Week 5 of Cycle 1

When deemed appropriate by the Investigator.
Every-2-Week Cohorts

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
Prior to the first IMC-CS4 infusion of Cycle 1 (sample to be collected prior to the first 
infusion of Cycle 1 so that results are obtained before dosing)

Prior to the second IMC-CS4 infusion of Cycle 1 (≤3 days)

On Week 1 of Cycle 2; collected only if serum CK levels are ≥2.5 × ULN at Week 5 of 
Cycle 1

When deemed appropriate by the Investigator.
In all cohorts, blood samples for troponin analysis will be collected at the end of therapy and at 
the 30-Day Follow-up visit only if CK ≥2.5 × ULN at Week 5 of Cycle 1.
With the exception of the first IMC-CS4 infusion of Cycle 1, IMC-CS4 may be administered as 
planned while troponin results are pending, provided no cardiac symptoms have been revealed 
upon ECG or physical examination.  For the first IMC-CS4 infusion of Cycle 1 (all cohorts), 
troponin results should be obtained before dosing.
7.2.2.5
Bone Metabolism Markers CTX-I and P1NP
Serum levels of CTX-I and P1NP (bone metabolism markers) will be assessed at the following 
time points:
Weekly Cohorts and Cohorts 6b, 7b, and 8b

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

Prior to the second IMC-CS4 infusion of Cycle 1 (≤3 days)

Prior to the fourth IMC-CS4 infusion of Cycle 1 (≤3 days)

Prior to the second IMC-CS4 infusion of Cycle 3 (≤3 days).
Every-2-Week Cohorts

Prior to the first IMC-CS4 infusion of Cycle 1 (≤7 days)

Prior to the second IMC-CS4 infusion of Cycle 1 (≤3 days).
7.2.3
ECG Assessment
ECG assessment will be performed at the following time points (note that in cases where ECG 
and blood sample collection are scheduled at the same time, all blood sampling should be 
performed prior to ECG assessment):

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
Prior to the first infusion of Cycle 1 and 1 hour (±30 minutes) following the completion 
of the first infusion of Cycle 1

Prior to the last infusion of Cycle 1 and 1 hour (±30 minutes) following the completion of 
the last infusion of Cycle 1

Prior to the last infusion of all subsequent cycles and 1 hour (±30 minutes) following the 
completion of the last infusion of all subsequent cycles

When deemed appropriate by the Investigator.
7.2.3.1
Triplicate ECG Schedule (Part A Only)
As described in Section 4.1.2, additional subjects may be enrolled at the RP2D.  These subjects
only will undergo triplicate ECG testing (see Section 6.9.1) at each of the following time points:

Prior to the first infusion of Cycle 1 and 1 hour (±30 minutes) following the completion 
of the first infusion of Cycle 1

Prior to the last infusion of Cycle 1 and 1 hour (±30 minutes) following the completion of 
the last infusion of Cycle 1 (qw cohorts)

Prior to the last infusion of Cycle 3 and 1 hour (±30 minutes) following the completion of 
the last infusion of Cycle 3 (q2w cohorts only)

Prior to the last infusion of all subsequent cycles and 1 hour (±30 minutes) following the 
completion of the last infusion of all subsequent cycles.
Note that subjects undergoing triplicate ECG testing according to this schedule are not required 
to undergo additional single ECG per the schedule outlined in Section 7.2 (that is, these subjects
will undergo triplicate ECG only).
7.3
End-of-Therapy Evaluations
End-of-therapy evaluations will be assessed on subjects who are no longer receiving study 
therapy.  The end-of-therapy evaluations will include:

ECG (triplicate ECG for Part A only, as described in Sections 6.9.1 and 7.2.3.1);

ECOG PS assessment;

Physical examination;

Vital signs (including temperature, pulse rate, respiration rate, and blood pressure);

Weight measurement;

Toxicity/AE evaluations;

Concomitant medication assessment;

Hematology profile;

Serum chemistry profile;

C-reactive protein assessment;

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
Troponin (I or T) analysis and isoenzyme assessment of LDH, CK, and AP only if serum 
enzymes are ≥2.5 × ULN at Week 5 of Cycle 1; and

Urinalysis.
In cases of tumor progression, if the subject’s condition allows it, a (core needle or excisional)
biopsy of the tumor will be performed.  For subjects who discontinue study therapy for any 
reason other than PD, every effort will be made to obtain radiographic tumor assessments at 6 
and 12 weeks following the first dose of study therapy and/or until radiographic documentation 
of PD.
7.4
30-Day Follow-up Evaluations
All subjects will be followed for a minimum of 30 days after the last dose of study therapy; AEs
occurring during this period will be documented and reported according to the guidelines in 
Section 8.  A follow-up evaluation will be conducted approximately 30 days (+0-7 days) after the 
last dose of study therapy, and will include:

Serum β-hCG pregnancy test in WOCBP;

ECOG PS assessment;

Physical examination;

Vital signs (including temperature, pulse rate, respiration rate, and blood pressure);

Weight measurement;

Toxicity/AE evaluations;

Concomitant medication assessment;

Hematology profile;

Serum chemistry profile, including myoglobin;

C-reactive protein assessment;

Troponin (I or T) analysis and isoenzyme assessment of LDH, CK, and AP only if serum 
enzymes are ≥2.5 × ULN at Week 5 of Cycle 1;

Urinalysis;

Blood samples for PK, immunogenicity, and pharmacodynamic evaluations; and

Blood sample for flow cytometry analysis of peripheral leukocytes.
7.5
Extended Follow-up Evaluations
All SAEs and IMC-CS4-related AEs will be followed until the event is resolved, stabilized, 
returned to baseline, deemed irreversible, or otherwise explained (frequency of follow-up 
evaluations is left to the discretion of the Investigator).

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7.6
Study Events Table
Table 6 summarizes assessments, tests, and treatments scheduled to occur as part of Study IMCL CP24-1001.  “Days” refers to 
calendar days, unless otherwise indicated.
Table 6.  Flow Chart for Protocol
Procedures
Pretreatment
(Prior to first dose)
Treatment Cyclesa
End of 
Therapy
30-Day 
Follow-
up
Extended 
Follow-
up
Within
28 Days
Within
14 Days
Within
7 Days
Every
Weekb
Every 2
Weeks
Every 3
Weeks
Every 6
Weeks
Every 12
Weeks
Eligibility Assessments
Informed consent
Xc
N/A
Medical history
X
N/A
β-hCG Pregnancy test
Xd
Xd
Xd
ECG
X
Xe
X
MUGA/echocardiogram
X
Triplicate ECG (Part A only)
Xef
Xf
ECOG PS assessment
X
X
X
X
Safety Assessments
Physical examination
Xg
Xh
Xh
X
X
Vital signs
Xi
Xi
Xi
X
Weight measurement
X
X
X
X
Toxicity/AE assessment
Xj
X
X
X
Xk
Concomitant medication assessment
Xl
X
X
X
Laboratory Tests
Hematology profile
X
Xm,n
Xm
Xm
X
X
Coagulation profile
X
Xo
Serum chemistry profile
X
Xm,n
Xm
Xm
X
X
C-reactive protein assessment
X
Xm,n
Xm
X
X

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Table 6.  Flow Chart for Protocol
Procedures
Pretreatment
(Prior to first dose)
Treatment Cyclesa
End of 
Therapy
30-Day 
Follow-
up
Extended 
Follow-
up
Within
28 Days
Within
14 Days 
Within
7 Days
Every
Weekb
Every 2
Weeks
Every 3
Weeks
Every 6
Weeks
Every 12
Weeks
Urinalysis
X
Xo
X
Blood Sampling
All blood sampling
Refer to Table 7 (qw cohorts), Table 8 (q2w cohorts), and Table 9 (Cohorts 6b, 7b, and 8b).
Efficacy Assessments
Imaging studies (CT/MRI)
X
Xp
Bone scan
Xq
Xr
Tumor assessments
X
Xp
Tumor (core needle or excisional)
biopsy
X
Xs
Xt
Tumor tissue submission
Xu
Study Therapy Administration
Administer IMC-CS4
N/A
Refer to Table 2 (Part A - qw cohorts), Table 3 (q2w
cohorts), Table 4 (Part B – qw cohorts), and Table 5
(Cohorts 6b, 7b, and 8b).
N/A
Abbreviations:  β-hCG = beta human chorionic gonadotropin; AE = adverse event; CK = creatine kinase; CT/MRI = computed tomography (scan)/magnetic resonance imaging; 
DLT = dose-limiting toxicity; ECOG PS = Eastern Cooperative Oncology Group performance status; ECG = electrocardiogram;MUGA = multigated acquisition; N/A = not 
applicable; NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PET = positron emission tomography; PK = pharmacokinetic(s); qw = 
weekly; q2w = every 2 weeks; q3w = every 3 weeks; RP2D = recommended Phase 2 dose; ULN = upper limit of normal; 
WOCBP = women of childbearing potential.
a
Visit windows will coincide with the study therapy administration windows; that is, ±2 days for subjects in the qw cohorts and Cohorts 6b, 7b, and 8b, and ±3 days for 
subjects in the q2w cohorts.
b
Evaluations performed as part of the pretreatment assessment do not need to be repeated on Day 1 of Week 1 unless required in the opinion of the Investigator.
c
Written permission will be given by each subject prior to undergoing any protocol-specific pretreatment evaluations and prior to receiving treatment.
d
At baseline, serum pregnancy test is required for WOCBP.  Thereafter, including at Week 13 (that is, 12 weeks after the first dose), every 12 weeks (or according to local 
regulations, whichever is more frequent), and at the 30-Day Follow-up visit, a serum or urine pregnancy test may be performed.
e
ECG assessment will be performed at the following time points:  Prior to the first infusion of Cycle 1 and 1 hour (±30 minutes) following the completion of the first infusion 
of Cycle 1; prior to the last infusion of Cycle 1 and 1 hour (±30 minutes) following the completion of the last infusion of Cycle 1; prior to the last infusion of all subsequent 
cycles and 1 hour (±30 minutes) following the completion of the last infusion of all subsequent cycles; and when deemed appropriate by the Investigator.  Note that in cases 
where ECG and blood sample collection are scheduled at the same time, all blood sampling should be performed prior to ECG assessment.

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Table 6.  Flow Chart for Protocol
f
For additional subjects enrolled at the RP2D of Part A only; they will undergo triplicate (instead of single) ECG testing, according to the following schedule:  Prior to the first 
infusion of Cycle 1 and 1 hour (±30 minutes) following the completion of the first infusion of Cycle 1; prior to the last infusion of Cycle 1 and 1 hour (±30 minutes) following 
the completion of the last infusion of Cycle 1 (qw cohorts); prior to the last infusion of Cycle 3 and 1 hour (±30 minutes) following the completion of the last infusion of 
Cycle 3 (q2w cohorts only); and prior to the last infusion of all subsequent cycles and 1 hour (±30 minutes) following the completion of the last infusion of all subsequent 
cycles.
g
The complete physical examination includes height (at baseline only).
h
Every 2 weeks for the first 12 weeks of the study, and every 6 weeks thereafter.
i
Vital signs include temperature, pulse rate, respiration rate, and blood pressure.  Vital signs will be checked and recorded prior to each infusion of IMC-CS4, midway through 
each infusion, at the end of each infusion, and every 15 minutes for the first hour following each infusion, including Week 1, Day 1 (also to be checked and recorded at 
nontreatment visits during Cycle 1).
j
Any preexisting toxicity should be documented, recorded, and graded (NCI-CTCAE, Version 4.0 grade) as a part of the pretreatment medical history.
k
All SAEs and IMC-CS4-related AEs will be followed until the event is resolved, stabilized, returned to baseline, deemed irreversible, or otherwise explained (frequency of 
follow-up evaluations is left to the discretion of the Investigator).  Data on SAEs that occur before the end of the trial will be stored in the collection database and the Lilly 
Safety System.
l
Including those medications taken within 30 days prior to the first dose of study therapy.
m
Every week for the first 12 weeks on therapy.  After Week 12, C-reactive protein assessment will be performed q2w; hematology and serum chemistry will be performed q2w 
for Cohorts 1, 2, 3, 4, 5, 6a, 6c, 7a, 7c, 8a, and 8c and q3w for Cohorts 6b, 7b, and 8b (that is, on rest Weeks 3 and 6).
n
Hematology and serum chemistry evaluations performed within 7 days prior to the first dose do not need to be repeated at Week 1, Day 1.
o
Coagulation profile and urinalysis will be performed at the beginning of each cycle (that is, approximately every 6 weeks following the first dose of study therapy).
p
Radiographic assessment of tumor response should be performed prior to the start of a cycle so that results are available before the subject receives a new cycle of treatment.  
However, if a DLT is observed in Cycle 1 in a subject who is benefitting from treatment, Cycle 2 dosing may be initiated within 4 weeks of Cycle 1, Day 1, with Sponsor 
approval; in this case, no radiographic disease assessment is required prior to dosing in Cycle 2.
q
Not required if PET is performed within 28 days prior to the first dose of study therapy that is negative for bone disease.
r
Bone scan at baseline, as clinically indicated.  Routine bone scans during treatment must be performed only in the setting of bone-only disease (no lymph node, visceral, skin, 
or subcutaneous metastases), or as deemed appropriate by the Investigator.
s
At the end of Cycle 1, if the subject’s condition allows it, a biopsy of the tumor will be performed, regardless of whether the tumor progressed, stabilized, or regressed.  If the 
subjects’s condition does not safely permit a tumor biopsy, then a skin biopsy may be submitted.
t
In cases of disease progression, if the subject’s condition allows it, a tumor biopsy will be performed.
u
If, at any time during the study, tumor tissue is obtained through a core biopsy, surgical biopsy, or resection as routine clinical care, the Sponsor requests a tissue block or 
unstained slides for analysis of potentially relevant surrogate biomarkers.  Subjects must consent to these optional procedures.

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7.7
Pharmacokinetic and Other Sampling
Table 7, Table 8, and Table 9 summarize PK and other sampling scheduled to occur as part of 
Study IMCL CP24-1001.
Table 7.  Blood Collection Schedule (Parts A and B - Weekly Cohorts 1, 2, 3, 5, 6a, 
6c, 7a, 7c, 8a, and 8c)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
Trop
Bone
Pretreatment
Prior to the first infusion
Xc
Xd
Xd
Xd
Xd
Xd
Xd
Cycle 1 (Week 1)
Immediately after the end of the first infusion of 
Cycle 1
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
X
X
48 hr (Day 3) after the end of the first infusion
X
X
X
72 hr (Day 4) after the end of the first infusion
X
X
X
168 hr (Day 8) after the end of the first infusion 
immediately (unless otherwise footnoted) prior the 
second infusion of Cycle 1
X
X
X
X
Xe
Xe
Xe
Cycle 1 (Week 3)
Immediately (unless otherwise footnoted) prior to 
the third infusion of Cycle 1
X
Xe
Xe
Cycle 1 (Week 4)
Immediately (unless otherwise footnoted) prior to 
the fourth infusion of Cycle 1
X
X
X
X
Xe
Cycle 2 (Week 1)
Prior to the first infusion of Cycle 2
Xf
Xg
Cycle 2 (Week 6)
Immediately prior to the sixth infusion of Cycle 2
X
X
Cycle 3 (Week 1)
Immediately prior to the first infusion of Cycle 3
X
X
X
Immediately after the end of the first infusion
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
48 hr (Day 3) after the end of the first infusion
X
96 hr (Day 5) after the end of the first infusion
X
168 hr (Day 8) after the end of the first infusion, 
immediately (unless otherwise footnoted) prior to 
the second infusion of Cycle 3
X
X
X
Xe
Cycle 3 (Week 4)
Immediately prior to the fourth infusion of Cycle 
3
X
X
X
Cycles 4-6h
Prior to the last infusion of each cycle
X
X
Table is continued on the next page.

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Table 7.  Blood Collection Schedule (Parts A and B - Weekly Cohorts 1, 2, 3, 5, 6a, 
6c, 7a, 7c, 8a, and 8c)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
Trop
Bone
Cycle 5
Immediately prior to the first infusion of Cycle 5 
(6 months after the first infusion of Cycle 1)
X
End of Therapy
At the End-of-Therapy visit
Xf
Xg
Follow-up
30-Day Follow-up visiti
X
X
X
X
Xf
Xg
Abbreviations:  Bone = assessment of bone metabolism markers (CTX-I and P1NP); CK = creatine kinase; CTX-I = C-terminal 
cross-linking telopeptide of type I collagen; ECG = electrocardiogram; FC = flow cytometry analysis; IGx = immunogenicity; Iso 
= isoenzyme analysis; P1NP = procollagen type 1 N-terminal propeptide; PD = pharmacodynamic markers; PK = 
pharmacokinetic(s); Trop = troponin (I or T) assessment; ULN = upper limit of normal.
a
It is understood that it may not be feasible to collect samples at precise intervals following the end of the infusions.  Every 
attempt should be made to collect each of these samples as close to the time point as possible.  The date and time of all PK 
samplings must be clearly and accurately recorded.
b
PK samples will be collected from all subjects.  The date and time of all samplings must be clearly and accurately recorded.  
The blood samples collected for PK will also be used for immunogenicity analyses.  For each specified time point, 1 tube of 
blood is required to be drawn for any combination of PK or immunogenicity analyses.  As an example, if the timing of a PK 
sample should coincide with that of an immunogenicity sample, the same sample will suffice for these studies and the same 
total amount of blood (1 tube, approximately 7.5 mL/tube) will be collected.
c
Pretreatment sampling should be collected on the day of and immediately prior to the first infusion.
d
IGx, PD, FC, isoenzyme analysis, and bone metabolism markers:  Sample to be collected ≤7 days prior to the first infusion
of Cycle 1.  Troponin (I or T) analysis:  Sample to be collected prior to the first infusion of Cycle 1 so that results are 
obtained before dosing.
e
Sample to be collected at any time ≤3 days prior to the infusion.  IMC-CS4 may be administered as planned while troponin 
(I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or physical examination.
f
Analysis to be performed only if serum enzymes are ≥2.5 × ULN at Week 5 of Cycle 1.
g
Analysis to be performed only if serum CK levels are ≥2.5 × ULN at Week 5 of Cycle 1.  IMC-CS4 may be administered as 
planned while troponin (I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or 
physical examination.
h
For subjects who proceed to Cycles 4 to 6, blood samples will be collected prior to the last infusion of each cycle.  In the 
event that a subject does not proceed to these cycles, these samples will not be collected.
i
A sample will be collected 30 days after last dose of investigational agent, regardless of duration of therapy.
Note:  If at any time a subject experiences an infusion-related reaction to IMC-CS4, all attempts will be made to obtain a blood 
sample for immunogenicity analysis as close to the onset of the event as possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken for immunogenicity testing may be used for PK analysis, in the setting of 
infusion-related reactions.

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Table 8.  Blood Collection Schedule (Part A - Every-2-Week Cohort 4)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
Trop
Bone
Pretreatment
Prior to the first infusion
Xc
Xd
Xd
Xd
Xd
Xd
Xd
Cycle 1 (Week 1)
Immediately after the end of the first infusion of 
Cycle 1
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
X
72 hr (Day 4) after the end of the first infusion
X
X
X
168 hr (Day 8) after the end of the first infusion
X
X
336 hr (Day 15) after the end of the first infusion, 
immediately (unless otherwise footnoted) prior to 
the second infusion of Cycle 1
X
X
X
Xe
Xe
Xe
Cycle 1 (Week 3)
Immediately after the end of the second infusion
of Cycle 1
X
1 hr after the end of the second infusion
X
X
2 hr after the end of the second infusion
X
X
4 hr after the end of the second infusion
X
X
24 hr (Day 2) after the end of the second infusion
X
X
72 hr (Day 4) after the end of the second infusion
X
X
168 hr (Day 8) after the end of the second infusion
X
X
336 hr (Day 15) after the end of the second 
infusion (Week 5)
X
X
504 hr (Day 22) after the end of the second 
infusion (Week 6) of Cycle 1
X
X
Cycle 2 (Week 1)h
Prior to the first infusion of Cycle 2
Xf
Xg
Cycle 2 (Week 5)h
Immediately prior to the third infusion of Cycle 2
X
X
Cycle 3 (Week 1)h
Immediately prior to the first infusion of Cycle 3
X
X
X
Immediately after the end of the first infusion
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
72 hr (Day 4) after the end of the first infusion
X
168 hr (Day 8) after the end of the first infusion
X
336 hr (Day 15) after the end of the first infusion, 
immediately prior to the second infusion of Cycle 
3
X
X
X
Cycle 3 (Week 5)h
Immediately prior to the third infusion of Cycle 3
X
X
X
Cycles 4-6h
Prior to the last infusion of each cycle
X
X
Table is continued on the next page.

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Table 8.  Blood Collection Schedule (Part A - Every-2-Week Cohort 4)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
Trop
Bone
Cycle 5
Immediately prior to the first infusion of Cycle 5 
(6 months after the first infusion of Cycle 1)
X
End of Therapy
At the End-of-Therapy visit
Xf
Xg
Follow-up
30-Day Follow-up visiti
X
X
X
X
Xf
Xg
Abbreviations:  Bone = assessment of bone metabolism markers (CTX-I and P1NP); CK = creatine kinase; CTX-I = C-terminal 
cross-linking telopeptide of type I collagen; ECG = electrocardiogram; FC = flow cytometry analysis; IGx = immunogenicity; Iso 
= 
isoenzyme 
analysis; 
P1NP 
= 
procollagen 
type 
1 N-terminal 
propeptide;
PD = pharmacodynamic 
markers; 
PK = pharmacokinetic(s); Trop = troponin (I or T) assessment; ULN = upper limit of normal.
a
It is understood that it may not be feasible to collect samples at precise intervals following the end of the infusions.  Every 
attempt should be made to collect each of these samples as close to the time point as possible.  The date and time of all PK 
samplings must be clearly and accurately recorded.
b
PK samples will be collected from all subjects.  The date and time of all samplings must be clearly and accurately recorded. 
The blood samples collected for PK will also be used for immunogenicity analyses.  For each specified time point, 1 tube of 
blood is required to be drawn for any combination of PK or immunogenicity analyses.  As an example, if the timing of a PK 
sample should coincide with that of an immunogenicity sample, the same sample will suffice for these studies and the same 
total amount of blood (1 tube, approximately 7.5 mL/tube) will be collected.
c
Pretreatment sampling should be collected on the day of and immediately prior to the first infusion.
d
IGx, PD, FC, isoenzyme analysis, and bone metabolism markers:  Sample to be collected ≤7 days prior to the first infusion 
of Cycle 1.  Troponin (I or T) analysis:  Sample to be collected prior to the first infusion of Cycle 1 so that results are 
obtained before dosing.
e
Sample to be collected at any time ≤3 days prior to the second infusion of Cycle 1.  IMC-CS4 may be administered as 
planned while troponin (I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or 
physical examination.
f
Analysis to be performed only if serum enzymes are ≥2.5 × ULN at Week 5 of Cycle 1.
g
Analysis to be performed only if serum CK levels are ≥2.5 × ULN at Week 5 of Cycle 1.  IMC-CS4 may be administered as 
planned while troponin (I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or 
physical examination.
h
For subjects who proceed to Cycles 2 to 6, blood samples will be collected as shown in this table.  In the event that a subject 
does not proceed to these cycles, these samples will not be collected.
i
A sample will be collected 30 days after last dose of investigational agent, regardless of duration of therapy.
Note:  If at any time a subject experiences an infusion-related reaction to IMC-CS4, all attempts will be made to obtain a blood 
sample for immunogenicity analysis as close to the onset of the event as possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken for immunogenicity testing may be used for PK analysis, in the setting of 
infusion-related reactions.

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Table 9.  Blood Collection Schedule (Part B - Cohorts 6b, 7b, and 8b)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
Trop
Bone
Pretreatment
Prior to the first infusion
Xc
Xd
Xd
Xd
Xd
Xd
Xd
Cycle 1 (Week 1)
Immediately after the end of the first infusion of 
Cycle 1
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
X
X
48 hr (Day 3) after the end of the first infusion
X
X
X
72 hr (Day 4) after the end of the first infusion
X
X
X
168 hr (Day 8) after the end of the first infusion 
immediately (unless otherwise footnoted) prior 
the second infusion of Cycle 1
X
X
X
X
Xe
Xe
Xe
Cycle 1 (Week 2)
1 hr after the end of the second  infusion of Cycle 
1
X
2 hr after the end of the second infusion
X
4 hr after the end of the second infusion
X
24 hr (Day 2) after the end of the second infusion
X
48 hr (Day 3) after the end of the second infusion
X
72 hr (Day 4) after the end of the second infusion
X
168 hr (Day 8) after the end of the second 
infusion of Cycle 1
X
Cycle 1 (Week 4)
Immediately (unless otherwise footnoted) prior to 
the third infusion of Cycle 1
X
X
Xe
Xe
Cycle 1 (Week 5)
Immediately (unless otherwise footnoted) prior to 
the fourth infusion of Cycle 1
X
X
X
X
Xe
Cycle 2 (Week 1)
Prior to the first infusion of Cycle 2
Xg
Xh
Cycle 2 (Week 4)
Immediately prior to the third infusion of Cycle 2
X
Cycle 3 (Week 1)
Immediately prior to the first infusion of Cycle 3
X
X
X
Immediately after the end of the first infusion
X
1 hr after the end of the first infusion
X
X
2 hr after the end of the first infusion
X
X
4 hr after the end of the first infusion
X
X
24 hr (Day 2) after the end of the first infusion
X
X
X
48 hr (Day 3) after the end of the first infusion
X
X
72 hr (Day 4) after the end of the first infusion
X
X
168 hr (Day 8) after the end of the first infusion 
immediately (unless otherwise footnoted) prior to 
the second infusion of Cycle 3
X
X
X
Xf
Xg
Xe
Table is continued on the next page.

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Table 9.  Blood Collection Schedule (Part B - Cohorts 6b, 7b, and 8b)
Blood Collection Time Pointa
Analyses
PKb
IGxb
PD
FC
Iso
Trop
Bone
Cycle 3 (Week 2)
1 hr after the end of the second infusion of 
Cycle 3
X
2 hr after the end of the second infusion
X
4 hr after the end of the second infusion
X
24 hr (Day 2) after the end of the second 
infusion
X
48 hr (Day 3) after the end of the second 
infusion
X
72 hr (Day 4) after the end of the second 
infusion
X
168 hr (Day 8) after the end of the second 
infusion
X
Cycle 3 (Week 4)
Immediately prior to the third infusion of Cycle 3
X
X
Cycles 4-6h
Prior to the last infusion of each cycle
X
X
X
Cycle 5
Immediately prior to the first infusion of Cycle 
5 (6 months after the first infusion of Cycle 1)
X
End of Therapy
At the End-of-Therapy visit
Xf
Xg
Follow-up
30-Day Follow-up visiti
X
X
X
X
Xf
Xg
Abbreviations:  Bone = assessment of bone metabolism markers (CTX-I and P1NP); CK = creatine kinase; CTX-I = C-terminal 
cross-linking telopeptide of type I collagen; ECG = electrocardiogram; FC = flow cytometry analysis; IGx = immunogenicity; 
Iso = isoenzyme analysis; P1NP = procollagen type 1 N-terminal propeptide;
PD = pharmacodynamic markers; 
PK = pharmacokinetic(s); Trop = troponin (I or T) assessment; ULN = upper limit of normal.
a
It is understood that it may not be feasible to collect samples at precise intervals following the end of the infusions.  Every 
attempt should be made to collect each of these samples as close to the time point as possible.  The date and time of all PK 
samplings must be clearly and accurately recorded.
b
PK samples will be collected from all subjects.  The date and time of all samplings must be clearly and accurately recorded.  
The blood samples collected for PK will also be used for immunogenicity analyses.  For each specified time point, 1 tube 
(approximately 7.5 mL/tube) of blood is required to be drawn for any combination of PK or immunogenicity analyses.  As 
an example, if the timing of a PK sample should coincide with that of an immunogenicity sample, the same sample will 
suffice for these studies and the same total amount of blood (1 tube, approximately 7.5 mL/tube) will be collected.
c
Pretreatment sampling should be collected on the day of and immediately prior to the first infusion.
d
IGx, PD, FC, isoenzyme analysis, and bone metabolism markers:  Sample to be collected ≤7 days prior to the first infusion 
of Cycle 1.  Troponin (I or T) analysis:  Sample to be collected prior to the first infusion of Cycle 1 so that results are 
obtained before dosing.
e
Sample to be collected at any time ≤3 days prior to the infusion.  IMC-CS4 may be administered as planned while troponin 
(I or T) results are pending, provided no cardiac symptoms have been revealed upon ECG or physical examination.
f
Analysis to be performed only if serum enzymes are ≥2.5 × ULN at Week 5 of previous cycle.
g
Analysis to be performed only if serum CK levels are ≥2.5 × ULN at Week 5 of previous cycle.  IMC-CS4 may be 
administered as planned while troponin (I or T) results are pending, provided no cardiac symptoms have been revealed upon 
ECG or physical examination.
h
For subjects who proceed to Cycles 4 to 6, blood samples will be collected prior to the last infusion of each cycle.  In the 
event that a subject does not proceed to these cycles, these samples will not be collected.
i
A sample will be collected 30 days after last dose of investigational agent, regardless of duration of therapy.
Note:  If at any time a subject experiences an infusion-related reaction to IMC-CS4, all attempts will be made to obtain a blood 
sample for immunogenicity analysis as close to the onset of the event as possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken for immunogenicity testing may be used for PK analysis, in the setting of 
infusion-related reactions.

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8
ADVERSE EVENTS ASSESSMENTS
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting the Sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the subject.
The Investigator is responsible for the appropriate medical care of subjects during the study.
The Investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or are reportedly related to study treatment or that caused the subject to 
discontinue treatment before completing the study.  The subject should be followed until the 
event is resolved, the event is no longer considered to be drug-related, the event becomes 
stabilized or returns to baseline, the event is deemed irreversible or otherwise explained, a new 
treatment is initiated for the subject, or the subject dies or is lost to follow-up.  Frequency of 
follow-up evaluation is left to the discretion of the Investigator.
The timing of all safety evaluations is shown in the study schedule (see Section 7.6).
8.1
Adverse Events
The Sponsor has standards for reporting AEs that are to be followed regardless of applicable 
regulatory requirements that may be less stringent.  A clinical study AE is any untoward medical 
occurrence in a patient or clinical investigation subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  Any clinically 
significant findings from ECGs, laboratory assessments, vital sign measurements, or other 
procedures that result in a diagnosis should be reported to the Sponsor or its designee.
Lack of drug effect is not an AE in clinical trials, because part of the purpose of a clinical trial is 
to establish drug effect.
Cases of pregnancy that occur during maternal or paternal exposures to study treatment and up to 
12 weeks following last study treatment dose should be reported immediately.  Data on fetal 
outcome and breastfeeding are collected for regulatory reporting and drug safety evaluation.

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For all entered subjects, study site personnel will record the occurrence and nature of each 
subject’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the subject is on study, site personnel will record 
any change in these preexisting condition(s) and the occurrence and nature of any AEs.  In 
addition, all AEs related to protocol procedures are reported to the Sponsor or designee.
In addition, all AEs occurring after the subject receives the first dose of study treatment until 
30 days following the discontinuation of study treatment must be reported to the Sponsor or its 
designee via eCRF.
Investigators will be instructed to report to the Sponsor or its designee their assessment of the 
potential relatedness of each AE to protocol procedure or investigational product via eCRF.
The Investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to the study drug or procedure, the following terminologies are 
defined:

Probably related:  A direct cause and effect relationship between the study treatment 
and the AE is likely.

Possibly related:  A cause and effect relationship between the study treatment and the 
AE has not been demonstrated at this time and is not probable, but is also not impossible.

Does not know:  The Investigator cannot determine.

Not related:  Without question, the AE is definitely not associated with the study 
treatment.
All “probably related,” “possibly related,” or “does not know” AEs will be defined as related to 
study drug/study procedure.
Subjects will be evaluated for AEs at each visit and will be instructed to call their study 
physician to report any AEs between visits.
NCI-CTCAE, Version 4.0 will serve as the reference document for grading the severity of all 
AEs and other symptoms.  For AEs without matching terminology within the NCI-CTCAE,
Version 4.0, the Investigator will be responsible for selecting the appropriate System Organ 
Class and assessing severity grade based on the intensity of the event.

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In addition to collecting the AE verbatim and NCI-CTCAE severity grade, AE verbatim text will 
also be mapped by the Sponsor or designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA®).
If a subject’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to the Sponsor or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
8.2
Serious Adverse Events
Serious adverse event collection begins after the subject has signed the ICF and has received 
study treatment.  If a subject experiences an SAE after signing the ICF, but prior to receiving 
study treatment, the event will NOT be collected unless the Investigator feels the event may have 
been caused by a protocol procedure.
Study site personnel must alert the Sponsor or its designee of any SAE within 24 hours of 
Investigator awareness of the event via a Sponsor-approved method.  Alerts issued via telephone 
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.  An SAE is any adverse event from this study that results in one of the following 
outcomes:

Death;

Initial or prolonged inpatient hospitalization;

A life-threatening experience (that is, immediate risk of dying);

Persistent or significant disability/incapacity;

Congenital anomaly/birth defect; and/or

Considered significant by the Investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
Serious adverse events due to disease progression, including death, should not be reported unless 
the Investigator deems them to be possibly related to the study drug.

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Previously planned (that is, planned prior to signing the ICF) surgeries should not be reported as 
SAEs unless the underlying medical condition has worsened during the course of the study.
Preplanned hospitalizations or procedures for preexisting conditions that are already recorded in 
the subject’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study therapy or other protocol-required procedure) should not 
be considered SAEs.  However, if the preexisting condition worsened during the course of the 
study, it should be reported as an SAE.
Serious adverse events occurring after a subject has taken the last dose of study treatment will be 
collected for 30 days after the discontinuation of study treatment, regardless of the Investigator’s 
opinion of causation.  Thereafter, SAEs are not required to be reported unless the Investigator
feels the events were related to either study treatment or a protocol procedure.
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.  If an Investigator becomes aware of an SAE occurring after the subject’s 
participation in the trial has ended, and the Investigator believes that the SAE is related to a 
protocol procedure or study drug, the Investigator should report the SAE to the Sponsor, and the 
SAE will be entered into the Lilly Safety System.
8.3
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the 
Development Core Safety Information (DCSI) or in the IB and that the Investigator identifies as 
related to study drug or procedure.  The United States 21 CFR 312.32, the European Union 
Clinical Trial Directive 2001/20/EC, 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 regulatory regulations and the associated detailed guidances.
8.4
Safety Monitoring
The Sponsor CRP or designee will monitor safety data throughout the course of the study.

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The Sponsor CRP or designee will review SAEs within time frames mandated by company 
procedures.  The Sponsor CRP or designee, will, as is appropriate, consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist (CRS), 
and periodically review trends and laboratory analytes.
If a subject experiences elevated ALT ≥5 × ULN and elevated total bilirubin ≥2 × ULN, clinical 
and laboratory monitoring should be initiated by the Investigator.  For subjects entering the study 
with ALT ≥3 × ULN, monitoring should be triggered at ALT ≥2 × baseline.  Details for hepatic 
monitoring depend upon the severity and persistence of observed laboratory test abnormalities.  
To ensure subject safety and comply with regulatory guidance, the Investigator is to consult with 
the Sponsor CRP regarding collection of specific recommended clinical information and follow-
up laboratory tests.  Refer to Section 6.5 for a list of the hepatic monitoring tests to be 
performed.
All reportable SAEs will be submitted to the FDA in accordance with Title 21 Code of Federal 
Regulations (CFR) Part 312.32.
8.5
Complaint Handling
The Sponsor collects product complaints on study treatment and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Complaints related to concomitant drugs/drug delivery systems are reported directly to the 
manufacturers of those drugs/devices in accordance with the package insert.
The Investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

Recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose; and

Faxing the completed product complaint form within 24 hours to the Sponsor or its 
designee.
If the Investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.

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9
TREATMENT-RELATED ADVERSE EVENTS
Subjects will be closely monitored for treatment-related AEs, especially infusion-related
reactions, immune-related adverse events (irAE), periorbital edema, and signs indicative of 
hepatic impairment, leukocyte alterations, and inflammation.  Subjects will be evaluated for AEs 
at each visit and will be instructed to call their study physician to report any AEs between visits.
Adverse event collection will include verbatim term, onset and resolution dates, action taken, 
outcome, severity (NCI-CTCAE, Version 4.0 grade), relationship to the study therapy, and, if the 
event is serious, a clear indication of the seriousness.
9.1
IMC-CS4
9.1.1
Immune-Related Adverse Events
Symptoms occurring during or following infusion of investigational therapy will be defined 
according to the NCI-CTCAE, Version 4.0.
In the setting of symptoms consistent with irAE occurring following infusion of investigational 
therapy, investigators are encouraged to refer to Table 10 as a guideline for the management of 
potential toxicities encountered with immuno-oncology agents.  Due to the potential of rapid and 
serious sequelae associated with irAEs, early intervention with immunomodulatory agents as 
indicated is encouraged, concurrent with further diagnostic medical evaluations for possible non-
immune-related causes of AEs.  Table 10 is a guideline for the management of irAEs; local 
standards may supersede recommendations when deemed appropriate by the Investigator.

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Table 10.  Guidelines for the Management of Potential Toxicities Encountered with Immuno-Oncology Agents
System Organ 
Class
Adverse Event
CTCAE, Version 4.0 Grade (if applicable) and/or Symptomsa
Treatment Planb
Grade
Symptoms
Endocrine
Thyroid issues
Asymptomatic, with TSH <0.5 × LLN or >2 × ULN
Continue drug.
Symptomatic
Continue drug.  Administer thyroid replacement.
Hypotension, altered mental 
status, headache, fatigue
Endocrine issues aside from thyroid (for example,
hypophysitis)
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Resume drug when symptoms resolve and are 
stable on hormone replacement.  In case of adrenal crisis,
administer stress-dose steroids.
Gastrointestinal
Diarrhea, abdominal pain, 
blood in stool
2
Withhold drug for 1 wk.  Administer antidiarrheal 
medication and check etiology.  Resume drug when
symptoms resolve to Grade ≤1.
If >5 days’ duration despite antidiarrheals, begin steroids 
(0.5 mg/kg/d prednisone); can resume drug during taper
when symptoms resolve to Grade ≤1.
Diarrhea, ileus, perforation
≥3
Permanently discontinue drug.  Administer steroids (1-2 
mg/kg/d prednisone), except if the possibility of perforation 
exists.
If >3 days’ duration despite steroids, also administer
nonsteroidal immunosuppressive.
Pancreatitis
1-2
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Can resume drug during taper.
≥3
Permanently discontinue drug.

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Table 10.  Guidelines for the Management of Potential Toxicities Encountered with Immuno-Oncology Agents
System Organ 
Class
Adverse Event
CTCAE, Version 4.0 Grade (if applicable) and/or Symptomsa
Treatment Planb
Grade
Symptoms
Hepatobiliary
Transaminitis, elevated 
bilirubin
Subjects with baseline AST or ALT ≤2.5 × ULN:
AST or ALT >5 × ULN but ≤7.5 × ULN
and
total bilirubin ≤ULN
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Resume drug when AST or ALT ≤5 × ULN.
Subjects with baseline AST or ALT >2.5 × ULN 
and ≤5 × ULN:
AST or ALT >7.5 × but ≤10 × ULN
and
total bilirubin ≤ ULN
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Resume drug when AST or ALT ≤7.5 × ULN.
Subjects with baseline AST or ALT ≤2.5 × ULN:
AST or ALT >7.5 × ULN
or
total bilirubin > 3× ULN
Permanently discontinue drug.  Administer steroids (1-2 
mg/kg/d prednisone).
Subjects with baseline AST or ALT >2.5 × ULN 
and ≤5 × ULN:
AST or ALT >10 × ULN
or
total bilirubin >3× ULN
Permanently discontinue drug.  Administer steroids (1-2 
mg/kg/d prednisone).
Nervous
Weakness, paresthesia (for 
example, Guillain-Barré 
syndrome, myasthenia gravis)
No impact on activities of daily living (ADL).
Withhold drug.  Resume drug when symptoms resolve.
Impact on ADL.
Withhold drug.  Administer appropriate medical 
intervention and steroids (1-2 mg/kg/d prednisone).  Can 
resume drug during taper.
Respiratory
Dyspnea, hypoxia, 
pneumonitis
1
Consider to withhold drug.  Resume drug when stable.
2
mild-to-moderate symptoms
Withhold drug.  Administer steroids (1-2 mg/kg/d 
prednisone).  Can resume drug during taper.
≥3
Severe
Permanently discontinue drug.  Administer steroids (1-2
mg/kg/d prednisone).

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Table 10.  Guidelines for the Management of Potential Toxicities Encountered with Immuno-Oncology Agents
System Organ 
Class
Adverse Event
CTCAE, Version 4.0 Grade (if applicable) and/or Symptomsa
Treatment Planb
Grade
Symptoms
Renal and 
urinary
Elevated creatinine, decreased 
urine output, blood in urine, 
edema
1
<1.5 × baseline
Continue drug.
2-3
>1.5 × ULN but <6 × ULN
or
>1.5 × baseline
Withhold drug.  Administer steroids (1- 2 mg/kg/d 
prednisone).
If symptoms resolve to Grade ≤1, taper steroids over 1 
month.  Can resume drug during taper.
4
>6 × ULN
Permanently discontinue drug.  Administer steroids (1-2 
mg/kg/d prednisone).
Skin
Rash, pruritus
≤50% skin affected
Withhold drug.  If symptoms persist or worsen after 1 wk, 
administer topical or systemic steroids.
Resume drug if rash improves to mild (localized) and 
steroid dose <7.5 mg.
Stevens-Johnson syndrome, toxic epidermal 
necrolysis, necrosis, bullous or hemorrhagic lesions
Permanently discontinue drug.  Begin steroids (1-2 mg/kg/d 
prednisone).
Abbreviations: ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse 
Events; I.V. = intravenous(ly); LLN = lower limit of normal; TSH = thyroid-stimulating hormone; ULN = upper limit of normal.
a
If definition of grade not specified, use CTCAE, Version 4.0 definition.
b
Treatment plan should always include a thorough workup of the issue to rule out other potential etiologies.
Note regarding steroids: Steroids should be tapered over 1 month after symptoms have resolved; if withheld drug may be resumed (that is, not permanently discontinued), it can be 
resumed only after taper has begun. Other steroid options (besides those shown in this table) may be administered at equivalent doses. For severe adverse events, administration 
of I.V. steroids is recommended. In the case of adrenal crisis, mineralocorticoid should be administered in addition to steroids.

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9.1.2
IMC-CS4 Infusion-Related Reactions
Symptoms occurring during or following infusion of investigational therapy will be defined 
according to the NCI-CTCAE, Version 4.0 definition of infusion-related reaction (General 
Disorders and Administration Site Conditions) or as allergic reaction, anaphylaxis, or cytokine 
release syndrome (under “Immune System Disorders” in NCI-CTCAE, Version 4.0) as detailed 
in Table 11.
In the setting of symptoms occurring during or following infusion of investigational therapy, 
investigators are encouraged to use the AE term “infusion-related reaction” and any additional 
terms (including those not listed here) that best describe the event.  Those described above 
should be graded as follows:

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Table 11.  NCI-CTCAE, Version 4.0, Infusion-Related Reactions
Adverse 
Event
Grade
1
2
3
4
5
Infusion-
related 
reaction
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, I.V. 
fluids); prophylactic 
medications indicated for 
≤24 hr
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
after initial improvement; 
hospitalization indicated 
for clinical sequelae
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an adverse reaction to the infusion of pharmacological or biological substances.
Allergic 
reaction
Transient flushing 
or rash, drug fever 
<38°C (<100.4°F); 
intervention not 
indicated
Intervention or infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics); 
prophylactic medications 
indicated for ≤24 hr
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
after initial improvement; 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
-
-
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-
like substances from mast cells, causing a hypersensitivity immune response.  Clinically, it presents with breathing difficulty, 
dizziness, hypotension, cyanosis, and loss of consciousness and may lead to death.
Cytokine 
release 
syndrome
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, I.V. 
fluids); prophylactic 
medications indicated for 
≤24 hr
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
after initial improvement; 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Life-threatening 
consequences; 
pressor or 
ventilator 
support indicated
Death
Definition:  A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by 
the release of cytokines from the cells.
Consistent with usual medical practice, selected parenteral medications may be utilized for 
Grade 2 allergic/hypersensitivity reaction as detailed below.  The Sponsor CRP should be 
contacted immediately if questions arise concerning the grade of the reaction.  The following are 
treatment guidelines for IMC-CS4 infusion-related reactions:

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Grade 1

Slow the infusion rate by 50%.

Monitor the subject for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg I.V. 
(or equivalent); additional premedication may be administered at the Investigator’s 
discretion.
Grade 2

Stop the infusion.

Administer diphenhydramine hydrochloride 50 mg I.V. (or equivalent), acetaminophen 
650 mg orally for fever, and oxygen.

Resume the infusion at 50% of the prior rate once the infusion-related reaction has 
resolved to Grade ≤1; the infusion duration should not exceed 3 hours.

Monitor for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg I.V. 
(or equivalent); additional premedication may be administered at the Investigator’s 
discretion.
For a second Grade 1 or 2 infusion-related reaction, administer dexamethasone 10 mg I.V. (or 
equivalent); then, for subsequent infusions, premedicate with diphenhydramine hydrochloride 
50 mg I.V. (or equivalent), acetaminophen 650 mg orally, and dexamethasone 10 mg I.V. (or 
equivalent).  Once the infusion rate has been reduced for a Grade 1 or 2 infusion-related reaction, 
it is recommended to maintain the lower infusion rate for all subsequent infusions.
Grade 3

Stop the infusion and disconnect the infusion tubing from the subject.

Administer diphenhydramine hydrochloride 50 mg I.V. (or equivalent), dexamethasone 
10 mg 
I.V. 
(or 
equivalent), 
bronchodilators 
for 
bronchospasm, 
and 
other 
medications/treatment as medically indicated.

Subjects who have a Grade 3 infusion-related reaction will not receive further IMC-CS4 
treatment, but will continue to be followed on the protocol.

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Grade 4

Stop the infusion and disconnect the infusion tubing from the subject.

Administer diphenhydramine hydrochloride 50 mg I.V. (or equivalent), dexamethasone 
10 mg I.V. (or equivalent), and other medications/treatment as medically indicated.

Give epinephrine or bronchodilators as indicated.

Hospital admission for observation may be indicated.

Subjects who have a Grade 4 infusion-related reaction will not receive further IMC-CS4 
treatment, but will continue to be followed on the protocol.
If a subject should have an infusion-related reaction to IMC-CS4, all attempts will be made to 
obtain an anti-IMC-CS4 antibody blood sample as close to the onset of the event as possible, at 
the resolution of the event, and 30 days following the event.  In addition, these same samples 
may be assessed for levels of IMC-CS4 and for pharmacodynamic markers to provide 
information on the nature of the infusion-related reaction.  The procedure for sample collection 
and handling is described in a separate procedural manual.
9.1.3
Other Adverse Events
Based on observations in nonclinical toxicological studies with IMC-CS4 and/or observations in 
one clinical trial with another monoclonal antibody targeting CSF-1 (Sadis et al. 2009), subjects
receiving IMC-CS4 should be closely monitored for signs indicative of hepatic function 
impairment (for example, increases in transaminases, LDH, bilirubin, coagulation disorders), 
inflammation (for example, leukocyte alterations, C-reactive protein), CK increases, and 
periorbital swelling.  For details, refer to Section 1.3.3 of this protocol and the IMC-CS4 IB.

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10 DOSE MODIFICATIONS
10.1
General Dose Modifications – IMC-CS4
10.1.1
During Cycle 1
No IMC-CS4 dose reductions were permitted for any subject (in Cohort 1 or 2) following a DLT.  
If a subject (in Cohort 1 or 2) experienced a DLT during Cycle 1, IMC-CS4 was permanently 
discontinued.
If benefitting from treatment (that is, no disease progression or other withdrawal criteria), any 
subject in Cohort 3 and beyond who experiences a DLT may continue to receive IMC-CS4 upon 
agreement of the Sponsor and according to the dose reduction guidelines for this study
(Table 12).
In the setting of non-life-threatening reversible Grade ≤3 IMC-CS4-related toxicities in Cycle 1
that do not meet the definition of a DLT, IMC-CS4 may be held (if appropriate, in the opinion of 
the Investigator and upon agreement with the Sponsor) for a maximum of 3 weeks, until 
resolution to baseline or improvement to Grade ≤2.  Upon resolution to baseline or improvement 
to Grade ≤2, IMC-CS4 may be administered at a reduced dose (according to Table 12) beginning 
with Cycle 2, if appropriate, in the opinion of the Investigator and upon agreement with the 
Sponsor (no dose reductions are permitted during Cycle 1 [for subjects in Cohort 1 or 2]; 
subjects [in Cohort 1 or 2] who would require dose reductions during Cycle 1 must be 
discontinued).  If toxicity does not resolve to baseline or improve to Grade ≤2 within 3 weeks 
following the last administered dose, IMC-CS4 should be permanently discontinued.
10.1.2
After Cycle 1
Dose reductions, if required during Cycle 2 or after, in the context of IMC-CS4-related toxicity, 
may be implemented according to the guidelines in Table 12.  Any individual subject (including 
those experiencing an event that occurred after the DLT assessment period that otherwise would 
have been considered a DLT) may be dose reduced a maximum of 2 times during the course of 
the study (except as noted in Table 12; for example, subjects in Cohort 3 are only permitted to 
have one dose reduction).  Once a subject has had a dose reduction (has started a new cycle at the 
reduced dose), all subsequent infusions will be at the reduced dose level; there will be no 

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resumption to prior dose level(s).  Any subject experiencing toxicity that would necessitate more 
than 2 dose reductions must discontinue treatment.  Dose reductions must be confirmed by the 
Sponsor.
Any subject who experiences a Grade 4 toxicity after Cycle 1 may continue to receive study 
treatment only if agreed upon by the Investigator and the Sponsor CRP and according to the dose 
reduction guidelines for this study (Table 12).
Table 12.  General Dose Reduction Guidelines
Cohort
Starting Dose Level and 
Schedule
First Reduction
Second Reduction
Part A Only
1
2.5 mg/kg (qw)
Discontinue
Discontinue
2
0.3 mg/kg (qw)
Discontinue
Discontinue
3
0.6 mg/kg (qw)
0.3 mg/kg (qw)
Discontinue
4
1.25 mg/kg (q2w)
0.6 mg/kg (qw)
0.3 mg/kg (qw)
5
1.25 mg/kg (qw)
1.25 mg/kg (q2w)
0.6 mg/kg (qw)
Part B Only
6a
100 mg (qw)
75 mg (qw)
50 mg (qw)
6b
100 mg (Weeks 1, 2, 4, and 5)
75 mg (Weeks 1, 2, 4, and 5)
50 mg (Weeks 1, 2, 4, and 5)
6c
75 mg (qw)
50 mg (qw)
40 mg (qw)
7a
150 mg (qw)
125 mg (qw)
100 mg (qw)
7b
150 mg (Weeks 1, 2, 4, and 5)
125 mg (Weeks 1, 2, 4, and 5)
100 mg (Weeks 1, 2, 4, and 5)
7c
125 mg (qw)
100 mg (qw)
75 mg (qw)
8a
200 mg (qw)
175 mg (qw)
150 mg (qw)
8b
200 mg (Weeks 1, 2, 4, and 5)
175 mg (Weeks 1, 2, 4, and 5)
150 mg (Weeks 1, 2, 4, and 5)
8c
175 mg (qw)
150 mg (qw)
125 mg (qw)
Abbreviations:  qw = weekly; q2w = every 2 weeks.
10.1.3
Infusion-Related Reactions
Apart from measures for preemptive and/or therapeutic medical treatment as detailed in 
Section 9.1.2, the following recommendations regarding the administration of IMC-CS4 should 
be followed:
If a subject experiences Grade 1 infusion-related reaction/allergic reaction, infusion rate should 
be decreased by 50% for the duration of the infusion.  In case of a Grade 2 infusion-related 
reaction/allergic reaction, the infusion must be stopped until resolution to Grade ≤1; the infusion 
may then be resumed at 50% of the prior infusion rate (the duration of the infusion should not 

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exceed 3 hours).  Once the infusion rate has been reduced for a Grade 1 or 2 infusion-related
reaction, it is recommended to maintain the lower infusion rate for all subsequent infusions.
(Premedication must be provided prior to any subsequent doses of IMC-CS4 if the subject has 
experienced a Grade 1 or 2 infusion-related reaction.)  Occurrence of a Grade 3 or 4 infusion-
related reaction requires immediate and permanent discontinuation of IMC-CS4.
10.2
Removal of Subjects from Therapy
The Investigator must withdraw a subject from IMC-CS4 for any of the following reasons:

The Sponsor or Investigator terminates the study;

The Investigator/physician or Sponsor decides that the subject should be withdrawn from 
the study or study drug;

The subject, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication (discontinuation 
from the study drug to occur prior to introduction of the other agent);

An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the subject or requires >2 dose reductions);

A DLT occurring in a subject in Cohort 1 or 2 only (a DLT occurring in a subject in 
Cohort 3 or beyond would not necessarily be a withdrawal criterion);

A Grade 3-4 infusion-related reaction;

Any therapy-related event that is deemed life-threatening, regardless of NCI-CTCAE,
Version 4.0 grade;

Any event that would warrant IMC-CS4 therapy to be held for more than 3 weeks 
following the last administered dose, or to be dose reduced more than 2 times;

Radiographic documentation of PD (refer to Note in Section 4.1);

A decline in ECOG PS that, in the opinion of the Investigator, necessitates 
discontinuation of study therapy;

Subject noncompliance (in the opinion of the Investigator or Sponsor) with this study 
protocol;

Subject pregnancy or breastfeeding;

Enrollment by the subject in any other clinical trial involving an investigational product 
or enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study;

An intercurrent illness or change in the subject’s condition that renders the subject
unsuitable for further treatment in the opinion of the Investigator and/or Sponsor; and/or

Withdrawal of consent.
After termination of study therapy, the subject will be treated as clinically indicated by the 
Investigator or referring physician.  If the reason for withdrawal from the trial is the death of the 
subject, the 2 options for categorizing withdrawal are either: (1) PD or (2) an AE (more than one 

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AE may be documented as a reason for withdrawal).  Only one event will be recognized as the 
cause of death.
If a subject is discontinued from all study therapy:

The reason(s) for discontinuation should be documented in the subject’s medical record 
and eCRF.  The date of discontinuation from study treatment is to be reported on the 
eCRF.

An end-of-therapy evaluation should be performed.

A follow-up evaluation should be performed approximately 30 days after the last dose of 
study medication.  Subjects who discontinue will have follow-up procedures performed 
as shown in Table 6.

In addition, all subjects with unresolved SAEs or IMC-CS4-related AEs will be followed 
at regularly scheduled intervals beyond the 30-Day Follow-up visit until the event is 
resolved, the event is no longer considered to be drug-related, the event becomes 
stabilized or returns to baseline, the event is deemed irreversible or otherwise explained, 
a new treatment is initiated for the subject, or the subject dies or is lost to follow-up.
10.3
Concomitant Therapy
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment will be offered to all subjects on this trial.  Details of interventions (for example,
medications such as sedatives, antibiotics, analgesics, antihistamines, steroids, erythropoietin), 
procedures (for example, paracentesis, thoracentesis), or blood products (for example, blood 
cells, platelets, or fresh frozen plasma transfusions) should be recorded in eCRFs.
10.4
Prohibited and Restricted Therapies during the Study
10.4.1
Prohibited Therapies
Additional concurrent chemotherapy, radiation therapy, biologic response modifiers, or other 
investigational anticancer agents may not be administered to subjects on this study.  Palliative 
radiation to symptomatic sites of disease will not be permitted while on study. An exception to 
these prohibited therapies is that subjects with metastatic breast or prostate cancer who have been 
on a stable dose (≥28 days) of an approved (anticancer) hormonal agent will not be excluded (ie, 
they will be eligible).
10.4.2
Restricted Therapies
None, other than detailed above and in the inclusion/exclusion criteria (Sections 3.2 and 3.3).

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10.4.3
Precautions
See Section 9.1.2 regarding infusion-related reactions.
10.5
Nontherapy Precautions and Restrictions
None, other than detailed above and in the inclusion/exclusion criteria (Sections 3.2 and 3.3).
10.6
Supportive Care Guidelines
10.6.1
Granulocyte Colony-Stimulating Factors
Although neutropenia is not an expected side effect of IMC-CS4, the use of granulocyte colony-
stimulating factors (G-CSFs) is permitted during investigational therapy, based on American 
Society of Clinical Oncology (ASCO) guidelines (Smith et al. 2015).  G-CSF or similar agents 
are strongly recommended following Grade 3 or 4 neutropenia lasting more than 5 days duration 
or following any incidence of febrile neutropenia.
10.6.2
Erythroid Growth Factors
The use of erythroid stimulating factors (for example, erythropoietin) is permitted at the 
Investigator’s discretion based on current American Society of Hematology/ASCO guidelines
(Rizzo et al. 2010).
10.6.3
Transfusion of Blood Products
Transfusions of red blood cells, platelets, or other blood products are permitted at the 
Investigator’s discretion.
10.6.4
Antiemetic Therapy
Both prophylactic and symptom-directed antiemetic therapies are permitted and should be used 
in accordance with institutional guidelines (when existent) and/or at Investigator’s discretion.
10.6.5
Premedication for IMC-CS4
Premedication such as antihistamines or steroids for the prophylaxis of hypersensitivity is not 
recommended to be administered prior to the first infusion of IMC-CS4 administration.
Premedication must be implemented in the setting of a prior Grade 1-2 IMC-CS4-related 
infusion-related reaction and is detailed in Section 9.1.2.

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11 CRITERIA FOR TUMOR RESPONSE EVALUATION
Study evaluations will take place in accordance with the flow chart in Section 7.6.
Subjects will be evaluated for response according to RECIST 1.1 guidelines (Eisenhauer et al. 
2009).  Radiographic assessment of tumor response will be performed at the end of the initial 
6-week cycle, and the end of every subsequent cycle.  However, if a DLT is observed in Cycle 1
in a subject who is benefitting from treatment, Cycle 2 dosing may be initiated within 4 weeks of 
Cycle 1, Day 1, with Sponsor approval; in this case, no radiographic disease assessment is 
required prior to dosing in Cycle 2.
Refer to Note in Section 4.1 regarding the possibility of study treatment continuation in subjects 
until there is unequivocal evidence of PD. (Radiographically confirmed disease progression 
[that is, numerical disease progression, per RECIST] only is not sufficient to discontinue 
treatment.)
11.1
Baseline Tumor Assessments
The baseline tumor burden (unidimensionally measurable and nonmeasurable disease) will be 
assessed as closely as possible to the beginning of treatment and never more than 28 days prior 
to first dose of study therapy.  The Investigator will prospectively identify the lesions to be 
followed to evaluate the subject’s response to therapy (see Section 11.4).
11.2
Method of Tumor Response Assessment
All measurements should be taken and recorded in metric notation.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and at reassessment during treatment.  Only imaging-
based evaluations will be used to evaluate the antitumor effect of a treatment.  CT will be 
considered the best currently available and reproducible imaging method to measure target 
lesions (as defined in Section 11.4.1).  CT should be performed with cuts of 5 mm or less in slice 
thickness (as a general rule, lesion diameter should be no less than double the slice thickness).  
This applies to tumors of the chest, abdomen, and pelvis (RECIST guidelines specify that lesions 
on chest x-ray are acceptable as measurable lesions when they are clearly defined and 

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surrounded by aerated lung; however, chest CT is strongly preferred by RECIST guidelines and 
mandatory in this study).  MRI is also acceptable in certain conditions (for example, for body 
scans).  Ultrasound is not an acceptable method by which to measure disease.  Bone scans, PET
scans, or plain films are not sufficient to measure bone lesions, but may be used to confirm the 
presence or disappearance of such lesions.  Tumor markers alone are not sufficient to assess 
objective response.
11.3
Definitions
11.3.1
Measurable
Lesions that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥10 mm (this requirement based on a CT slice thickness of ≤5 mm; for slice 
thicknesses >5 mm, measurable lesions must have a longest diameter ≥2 times the slice 
thickness).
A lymph node will be considered pathologically enlarged and measurable if its short axis is 
≥15 mm; the short axis should be measured and followed throughout.  Nodes with a short axis 
≥10 mm and <15 mm will be considered pathologically enlarged but nonmeasurable (see below).
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft-tissue components will be 
considered measurable if the soft-tissue component can be evaluated by cross-sectional imaging 
(that is, CT scan) and meets the general definition of measurability.
Simple cysts will not be considered malignant lesions, and will be neither measurable nor 
nonmeasurable.  Cystic lesions believed to be metastases may be considered measurable if they 
meet the general definition of measurability, but noncystic lesions are preferred as target lesions.
A lesion located in a previously irradiated area, or in an area previously subjected to any 
locoregional therapy, will be considered measurable only if there has been a documented 
increase in lesion size subsequent to prior treatment but prior to study entry.
11.3.2
Nonmeasurable
All other lesions including small lesions (longest diameter <10 mm or pathological lymph nodes 
with a short axis of ≥10 mm and <15 mm) and truly nonmeasurable lesions.

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Lesions considered to be truly nonmeasurable include the following:  bone lesions; ascites; 
pleural/pericardial effusion; inflammatory breast disease; lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.  Blastic bone lesions are nonmeasurable.
11.4
Definitions of Response
Overall tumor response, as defined in Table 13, will be based on an integration of the evaluation 
of target, nontarget, and new lesions, as described below:
11.4.1
Target Lesions
Target lesions are all measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs.  Target lesions should be selected on the basis of their 
size (those with the longest diameters) and their suitability for accurate repeated measurements.
The short axis of any lymph nodes selected as target lesions at baseline (≥15 mm) will be 
measured and recorded at each evaluation time point, even if the nodes become nonpathological 
(short axis <10 mm).
The sum of the diameters of all target lesions (longest for non-nodal lesions, short axis for nodal 
lesions) will be calculated at baseline and reported as the baseline sum diameter.  This baseline 
sum diameter will be used as the reference by which to characterize the objective tumor 
response.  For lesions measurable in 2 or 3 dimensions, always report the longest diameter at the 
time of each assessment.
Complete Response (CR):
The disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes 
reduced to <10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of the diameters of target lesions (including the short axes of 
any target lymph nodes), taking as reference the baseline sum diameter.

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Stable Disease (SD):
Neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify 
PD, taking as reference the smallest sum diameter since the treatment started.
Progressive Disease (PD):
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note: The appearance of one or more new lesions is also considered progression.)
Inevaluable or Non-evaluable (NE):
A target lesion present at baseline which is subsequently not measured or which is unable to be 
evaluated or there is a change in the method of measurement from baseline that impacted the 
ability to make a reliable evaluation of response, leading to an inability to determine the status of 
that particular tumor for the time point in question.  This category also includes scans that are not 
performed at this time point to evaluate the target lesion(s).  The reason(s) explaining the 
absence of the evaluation or non-evaluable (NE) nature of the lesion(s) should be specified at the 
time of the assessment (for example, early death due to malignant disease; early death due to 
toxicity; tumor assessments not repeated or incomplete; other [specify]).
11.4.1.1
Lesions Too Small to Measure
Lesions that become too small to measure during treatment must be assigned a default 
measurement of either 0 mm (if the Investigator believes the lesion has disappeared) or 5 mm (if 
the lesion is still present).
11.4.1.2
Lesions That Split or Coalesce
If a target lesion splits into multiple fragments during treatment, the longest diameters of each 
fragment should be added together to generate the total sum for that lesion.  When lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter 
measurements for each individual lesion.  If the lesions are no longer separable, the vector of the 
longest diameter in this instance should be the maximal longest diameter for the coalesced 
lesion.

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11.4.2
Nontarget Lesions
All lesions (or sites of disease) not characterized as target lesions (see Section 11.4.1), both 
measurable and nonmeasurable, will be identified as nontarget lesions and will be recorded at 
baseline.  Measurements will not be required, and these lesions will be followed as “present,” 
“absent,” or “unequivocal progression” (see below).
Complete Response (CR):
The disappearance of all nontarget lesions, the normalization of the tumor marker level (if tumor 
markers are measured and are initially above the ULN, those must normalize for a subject to be 
considered in complete clinical response).  All lymph nodes must be <10 mm (short axis).
Non-CR/Non-PD:
The persistence of one or more nontarget lesions and/or the maintenance of the tumor marker 
level above normal limits.
Progressive Disease (PD):
The appearance of one or more new lesions and/or unequivocal progression of existing nontarget 
lesions.  Progressive disease may be declared on the basis of “unequivocal progression” in cases 
where the overall tumor burden increases significantly enough to require a change in therapy; in 
most cases, a modest increase in the size of one or more nontarget lesions is not sufficient to 
qualify (especially in the presence of stable disease [SD] or PR in target disease).
Inevaluable or Non-evaluable (NE):
A nontarget lesion present at baseline that is subsequently not measured or which is unable to be 
evaluated or there is a change in the method of measurement from baseline that impacted the 
ability to make a reliable evaluation of response, leading to an inability to determine the status of 
that particular tumor for the time point in question.  This category also includes scans that are not 
performed at this time point to evaluate the nontarget lesion(s).  The reason(s) explaining the 
absence of the evaluation or NE nature of the lesion(s) should be specified at the time of the 
assessment (for example, early death, malignant disease; early death, toxicity; tumor assessments 
not repeated or incomplete; other [specify]).

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11.4.3
New Lesions
The finding of a new lesion should be unequivocal (that is, not attributable to a change in 
scanning technique or imaging modality, and not thought to represent something other than a 
tumor).  If a possible new lesion is equivocal, treatment and radiological evaluation should 
continue per this protocol until confirmation of disease progression or until additional scans 
confirm the presence of a new lesion.  In such a case, the date of progression will be the date of 
the initial scan at which the equivocal new lesion was observed.
A lesion identified on a follow-up study of an anatomical location not studied at baseline will
qualify as a new lesion.
Fluorodeoxyglucose (FDG)-PET scanning may be employed as a complement to CT scanning in 
the assessment of possible new lesions.  A negative FDG-PET scan at baseline with a positive 
scan on study will be evidence of PD.  If there is no FDG-PET scan at baseline and a positive 
FDG-PET scan during the study, it will be considered evidence of PD if the positive FDG-PET 
corresponds to a new site of disease confirmed by CT scan.  A positive on-study FDG-PET result 
corresponding to a preexisting site of disease with no radiological evidence of progression will 
not be considered evidence of PD.
11.5
Determination of Overall Response
Each response parameter (target, nontarget, and new lesions) will be reported independently at 
each radiologic read.  The Investigator will make a determination of overall response based on 
the evaluation of target, nontarget, and new lesions, as shown in Table 13.

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Table 13.  Overall Response
Target Lesions
Nontarget 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 evaluateda
No
PR
SD
Non-PD or not all evaluateda
No
SD
Not all evaluateda
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations:  CR = complete response; NE = non-evaluable or inevaluable; PD = progressive disease; PR = partial response; 
SD = stable disease.
a
In general, if only a subset of lesion measurements are taken at a given assessment time point, the subject as a whole is 
considered NE for that time point, unless a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response.
For subjects who discontinue therapy for reasons other than disease progression (for example,
toxicity), every effort will be made to document tumor measurements and the extent of disease, 
even after discontinuation of therapy, in order to classify subjects for overall response as 
described above.
Symptomatic deterioration sufficient to warrant discontinuation of therapy will not be considered 
a descriptor of response, but rather only a reason for stopping therapy.  Whenever possible, 
subjects removed from therapy solely for symptomatic progression should be followed for 
subsequent radiographic progression.  Response evaluation in a subject who discontinues 
treatment due to symptomatic deterioration in the absence of radiological confirmation of PD
should be based on evaluation of target and nontarget lesions as described above.
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated and ruled out (for example, by FNA/biopsy) before confirming the CR
status.  FDG-PET scanning may also be used to confirm a response of CR under appropriate 
circumstances (for example, similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring).

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12 PLANNED STATISTICAL METHODS
12.1
General Considerations
Statistical analysis of this study will be the responsibility of the Sponsor.
The interpretation of the study results will be the responsibility of the investigators with the Lilly 
CRP or CRS, pharmacokineticist, and statistician.  The CRP or CRS and statistician will also be 
responsible for the appropriate conduct of an internal review for both the final study report and 
any study-related material to be authorized by Lilly for publication.
The analyses for this study will be descriptive, except for possible exploratory analyses as 
deemed appropriate.  Data analyses will be provided by dose levels and for all subjects
combined, wherever appropriate.  For continuous variables, summary statistics will include 
number of subjects (N), mean, median, standard deviation, minimum, and maximum. 
Categorical endpoints will be summarized using N, frequency, and percentages. Missing data 
will not be imputed.  Exploratory analyses of the data that are not described in the protocol will 
be conducted as deemed appropriate.  A detailed description of data analyses will be provided in 
a separate statistical analysis plan document for this study.
This is a Phase 1 study with an open-label, dose-escalation design. Subjects will be enrolled into 
cohorts sequentially without randomization to dose level.  During dose escalation, the total 
sample size per cohort will be guided by the standard oncology 3+3 method and determined by 
the occurrences of DLTs for the treated subjects. The total sample size for Parts A and B is 
estimated to be approximately 72 treated subjects.  In Part A, the sample size is estimated to be
approximately 30 subjects.  In Part B, the sample size is estimated to be approximately 9 to 42
subjects.
Pretreatment and posttreatment anti-IMC-CS4 samples will be assayed using an immunoassay.  
A sample will be considered positive for IMC-CS4 antibodies if it exhibits a postbaseline 
antibody level that exceeds the upper 95% confidence interval of the mean determined from the 
normal anti-IMC-CS4 level seen in healthy untreated individuals.

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12.2
Analysis Populations
All enrolled subjects who received at least one dose of IMC-CS4 will be included in the safety 
population.
Subjects who complete the initial 6 weeks of therapy (that is, receive all scheduled treatments for 
Cycle 1 and complete the observation period, as needed) or experience a DLT will be included in 
the DLT population.  The DLT population will be used for the determination of the RP2D, 
including evaluation of DLTs.  All other variables (including demographic and baseline subject
characteristics, efficacy and safety variables) will be analyzed using the safety population.
12.3
Subject Disposition
All subject discontinuations will be documented, and the extent of each subject’s participation in 
the study will be reported.  If known, a reason for discontinuation will be given.
Additional summary of subject participation flow will be performed for the purpose of fulfilling 
the Clinical Trial Registry (CTR) requirements.  A participant flow will describe how many 
enrolled subjects completed the study, and for those who did not, the frequency of each reason 
for not completing.
12.4
Demographics and Baseline Characteristics
Baseline demographics, disease characteristics, prior anticancer therapy, and medical history will 
be listed and/or tabulated by cohort.
12.5
Analyses of Safety Data
12.5.1
Extent of Exposure
Exposure analyses will be based on the actual dose administered (in mg) and body weight (in kg) 
per the eCRF.  The baseline body weight will be used for calculating each dose unless the 
subject’s weight changes ≥10% from baseline and a dose change is required.  Dose intensity and 
relative dose intensity will be calculated based on the dose administered and the most recent 
body weight recorded prior to treatment administration.  Exposure analyses will include duration 
of treatment (weeks), number of subjects treated by cycle, number of infusions per subject, 

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cumulative dose, dose intensity and relative dose intensity, and number (%) of subjects with dose 
modifications (reduced or delayed).
12.5.2
Safety Analysis
The number of subjects who experience any DLT will be presented based on all DLT-evaluable 
subjects (DLT population).  All other safety analyses will be performed using the safety 
population (that is, all subjects who received any dose of study therapy).
All subjects will be assessed regularly for potential occurrence of AEs from the time that the 
subject provides informed consent, until 30 days after the last dose of study therapy.  An AE will 
be regarded as treatment-emergent if its onset date occurs:  any time after the administration of 
the first dose of study medication, up to 30 days after the last dose of study medication (or up to 
any time if related to study medication), or prior to first dose date and worsens while on study 
medication.
AEs will be summarized by MedDRA System Organ Class and Preferred Term, classified from 
verbatim terms.  The incidence and percentage of subjects with at least one occurrence of a 
Preferred Term will be included, according to the most severe NCI-CTCAE, Version 4.0 grade.  
Causality (relationship to study drug) will be summarized separately.
All treatment-emergent AEs, SAEs, and NCI-CTCAE, Version 4.0 Grade 3 or higher AEs;
related AEs, SAEs, and NCI-CTCAE, Version 4.0 Grade 3 or higher AEs; AEs leading to dose 
modification and study medication discontinuation; and deaths will be summarized according to 
MedDRA Preferred Terms. Duration of AE will be determined and included in listings along 
with action taken and outcome.
Laboratory results will be classified according to NCI-CTCAE, Version 4.0.  Laboratory results 
not corresponding to an NCI-CTCAE, Version 4.0 term will not be graded.  Laboratory toxicity 
shifts from baseline to worst grade will be provided. The last measurement before study 
medication will serve as the baseline measurement. Results for variables that are not part of the 
NCI-CTCAE, Version 4.0 will be presented in the listings as below, within, or above the normal 
limits of the local laboratory.

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The results from physical examination, vital sign measurement, and other assessments will be 
tabulated, if appropriate.
12.6
Analyses of Antitumor Response
Radiographic assessment of tumor response will be performed at the end of the initial 6-week 
cycle and the end of every subsequent cycle.  However, if a DLT is observed in Cycle 1 in a 
subject who is benefitting from treatment, Cycle 2 dosing may be initiated within 4 weeks of 
Cycle 1, Day 1, with Sponsor approval; in this case, no radiographic disease assessment is 
required prior to dosing in Cycle 2.  Tumor response data will be summarized, if appropriate.
12.7
Other Assessments or Analyses
12.7.1
Pharmacokinetic Assessments
Blood samples for PK will be analyzed at a laboratory designated by the Sponsor.  Parameters to 
be reported may include, but not be limited to, Cmax, Cmin, AUC, t1/2, Cl, and Vss of IMC-CS4, 
and will be generated using a noncompartmental model.  PK parameters will be summarized 
using descriptive statistics.
12.7.2
Pharmacodynamic Assessments
Pharmacodynamic analyses will be descriptive, and correlations to safety and/or efficacy will be 
performed as appropriate. Those biomarkers collected from different types of tissues or assays 
will be analyzed separately. Whether a subject is available or willing to provide tissue samples 
may be considered as a potential confounding variable for exploratory pharmacodynamic
analysis.
12.8
Data Safety Monitoring Plan
In order to track and clearly document/record the occurrence of DLTs and identify the decisions 
made regarding dose escalation, the study investigators, the Sponsor CRP, and other members of 
the study team, as appropriate, will meet at specific times throughout this clinical study to review 
subject safety data.  They will make the determination regarding dose escalation based upon their 
review of the safety/tolerability data and upon availability the PK data from the previous cohorts.  
At a minimum, they will meet:

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
If there are 2 subjects with DLTs within a single cohort during the DLT assessment 
period;

At the completion of each dose cohort, in order to determine if dose escalation will 
proceed (as described in Section 4.1).  This review will include safety data collected to 
date, across all dose cohorts;

After the RP2D is determined, to determine whether dose escalation should proceed; and

At least quarterly.
The aforementioned team will determine if the number of subjects experiencing DLTs, as well as
any events that occurred after the DLT assessment period that otherwise would have been 
considered DLTs, exceeds that expected with IMC-CS4 and recommend action, if necessary.  
The recommended actions may include protocol modification, termination, or additional safety 
review at specified time points.  The Sponsor CRP may perform additional periodic reviews of 
relevant safety data (such as a review of Council for International Organizations of Medical 
Sciences [CIOMS] reports); these evaluations will be documented according to the trial-level 
safety review plan (a separate, study-specific document that will further detail the process).

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13 ADMINISTRATIVE CONSIDERATIONS
13.1
Organizational Structure of the Study
The study sponsor, Eli Lilly and Company, may delegate certain tasks to designees, including a 
contract research organization or other third-party vendor.
13.2
Institutional Review Board/Approving Ethics Committee Approval
The IRB/aEC must operate in accordance with 21 CFR Part 56, or applicable local regulatory 
requirements, which at a minimum complies with Part 312.120.  Before study initiation, the 
Investigator must have specified written and dated approval from the IRB/aEC for the protocol, 
ICF, subject recruitment materials/process (for example, advertisements), and any other written 
information to be provided to the subjects.  Any member of the IRB/aEC who is directly 
affiliated with this study as an Investigator or as site personnel must abstain from the vote on the 
approval of the protocol.  The Investigator also should provide the IRB/aEC with a copy of the 
IB or product labeling, information to be provided to the subjects, any relevant curricula vitae, 
and any updates.
The Investigator should provide the IRB/aEC with reports, updates, and other information (for 
example, safety updates, amendments, and administrative letters) according to all regulatory 
requirements and institution procedures.
13.3
Ethical Conduct of the Study
The findings of this study are expected to significantly contribute to subsequent global regulatory 
submissions.  The Investigator is responsible for ensuring that the clinical study is conducted in 
accordance with the protocol, FDA GCP guidelines, FDA Financial Disclosure regulations, as 
well as International Conference on Harmonisation (ICH) guidelines, consensus ethics principles 
derived from international ethics guidelines, including the Declaration of Helsinki and CIOMS 
International Ethical Guidelines, and any other regional/national requirements for clinical trials, 
as applicable.

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13.4
Compliance with the Protocol and Protocol Revisions
The Sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each Principal Investigator will sign the protocol signature page and 
send a copy of the signed page to a Sponsor representative.
The Investigator must comply with all requirements of the protocol.  If a situation occurs that 
requires a temporary departure from the protocol, the Investigator or other physician in 
attendance must contact the Sponsor CRP as soon as possible to discuss the situation and agree 
on an appropriate course of action.  The Investigator will describe the departure from the 
protocol and the circumstances requiring it on the applicable subjects’ eCRFs and will notify the 
IRB/aEC as appropriate.
The Investigator may not modify this protocol.  Modifications to the protocol initiated by the 
Sponsor or its designee will be confirmed in writing in the form of a protocol amendment.  All 
such amendments must be approved by the IRB/aEC; however, amendments initiated by the 
Sponsor that reduce risks to the subjects
may be implemented prior to obtaining 
IRB/aEC approval.  Subjects may not be enrolled in an amended protocol until that amendment 
has been approved by the IRB/aEC.  Documentation of approval signed by the chairperson or 
designee of the IRB/aEC must be sent to the Sponsor or its designee.  If the revision is an 
administrative letter, investigators must inform and obtain approval from their IRB/aEC.
13.5
Subject Information and Consent
Written informed consent will be given by each subject before entering the study, in accordance 
with FDA regulations (21 CFR Parts 50.20 through 50.27), ICH guidelines as implemented in 
the European Union and Japanese guidelines, GCP guidelines, and/or applicable local regulatory 
requirements.
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical trials in which they volunteer to participate, 
including answering any questions the subject may have throughout the study and sharing in a 

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timely manner any new information that may be relevant to the subject’s willingness to continue 
his or her participation in the study in a timely manner.
13.5.1
Informed Consent Procedures
The ICF will be used to explain the potential risks and benefits of study participation to the 
subject in simple terms before the subject is entered into the study and to document that the 
subject is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The Sponsor must agree with all ICFs before they are submitted to the IRB/aEC or used at 
investigative sites(s).  The ICF must include all elements required by the FDA, ICH guidelines as 
implemented in the European Union and Japanese guidelines, GCP, and/or applicable local 
regulatory requirements.  The ICF also must include a statement that the Sponsor, its agents, and 
the regulatory authorities have direct access to subject records.  Prior to the beginning of the 
study, the Investigator must have the IRB/aECs written approval/favorable opinion of the written 
ICF and any other information to be provided to the subjects.
The Investigator is ultimately responsible for ensuring that informed consent is given by each 
subject or legal representative before the study is started.  This includes obtaining the appropriate 
signatures and dates on the ICF prior to the performance of any protocol procedures and prior to 
the administration of study drug.
The Investigator must provide the subject with a copy of the ICF and written information about 
the study in the language in which the subject is most proficient.  The language must be 
nontechnical and easily understood.  The Investigator should allow time necessary for the subject
to inquire about the details of the study; the ICF must be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The subject should 
receive a copy of the signed ICF and any other written information provided to study subjects
prior to the subject’s participation in the trial.
13.5.2
Update of the Informed Consent
The ICF and any other information provided to subjects should be revised whenever important 
new information becomes available that is relevant to the subject’s consent and should receive 

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IRB/aEC approval/favorable opinion prior to use.  The Investigator, or a person designated by 
the Investigator, should fully inform the subject of all pertinent aspects of the study and of any 
new information relevant to the subject’s willingness to continue participation in the study.  This 
communication should be documented.  During a subject’s participation in the trial, any updates 
to the ICF and any updates to the written information will be provided to the subject.
If a protocol amendment substantially alters the study design or increases the potential risk to the 
subject:  (1) the ICF must be revised and submitted to the IRB/aEC for review and approval, 
(2) the revised ICF must be used to obtain consent from subjects currently enrolled in the study, 
and (3) the new ICF must be used to obtain consent from new subjects prior to first dose of 
investigational agent.
13.6
Study Monitoring
The Sponsor and its representatives must be allowed to visit all study site locations periodically 
to assess the data, quality, and study integrity.  On site, they will review study records and 
directly compare them with source documents, review
regulatory documents, verify 
investigational agent accountability, discuss the conduct of the study with the Investigator, verify 
compliance with the study protocol, and verify that the facilities remain acceptable.
13.7
Case Report Forms and Study Records
For this study, the Sponsor will be using an electronic data capture (EDC) system for the 
collection of all study-related data.  Any data for which the eCRF will serve as the source 
document will be identified and documented by each site in that site’s study file.
An Investigator is required to prepare and maintain adequate case histories designed to record all 
observations and other data pertinent to the investigation on each subject enrolled in this trial.  
All data reported on the eCRF must be derived from source documents and be consistent with 
those source documents, or the discrepancies must be explained.
The confidentiality of records and information that could identify subjects must be protected, 
respecting the privacy and confidentiality rules in accordance with applicable regulatory 
requirements.

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The Investigator will maintain, in confidence, all information furnished by the Sponsor or 
designees and all data generated in the study, except as provided or required by law, and will 
divulge such information to the IRB/aEC with the understanding that confidentiality will be 
maintained by the committee.
The eCRFs should be completed as soon as possible when the data are available.  If an item is 
not available or is not applicable, it must be documented as such by either entering “NA” in the 
comment field or checking the corresponding “NA” box; do not leave a space blank.
The Investigator will maintain a Delegation of Authority Page to document all persons 
authorized to make entries and corrections on eCRFs.  A correction is made by changing the 
corresponding entry on the eCRF.  The system will automatically ask for a reason for the change 
and store the original value, the new value, the date and time of the change, and the person who 
made the change in the audit trail.
The completed eCRF must be reviewed, electronically signed, and dated by a qualified physician 
who is an Investigator or subinvestigator using the built-in electronic signature feature of the 
EDC system.  If any changes are made or additional data are added to an eCRF after the 
Investigator has signed and dated the form, the electronic signature will be automatically 
invalidated and the form will have to be re-signed.  All changes and signatures are automatically 
stored in the audit trail of the eCRF.
13.8
Access to Source Documentation
The study may be evaluated by auditors designated by the Sponsor and by government inspectors 
who must be allowed access to eCRFs, source documents, and all other study files.  Sponsor 
audit reports will be kept confidential.
THE INVESTIGATOR MUST NOTIFY THE SPONSOR PROMPTLY OF ANY 
INSPECTIONS SCHEDULED BY REGULATORY AUTHORITIES AND PROMPTLY 
FORWARD COPIES OF INSPECTION REPORTS TO THE SPONSOR.

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13.9
Retention of Data
The Investigator must retain disposition records, copies of electronic files, and source documents 
(including scans) for the maximum period required by applicable regulations and guidelines, 
institution procedures, or the period specified by the Sponsor or its designee, whichever is 
longer.  The Investigator must contact the Sponsor and its designee before destroying any 
records associated with the study.  The Sponsor and its designee will notify the Investigator 
when the trial records are no longer needed.  If the Investigator withdraws from the study (for 
example, relocation, retirement), all records will be transferred to a mutually agreed-upon 
designee (for example, another Investigator, IRB/aEC) who will assume responsibility for the 
study and its conduct.  Notice of such transfer will be given in writing to the Sponsor or its 
designee.
13.10 Financial Disclosure
Financial disclosure information must be provided by all investigators and sub-investigators and 
will be collected by the Sponsor before the start of the study.
13.11 Publication and Disclosure Policy
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.  In addition, the Sponsor’s responsible medical 
officer and responsible statistician will approve the final clinical study report for this study, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the study.
All information concerning the investigational agent supplied by the Sponsor in connection with 
this study and by any other party collaborating with the Sponsor within this study, and not 
previously published, is considered confidential and proprietary information.  This information 
includes, but is not limited to, the IB, clinical protocol, workbooks (if applicable), eCRFs, assay 
methods, Sponsor technical methodology, and basic scientific data.  This confidential and 
proprietary information shall remain the sole property of the Sponsor and shall not be disclosed 

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to others without prior written consent from the Sponsor with respect to their confidential and 
proprietary nature and shall not be used except in the performance of this study.
To allow for the use of the information derived from this clinical study and to ensure compliance 
with current regulations, the Investigator is obligated to provide the Sponsor with complete test 
results and all data obtained in this study.
No publication, abstract, or presentation of the study will be made without the approval of the 
Sponsor.  The Sponsor will review the manuscript to prevent forfeiture of patent rights to data 
not in the public domain.  Prior to publication, the authorship list will be agreed upon by the 
Sponsor.  The results of the study may be published as an original article in an appropriate 
medical journal.  The choice of the journal will be made by the Sponsor in agreement with the 
coauthors.
Lilly’s authorship criteria are based on the International Committee of Medical Journal Editors 
(ICMJE) Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical Journals (www.ICMJE.org, updated August 2013):
1. Substantial contributions to conception and design of the work, or the acquisition, analysis, or 
interpretation of data for the work
2. Drafting the article or revising it critically for important intellectual content
3. Final approval of the version to be published 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
NOTE:  Authors must meet conditions 1, 2, 3, and 4.

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PPD
Leo Document ID = 0c9a9e81-8754-42a1-91ff-4f9fa67ea8da
Approver: 
Approval Date & Time: 03-Sep-2015 13:45:07 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 03-Sep-2015 15:31:14 GMT
Signature meaning: Approved
PPD