A Phase 1/2, Open-Label, Single-Arm, Dose-Escalation and Dose-Expansion Study of the Safety, Tolerability, Pharmacokinetic, and Antitumor Activity of E-602 as a Single Agent and in Combination With Cemiplimab in Patients With Advanced Cancers
Phase: PHASE1
Conditions: Oncology, Melanoma, Ovarian Cancer, NSCLC, Non Small Cell Lung Cancer, Colorectal Cancer, Pancreatic Cancer, Cancer, CRC, Colon Cancer, Breast Cancer, Gastric Cancer, EGJ, Esophagogastric Junction Cancer, Head and Neck Cancer, Urothelial Cancer, Bladder Cancer
Sponsor: Palleon Pharmaceuticals, Inc.

Clinical Study Protocol 
A Phase 1/2, Open-Label, Single-Arm, Dose-Escalation and Dose-Expansion 
Study of the Safety, Tolerability, Pharmacokinetic, and Antitumor Activity of 
E-602 as a Single Agent and in Combination with Cemiplimab in Patients 
with Advanced Cancers 
Protocol Number: 
PAL-E602-001 
Version Number: 
8.0 
Compound: 
E-602 
Brief Title: 
Glycan Mediated Immune Regulation with a Bi-
Sialidase Fusion Protein (GLIMMER-01) 
Study Phase: 
Phase 1/2 
Sponsor: 
Palleon Pharmaceuticals 
Address: 
266 2nd Ave, Waltham, MA 02451 
Contract Research Organization: 
Medpace, Inc. 
Medical Monitor: 
Palleon Pharmaceuticals 
Regulatory Agency Identifier 
Number(s): 
IND 152471 
Approval Date: 
24 AUG 2023 
 
  
 
 
 
 
 
  
 
 
 

Phase 1/2 Clinical Study Protocol 
Protocol Number: PAL-E602-001 
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Table of Contents 
 
1. 
Protocol Summary ..........................................................................................................5 
1.1. 
Synopsis ............................................................................................................................5 
1.2. 
Schema ............................................................................................................................13 
1.3. 
Schedule of Activities (SoA) ..........................................................................................14 
1.3.1. 
Phase 1 E-602 Monotherapy: Dose Escalation and Backfill ..........................................14 
1.3.2. 
Phase 1 Combination Dose Escalation and Backfill; Phase 2 E-602 
Monotherapy and Combination ......................................................................................17 
2. 
Introduction ...................................................................................................................20 
2.1. 
Study Rationale ...............................................................................................................20 
2.2. 
Background .....................................................................................................................20 
2.2.1. 
Nonclinical Studies .........................................................................................................21 
2.2.2. 
Cemiplimab Pharmaceutical and Therapeutic Background ............................................22 
2.3. 
Benefit/Risk Assessment ................................................................................................23 
3. 
Objectives and Endpoints ............................................................................................24 
4. 
Study Design ..................................................................................................................26 
4.1. 
Overall Design ................................................................................................................26 
4.1.1. 
Study Design Overview ..................................................................................................26 
4.1.2. 
Continued Treatment Beyond Disease Progression ........................................................27 
4.1.3. 
Post-treatment Follow-up................................................................................................28 
4.1.4. 
Phase 1 Dose-escalation Guidelines ...............................................................................28 
4.1.5. 
Dose-Limiting Toxicity (DLT) Definition......................................................................28 
4.2. 
Scientific Rationale for Study Design ............................................................................30 
4.3. 
Justification for Dose ......................................................................................................30 
4.3.1. 
Justification for E-602 Dose ...........................................................................................30 
4.3.2. 
Justification for Cemiplimab Dose .................................................................................31 
4.4. 
End of Study Definition ..................................................................................................31 
5. 
Study Population ...........................................................................................................32 
5.1. 
Inclusion Criteria ............................................................................................................32 
5.2. 
Exclusion Criteria ...........................................................................................................35 
5.3. 
Lifestyle Considerations .................................................................................................37 
5.4. 
Screen Failures ................................................................................................................37 
6. 
Study Treatment and Concomitant Therapy .............................................................38 
6.1. 
Study Treatment Administered .......................................................................................38 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................39 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................40 
6.4. 
Study Treatment Compliance .........................................................................................40 
6.5. 
Dose Modification ..........................................................................................................40 
6.6. 
Management of Infusion Reactions ................................................................................42 
6.7. 
Treatment of Overdose ...................................................................................................42 
6.8. 
Concomitant Therapy .....................................................................................................43 
6.8.1. 
Rescue Medicine .............................................................................................................43 

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7. 
Discontinuation of Study Treatment and Withdrawal of 
Consent ..........................................................................................................................44 
7.1. 
Discontinuation of Study Treatment ...............................................................................44 
7.1.1. 
Temporary Interruption of Study Treatment ...................................................................44 
7.1.2. 
Subject Replacement .......................................................................................................44 
7.1.3. 
Study Stopping Criteria...................................................................................................44 
7.2. 
Subject Withdrawal from the Study................................................................................45 
7.3. 
Lost to Follow-up............................................................................................................45 
8. 
Study Assessments and Procedures.............................................................................46 
8.1. 
Efficacy Assessments .....................................................................................................46 
8.2. 
Safety Assessments .........................................................................................................47 
8.2.1. 
Physical Examinations ....................................................................................................47 
8.2.2. 
Vital Signs .......................................................................................................................47 
8.2.3. 
Weight and Height ..........................................................................................................47 
8.2.4. 
Electrocardiograms .........................................................................................................47 
8.2.5. 
Clinical Safety Laboratory Tests ....................................................................................47 
8.2.6. 
Pregnancy Testing ...........................................................................................................48 
8.3. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and Other 
Safety Reporting .............................................................................................................48 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................48 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................49 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................49 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................49 
8.3.5. 
Pregnancy ........................................................................................................................49 
8.3.6. 
Death Events ...................................................................................................................50 
8.3.7. 
Adverse Events of Special Interest .................................................................................50 
8.4. 
Pharmacokinetics ............................................................................................................50 
8.5. 
Biomarkers ......................................................................................................................51 
8.5.1. 
Pharmacodynamics .........................................................................................................51 
8.5.2. 
Genetics...........................................................................................................................53 
8.5.3. 
Tumor Biopsy .................................................................................................................54 
8.6. 
Immunogenicity Assessments.........................................................................................55 
9. 
Statistical Considerations .............................................................................................56 
9.1. 
Analysis Sets ...................................................................................................................56 
9.2. 
Statistical Analyses .........................................................................................................56 
9.2.1. 
General Considerations ...................................................................................................56 
9.2.2. 
Subject Disposition .........................................................................................................56 
9.2.3. 
Baseline Characteristics ..................................................................................................57 
9.2.4. 
Safety Analyses ...............................................................................................................57 
9.2.5. 
Efficacy analysis .............................................................................................................58 
9.2.6. 
Pharmacokinetics and Immunogenicity ..........................................................................58 
9.2.7. 
Exploratory Analysis: Pharmacodynamics .....................................................................58 
9.2.8. 
Covariates and Subgroup analysis ..................................................................................58 
9.3. 
Interim Analysis ..............................................................................................................59 

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9.4. 
Sample Size Determination ............................................................................................59 
10. 
Supporting Documentation and Operational Considerations ..................................60 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................60 
10.1.1. Regulatory and Ethical Considerations ...........................................................................60 
10.1.2. Financial Disclosure ........................................................................................................60 
10.1.3. Informed Consent Process ..............................................................................................60 
10.1.4. Data Protection................................................................................................................61 
10.1.5. Committees Structure......................................................................................................61 
10.1.6. Dissemination of Clinical Study Data .............................................................................61 
10.1.7. Data Quality Assurance ..................................................................................................62 
10.1.8. Source Documents ..........................................................................................................62 
10.1.9. Study and Site Start and Closure ....................................................................................63 
10.1.10. Publication Policy ...........................................................................................................63 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................64 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................66 
10.3.1. Definition of AE .............................................................................................................66 
10.3.2. Definition of SAE ...........................................................................................................67 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................68 
10.3.4. Reporting of SAEs ..........................................................................................................70 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................71 
10.4.1. Definitions.......................................................................................................................71 
10.4.2. Contraception Guidance ..................................................................................................72 
10.5. 
Appendix 5: Infusion Reaction Assessments and Management .....................................73 
10.6. 
Appendix 6: Abbreviations .............................................................................................76 
11. 
References ......................................................................................................................79 
 
List of Tables 
Table 1 
50% And 20% effective concentrations (EC50 and EC20) of E-602 for 
desialylation of human CD8 and CD4 T cells ................................................... 31 
Table 2 
Dose modifications for E-602 monotherapy and combination therapy with 
cemiplimab ......................................................................................................... 40 
Table 3 
Blood sample collection time points for pharmacokinetic analyses .................. 50 
Table 4 
Phase 1 E-602 monotherapy biomarker sample collection time points for 
pharmacodynamic, genetic and immunogenicity analyses ................................ 52 
Table 5 
Phase 1 combination and Phase 2 biomarker sample collection time points for 
pharmacodynamic, genetic and immunogenicity analyses ................................ 52 
Table 6 
Collection time point requirements for tumor biopsy ........................................ 54 
Table 7 
Protocol-required safety laboratory tests ........................................................... 64 
 

Phase 1/2 Clinical Study Protocol 
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• 
Tumor 
IHC 
analysis 
for 
immune 
modulation of different immune cell 
subtypes 
• 
Tumor gene expression and mutation 
profiling  
• 
Glycoproteomic profiling 
• 
Genetic variation or single nucleotide 
polymorphisms (SNPs) in select genes 
(e.g., glycogenes) (Phase 1 combination 
and Phase 2 only) 
 
Overall Design: 
This is a Phase 1/2, first-in-human (FIH), open-label, dose escalation and dose expansion study of 
E-602, administered as a single agent and in combination with cemiplimab, to evaluate the safety, 
tolerability, PK, pharmacodynamics, and antitumor activity in subjects with advanced cancers. 
Phase 1: Dose Escalation, Monotherapy and Combination Therapy 
Phase 1 of the study consists of 5 planned dose escalation cohorts of E-602 as a monotherapy and 
2 planned dose escalation cohorts of E-602 in combination with cemiplimab. Phase 1 monotherapy 
will treat eligible subjects with melanoma, ovarian cancer, non-small cell lung cancer (NSCLC), 
colorectal cancer, pancreatic cancer, breast cancer, gastric/esophagogastric junction (EGJ) cancer, 
head and neck cancer, or urothelial cancer. Phase 1 combination with cemiplimab will treat eligible 
subjects with melanoma, NSCLC, gastric/EGJ cancer, head and neck cancer or urothelial 
carcinoma. The safety of the dose regimens will be evaluated to identify the maximum tolerated 
dose (MTD) and recommended Phase 2 dose (RP2D) to be used during Phase 2. 
The cohorts of E-602 monotherapy will receive E-602 at the doses of 1, 3, 10, 20 and 30 mg/kg, 
respectively, via intravenous (IV) infusion once a week. Intermediate dosing cohorts may be added 
in Phase 1. The first subject dosed in a cohort will be a sentinel subject, with at least 24 hours until 
any subsequent subjects are dosed in the cohort. No intrasubject dose escalation of E-602 will be 
permitted.  
The cohorts of E-602 in combination with cemiplimab will be initiated at dose level(s) that have 
previously completed DLT assessments (Cycle 1) as monotherapy. Intermediate dosing cohorts 
may be added in Phase 1. Subjects in the combination cohorts will receive 20 mg/kg E-602 IV 
once a week (additional dose levels to be determined) and 350 mg cemiplimab IV once every 3 
weeks. The first subject dosed in a cohort will be a sentinel subject, with at least 24 hours until any 
subsequent subjects are dosed in the cohort. No intrasubject dose escalation of E-602 will be 
permitted. 
Each treatment cycle consists of 21 days. E-602 will be administered on Days 1, 8, and 15 of each 
cycle. Cemiplimab, if given, will be administered on Day 1 of each cycle. When the cemiplimab 
combination is administered, cemiplimab should be administered first and E-602 administered at 
least 30 minutes after the cemiplimab infusion is completed. Subjects receiving ≥10 mg/kg of E-
602 as monotherapy or in combination with cemiplimab should receive premedication including 
antihistamines and acetaminophen as indicated in the Pharmacy Manual. Corticosteroids should 
be used as premedication for subjects with previous infusion reaction(s) to E-602 as indicated in 
the Pharmacy Manual (see Pharmacy Manual, Section 10.5). 

Phase 1/2 Clinical Study Protocol 
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Dose escalation guidelines for all Phase 1 dose cohorts will utilize a modified 3+3 design. 
Assessments of DLTs will occur during Cycle 1 (defined as a subject receiving 3 doses of E-602 
for monotherapy cohorts and 3 doses of E-602 and 1 dose of cemiplimab for combination therapy 
cohorts) for all dose cohorts. Safety monitoring for immune-related toxicities will continue for all 
subjects for 90 days after treatment discontinuation unless a subsequent cancer therapy is started. 
All available data will be taken into consideration in selecting the RP2D. 
E-602 dose escalation will continue until the MTD is exceeded, unacceptable toxicity is reached, 
or the RP2D is determined. The Sponsor may terminate dose escalation at a RP2D prior to reaching 
the MTD based on emerging PK, pharmacodynamic, and safety data.   
Any Phase 1 cohort may be backfilled at the judgement of the Sponsor, up to a total of 15 subjects 
in the dose cohort (dose escalation and backfill) as needed to obtain additional safety, PK and 
pharmacodynamic data at a particular dose level.  
In addition to DLTs, subjects will be evaluated for safety and tumor response as well as PK and 
pharmacodynamics, as listed in the Schedule of Activities (SoA) in Section 1.3. 
Phase 2: Dose Expansion, Monotherapy and Combination Therapy 
Phase 2 consists of dose expansion disease cohorts in subjects with 3 types of advanced tumors: 
melanoma, NSCLC, and the third type to be determined (ovarian, colorectal, pancreatic, breast, 
gastric/EGJ, head and neck, or urothelial) based on available data including the Phase 1 results. 
Phase 2 of the study will employ a 2-stage design, as outlined in Section 9.4. Each disease cohort 
will be analyzed separately. The E-602 dose(s), i.e., RP2D(s), chosen based on Phase 1 data will 
be used. E-602 as monotherapy and in combination with cemiplimab will be evaluated separately. 
Subjects will be evaluated for safety and tumor response as well as PK and pharmacodynamics, as 
listed in the Schedule of Activities (SoA) in Section 1.3. 
Treatment Discontinuation Criteria 
Subjects will permanently discontinue study treatment for any of the following:  
• Progressive disease (confirmed PD for subjects who continued treatment beyond PD, see 
Section 4.1.2) 
• Initiation of alternative cancer therapy 
• Unacceptable toxicity including permanent discontinuation criteria defined in Section 6.5 
• Subject’s decision to discontinue treatment 
• Withdrawal of consent 
• Investigator’s decision to discontinue treatment 
• Sponsor’s decision to discontinue treatment 
• Inability of the subject to comply with the requirements of the study 
• Completion of maximum treatment duration of 1 year from Cycle 1 Day 1 
Treatment Beyond Disease Progression 
Treatment beyond PD will be allowed as per iRECIST guidelines. The following criteria must be 
met for continued use of the study treatment beyond PD: 
• Absence of symptoms and signs indicating clinically significant progression of disease 

Phase 1/2 Clinical Study Protocol 
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• No decline in the Eastern Cooperative Oncology Group (ECOG) performance status 
• Absence of symptomatic rapid disease progression requiring urgent medical intervention 
(e.g., symptomatic pleural effusion, spinal cord compression). 
At the time of radiographic progression of disease, a subject will be reconsented with emphasis on 
the FDA-approved therapy and potential clinical benefit that the subject may be foregoing to 
continue treatment. 
Post-treatment Follow-up 
For subjects who complete the 1-year treatment, an end-of-treatment (EOT) visit will be conducted, 
and subjects will return for safety follow-up visits 30 and 90 days after the last dose of study 
treatment to monitor for safety, including late immune-related toxicities. If prior to completing the 
90-day safety follow-up period a subject begins a new cancer treatment, no further safety follow-
up is required.  
For subjects who discontinue treatment early, an EOT visit will be conducted, and subjects will 
return for safety follow-up visits 30 and 90 days after the last dose of study treatment. If prior to 
completing the 90-day safety follow-up period a subject begins a new cancer treatment, no further 
safety follow-up is required. These subjects will continue to be contacted once every 3 months for 
disease and survival status through approximately 15 months after the first dose of the study 
treatment unless the subject has died or withdrawn consent.  
Phase 1 Dose-escalation Guidelines: 
The following modified 3+3 guidelines will be employed on the basis of the number of DLTs 
observed during Cycle 1 (3 doses of E-602 administered for monotherapy cohorts and 3 doses of 
E-602 and 1 dose of cemiplimab administered for combination therapy cohorts): 
• Each dose level cohort will treat 3-6 subjects. At each dose level, at least 3 subjects must 
be DLT-evaluable prior to dose escalation.  
• If 0 subjects experience a DLT, the next cohort will be treated at the next higher dose level. 
• If only 1 subject experiences a DLT in 6 DLT-evaluable subjects, the next cohort will be 
treated at the next higher dose level. 
• If 2 or more subjects in any cohort experience a DLT, the MTD will have been exceeded 
and no further subjects will be treated at this or higher dose levels. Additional subjects will 
be treated at the next lower dose level if needed to have at least 6 subjects treated at that 
prior dose level. If at least 6 subjects were previously treated at the prior dose level, that 
prior dose level will be considered the MTD.  
Dose-Limiting Toxicity (DLT) Definition: 
The DLT window of observation for the purposes of dose escalation will be Cycle 1 defined as a 
subject receiving 3 doses of E-602 for monotherapy cohorts and 3 doses of E-602 and 1 dose of 
cemiplimab for combination therapy cohorts. Any of the following events will meet the definition 
of a DLT if assessed by the investigator to be possibly, probably, or definitely related to study 
treatment: 
• Any death not clearly due to the underlying disease or extraneous causes 
• Hy’s law: 

Phase 1/2 Clinical Study Protocol 
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o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3×the 
upper limit of normal (ULN) AND 
o Total bilirubin >2×ULN AND 
o Alkaline phosphatase <2×ULN AND 
o No other reason for liver injury 
• Neutropenic fever 
• Any Grade ≥3 non-hematologic toxicity (with exceptions noted below) 
• Grade 4 neutropenia or thrombocytopenia >7 days 
• Grade 3 thrombocytopenia with bleeding 
• Grade 4 vomiting or diarrhea of any duration 
• Grade 3 fatigue ≥7 days 
• Grade ≥3 electrolyte abnormality that lasts >72 hours, unless the subject has clinical 
symptoms, in which case all Grade ≥3 electrolyte abnormality regardless of duration will 
be a DLT. 
• For subjects with hepatic metastases, AST or ALT >8×ULN or AST or ALT >5×ULN for 
≥14 days 
• Recurrent Grade 3 infusion-related reaction despite pre-medication 
• Grade 4 infusion-related reaction on the first occurrence 
• Dose delay of >14 days for the study treatment due to an AE 
However, the following AEs are NOT considered a DLT:   
• Hematologic toxicity: 
o Grade 3 anemia 
o Grade 3 lymphopenia 
o Grade 3 or 4 neutropenia that is not associated with clinical sequelae and lasts <7 
days 
o Grade 3 or 4 thrombocytopenia without bleeding 
• Cardiovascular toxicity: 
o Grade 3 hypertension 
• Other toxicities: 
o Grade 3 fatigue lasting <7 days 
o Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate 
antiemetic and other supportive care 
o Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated and resolves spontaneously or responds to conventional medical 
interventions 
o Grade 3 or higher amylase or lipase that is not associated with symptoms or clinical 
manifestations of pancreatitis 
o Isolated Grade 3 infusion reaction  
o AEs that are clearly and incontrovertibly due to disease progression or extraneous 
causes. 

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Subjects treated in the Phase 1 dose escalation part of the study will discontinue treatment if he/she 
experience DLT(s) during Cycle 1. 
Brief Summary: 
The purpose of this study is to evaluate the safety, tolerability, preliminary efficacy, PK and 
pharmacodynamics of E-602, as a single agent or in combination with cemiplimab, for the 
treatment of subjects with advanced tumors. A maximum tolerated dose (MTD) and/or a 
recommended Phase 2 dose (RP2D) will be determined during Phase 1 to facilitate the conduct of 
Phase 2.   
Study details include: 
• Study duration: approximately 2 years from screening of the first subject to the last visit of 
the last subject (end of study). 
• Treatment duration for individual subjects: 
o Screening period: up to 4 weeks before Cycle 1 Day 1 
o Treatment period: up to 1 year from Cycle 1 Day 1 regardless of treatment delays 
o Follow-up period: up to approximately 15 months from Cycle 1 Day 1 
• Visit frequency: approximately up to 7 visits in Cycle 1; up to 5 visits in Cycle 2 and from 
Cycle 3 onward, weekly visits in each 21-day cycle. 
Number of Subjects: 
The planned total number of subjects to be treated in Phase 1 of the study is up to 87 subjects 
including up to 42 subjects in dose escalation and 45 subjects in backfilled cohorts. The planned 
total number of subjects to be treated in Phase 2 of the study is up to 186 subjects. 
Total study treatment is up to 273 subjects. 
Treatment Groups and Durations: 
Phase 1 Treatment (Planned):  
Five escalating dose cohorts of E-602 monotherapy and 2 escalating dose cohorts of combination 
therapy will be treated.  
Cohort 
Number of 
Subjectsa 
Dose of E-602 
Frequency of E-602 
Dose of 
Cemiplimab 
Frequency of 
Cemiplimab 
101 
3 – 6 
1 mg/kg 
once a week 
n/a 
n/a 
102 
3 – 6 
3 mg/kg 
once a week 
n/a 
n/a 
103 
3 – 6 
10 mg/kg 
once a week 
n/a 
n/a 
104 
3 – 6 
20 mg/kg 
once a week 
n/a 
n/a 
105 
3 – 6 
30 mg/kg 
once a week 
n/a 
n/a 
111 
3 – 6 
20 mg/kg 
once a week 
350 mg 
once every 3 weeks 
112 
3 – 6 
to be determined 
once a week 
350 mg 
once every 3 weeks 
a Phase 1 cohorts may be backfilled to a maximum of 15 subjects.  

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The dose for E-602 in the combination therapy cohorts will be initiated at dose level(s) that have 
previously completed dosing and DLT assessments (Cycle 1) as monotherapy.   
Dose modifications will be made according to the protocol (Section 6.5).  
Phase 2 Treatment (Planned): 
Subjects in Phase 2 will receive the following treatment: 
Cohort 
Number of 
Subjects 
Advanced 
Disease 
Dose of E-602 
Frequency 
of E-602 
Dose of 
Cemiplimab 
Frequency of 
Cemiplimab 
201 
16 − 31 
melanoma 
monotherapy RP2D 
once a week 
n/a 
n/a 
202 
16 − 31 
NSCLC 
monotherapy RP2D 
once a week 
n/a 
n/a 
203 
16 − 31 
TBDa 
monotherapy RP2D 
once a week 
n/a 
n/a 
211 
16 − 31 
melanoma 
combination RP2D 
once a week 
350 mg 
once every 3 
weeks 
212 
16 − 31 
NSCLC 
combination RP2D 
once a week 
350 mg 
once every 3 
weeks 
213 
16 − 31 
TBDa 
combination RP2D 
once a week 
350 mg 
once every 3 
weeks 
a The third cohort will treat subjects with one of ovarian, colorectal, pancreatic, breast, gastric/EGJ, head and neck, or 
urothelial cancers based on available data including the Phase 1 results. 
Duration of Treatment: 
The maximum duration of treatment for each subject will be 1 year, regardless of treatment delays.  
Safety Data Review Committee 
A Safety Data Review Committee (SDRC) consisting of the principal investigators and members 
of the Sponsor will be formed and will meet regularly to review ongoing safety data. The 
committee will oversee subject safety and make recommendations to the Sponsor for all cohort 
dosing and dose escalation decisions.

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1.2. 
Schema 
 
 
Abbreviations: NSCLC=non-small cell lung cancer, TBD=to be determined 
aTumor types in Phase 1: melanoma, ovarian, NSCLC, colorectal, pancreatic, breast, gastric/EGJ, head and neck, and urothelial. Phase 1 cohorts may be backfilled 
to a maximum of 15 subjects. The combination therapy cohort(s) will be initiated at dose level(s) that have previously completed DLT assessments (Cycle 1) as 
monotherapy and include only melanoma, NSCLC, gastric/EGJ, head and neck, or urothelial carcinoma subjects. Intermediate dosing cohorts may be added. 
bThe third cohort will treat subjects with one of ovarian, colorectal, pancreatic, breast, gastric/EGJ, head and neck, or urothelial, based on available data including 
the Phase 1 results.  
 

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13. Plasma samples for ADA analysis will be collected pre-dose. An unscheduled plasma ADA sample should be collected in the event of an infusion related reaction. 
14. Either serum or urine pregnancy test is allowed. The choice of test is at the investigator’s discretion.  
15. Physical examination will include, at a minimum, the assessment of cardiovascular, respiratory, gastrointestinal, dermatological and neurological systems along with the lymph 
nodes and liver. Physical examination should be performed during screening, within 72 hours of or on Cycle 1 Day 1 and on Day 1 of each subsequent cycle.  
16. Radiology examination of tumors includes contrast-enhanced CT (preferred) or MRI imaging of the chest, abdomen, and pelvis. The same method (CT, PET/CT, MRI) and the 
same technique should be used to characterize each identified and reported lesion at screening and during the study. Radiology examinations will be performed during screening 
(permitted up to 35 days prior to Cycle 1, Day 1), 9 weeks (±1 week) after the first dose and every 9 weeks (±1 week) thereafter, regardless of any study treatment(s) delay. An 
EOT examination should be performed unless the subject already has radiographic confirmation of PD ≤4 weeks prior to the EOT visit. For ovarian cancer subjects, at each 
radiology examination, CA-125 should also be tested. 
17. See Section 8.5 for further information on sample collection and analyses.  
18. Biomarkers of disease may be performed up to 72 hours prior to Day 1 as follows: carcinoembryonic antigen (CEA) and CA-125 for subjects with NSCLC, 
CEA and CA19-9 for subject with colorectal or pancreatic cancer, and CA-125 for subjects with ovarian cancer. 
19. Circulating tumor DNA samples will be collected with radiological assessments. See Footnote 16. 
20. Tumor biopsy is optional at screening and on Cycle 2 Day 1 (+4 days) during Phase 1. An archive tissue sample is required for all subjects. See Section 8.5.3 for further 
information. 
21. Dosing visits should not be skipped due to dose delays.  
 
 
 
 

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15. Physical examination will include, at a minimum, the assessment of cardiovascular, respiratory, gastrointestinal, dermatological and neurological systems along with the lymph 
nodes and liver. Physical examination should be performed during screening, within 72 hours of or on Cycle 1 Day 1 and on Day 1 of each subsequent cycle.  
16. Radiology examination of tumors includes contrast-enhanced CT (preferred) or MRI imaging of the chest, abdomen, and pelvis. The same method (CT, PET/CT, MRI) and the 
same technique should be used to characterize each identified and reported lesion at screening and during the study. Radiology examinations will be performed during screening 
(permitted up to 35 days prior to Cycle 1, Day 1), 9 weeks (±1 week) after the first dose and every 9 weeks (±1 week) thereafter, regardless of any study treatment(s) delay. An 
EOT examination should be performed unless the subject already has radiographic confirmation of PD ≤4 weeks prior to the EOT visit. For ovarian cancer subjects, at each 
radiology examination, CA-125 should also be tested. 
17. See Section 8.5 for further information on sample collection and analyses.  
18. Biomarkers of disease may be performed up to 72 hours prior to Day 1 as follows: carcinoembryonic antigen (CEA) and CA-125 for subjects with NSCLC, CEA and CA19-9 
for subject with colorectal or pancreatic cancer, and CA-125 for subjects with ovarian cancer. 
19. Circulating tumor DNA samples will be collected with radiological assessments and at EOT visit. See Footnote 16. 
20. Fresh tumor biopsy is required for all subjects in Phase 1 combination at screening and on Cycle 2 Day 1 post-dose (+4 days). Fresh tumor biopsy is required for all subjects in 
Phase 2 at screening and post-dose on Cycle 2 Day 1 or Day 8. The biopsy should be performed on Day 2 or 3 if performed post Cycle 2 Day 1 E-602 administration or Day 9 
or 10 if performed post Cycle 2 Day 8 E-602 administration. An archive tissue sample is required for all subjects. See Section 8.5.3 for further information. 
21. Dosing visits should not be skipped due to dose delays. 
22. Unscheduled cytokine panel samples should be collected in the event of an infusion related reaction. 

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2. 
Introduction 
E-602, also known as Bi-Sialidase, 
 
 E-602 is being developed as an immune therapy to treat 
advanced cancers.  
2.1. 
Study Rationale 
The sialidase moiety of E-602 cleaves off immunosuppressive sialoglycans from immune and 
tumor cells to enhance antitumor immunity. In preclinical studies, E-602 has been shown to 
enzymatically remove sialic acids from cell surface sialoglycans and functions as an immune 
checkpoint blocker by releasing sialoglycan-mediated immunosuppression of antitumor immune 
cells. E-602 has been shown to enhance immune responses to tumor cells through multiple aspects, 
including restoring the function of exhausted-like T cells, improving antigen-specific T-cell 
response, and enhancing dendritic cell (DC) priming and activation of naïve T cells. In addition, 
E-602 has a wide safety margin, as it is not an immune agonist and therefore does not cause 
cytokine activation. In humans, E-602 is expected to have antitumor activities either as a single 
agent or in combination with an anti-programmed death-1 (PD-1)/ programmed death ligand-1 
(PD-L1) agent. 
2.2. 
Background 
Sialoglycans have recently emerged as a critical glyco-immune checkpoint that impairs the 
efficacy of antitumor treatment by inhibiting innate and adaptive immunity (Rodriguez et al, 2018). 
Sialoglycans are structurally heterogeneous and upregulated on activated and exhausted T cells as 
a compensatory regulation mechanism that is similar to the programmed death-ligand 1 (PD-L1) / 
programmed cell death protein 1 (PD-1) immune checkpoints. Multiple types of tumors upregulate 
cell-surface sialoglycans as an immune escape mechanism. Sialoglycans interact with various 
immune receptors, including 15 Siglecs and other receptors on immune cells. Several decades of 
literature have shown various upregulated sialoglycans, such as sialyl ST, STn, sialyl Lewis X/A, 
GD2, GD3, GM3, and α2-3 sialylation, correlate with poor clinical outcomes in over a dozen tumor 
types (Crocker and Varki, 2001; Varki and Gagneux, 2012). As such, therapeutic interventions 
targeting this pathway remains challenging due to receptor redundancy and glyco-ligand 
heterogeneity (Xiao et al, 2016). 
E-602, a human sialidase-based modality, overcomes this challenge by enzymatically removing 
the critical common immunosuppressive moiety, terminal sialic acids, from cell surface 
sialoglycans, regardless of their structures or receptor preferences. E-602 functions as an immune 
checkpoint blockade by releasing sialoglycan-mediated immunosuppression without causing 
systematic immune activation.  
In preclinical research, E-602 has been shown to enhance immune responses in multiple assays 
with primary human immune cells, including restoring the immune function of exhausted-like T 
cells, improving antigen-specific T-cell response, and enhancing DC priming and activation of 
naïve T cells. E-602 monotherapy has shown antitumor activity in immune-competent syngeneic 
mouse tumor models. Synergistic antitumor activity has also been observed when its desialylation 
mechanism, ie, blocking sialoglycan-mediated immunosuppression, is combined with anti-PD-
1/PD-L1 blockade. Furthermore, E-602 shows a wide safety margin in nonclinical research. 

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Because E-602 is not an immune agonist but instead works by releasing sialoglycan-mediated 
immunosuppression, it does not cause cytokine activation in human peripheral blood mononuclear 
cell (PBMC) assays.  
This is the first-in-human clinical trial of E-602. 
During this trial, E-602 will be combined with cemiplimab. Cemiplimab (REGN2810) is a high 
affinity hinge-stabilized IgG4P human antibody to the PD-1 receptor (PDCD1, CD279) that blocks 
PD-(L)1 mediated T cell inhibition. Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 
receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of 
PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to 
inhibition of active T-cell immune surveillance of tumors. Blockade of the PD-1 signaling pathway 
has demonstrated clinical benefit by inducing regression of advanced and metastatic tumors and 
improving survival with a favorable safety profile with manageable immune-related adverse events 
(Topalian 2014, Chen 2015). 
2.2.1. 
Nonclinical Studies 
2.2.1.1. 
E-602 Pharmacology 
In in vitro models, E-602 was shown to desialylate synthetic sialic acid probes and natural cell 
surface sialoglycans. E-602 does not bind to sialoglycan-abundant T cells and does not cause 
antibody-dependent cellular toxicity (ADCC). E-602 desialylated activated or exhausted-like T 
cells and restores the function of exhausted-like T cells. By cleaving off sialoglycans, E-602 
enhanced T-cell response against antigens. Further, E-602 augmented T-cell activation and 
proliferation in a human mixed lymphocyte reaction (MLR) with naïve T cells, suggesting that 
desialylation during T-cell priming could enhance its activation and contribute to a more robust 
immune response.  
In a mouse model, E-602 enhanced antigen-specific CD8+ T-cell proliferation and activation in 
cultured and purified naïve CD8+ T cells from OT-I transgenic mouse splenocytes.  
In an immunocompetent syngeneic mouse A20 (murine B cell) tumor model, treatment with 
single-agent E-602 led to evidence of antitumor activity. Desialylation was shown to result in 
antitumor response in a cold B16F10 (melanoma) tumor model, which is known to be resistant to 
PD-1/PD-L1 blockade. 
In a mouse MC38 (colon) tumor model, combination treatment with anti-mouse PD-L1 treatment 
and E-601, a precursor molecule structurally similar to E-602, showed synergistic antitumor 
activity that was higher than either treatment alone. 
For the assessment of safety, a cytokine release assay was performed on human peripheral blood 
mononuclear cells (PBMC) from 4 donors after treatment with E-602 in the range of 125 μg/mL 
to 15.6 μg/mL with 1:2 dilutions. E-602 did not cause cytokine secretion such as IL-6, IL-10, 
IFN-γ, TNF-α, and IL-2 even at a high concentration of 125 μg/mL, compared with immune 
agonist controls. The results were consistent with the immune-checkpoint mechanism of 
sialoglycans, since desialylation only releases sialoglycan-mediated immunosuppression, which 
does not activate immune cells in the absence of immune stimuli. 

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2.2.1.2. 
E-602 Pharmacokinetics 
The PK profile of E-602 in cynomolgus monkeys was evaluated in a toxicokinetic study, in which 
single and repeat doses ranging from 5 to 200 mg/kg were administered as 30-minute IV infusions.  
E-602 exposure (measured by AUCtau) increased greater than 2-fold over the dose range of 100 to 
200 mg/kg. The apparent t1/2 and Vss were comparable among the repeated dosing groups. No 
accumulations were observed between Day 8 and Day 1 (weekly dosing) or Day 11 and Day 1 
(twice-weekly dosing). The accumulation ratios of Cmax and AUCtau ranged from 0.805 to 1.04. 
The exposures were comparable between the 100 mg/kg weekly and 100 mg/kg twice-weekly 
dosing schedules. Please refer to the current E-602 investigator’s brochure (IB) for additional 
information.  
2.2.1.3. 
E-602 Toxicology 
The toxicity of E-602 IV infusion was evaluated in male and female cynomolgus monkeys in a 
toxicology and toxicokinetic study. E-602 was administered at doses of 5 to 200 mg/kg as a single 
dose at 5 or 30 mg/kg, weekly at 100 or 200 mg/kg, or twice weekly at 100 mg/kg. All infusions 
were given in 30 minutes. 
E-602 at all doses was well tolerated and resulted in only minimal changes in liver enzymes 
(minimal increases in ALT and AST and minimal decreases in ALP and gamma-glutamyl 
transferase (GGT) in animals administered ≥100 mg/kg), which were generally within the normal 
range of levels for cynomolgus monkeys at the test facility and considered of uncertain relationship 
to E-602 administration and non-adverse. The no-observed-adverse-effect level (NOAEL) was 
considered 100 mg/kg for weekly dosing.  
Please refer to the current E-602 IB for additional information. 
2.2.2. 
Cemiplimab Pharmaceutical and Therapeutic Background 
Cemiplimab is a fully-human monoclonal antibody targeting the immune checkpoint receptor 
PD-1 on T-cells. By binding to PD-1, cemiplimab has been shown to block cancer cells from using 
the PD-1 pathway to suppress T-cell activation. 
Anti-PD-1 immunotherapy and chemotherapy combination studies have been conducted in 
patients with NSCLC. A wealth of clinical data shows that anti-PD-1 monotherapy prolongs 
progression free survival (PFS) and overall survival (OS) in NSCLC, with the greatest clinical 
benefit observed in tumors expressing high levels of PD-L1. In addition, clinical data in patients 
with advanced NSCLC suggest that first line treatment with cemiplimab in combination with 
chemotherapy, irrespective of PD-L1 expression levels, provides clinically meaningful and 
statistically significant improvement in OS, PFS, objective response rate (ORR) and duration of 
response (DOR) vs chemotherapy alone, with a safety profile consistent with cemiplimab 
monotherapy and platinum-based chemotherapy (Gogishvilli, 2022). Recently, the FDA and the 
European Commission approved cemiplimab (Libtayo®) for first-line treatment of patients with 
locally advanced or metastatic, non-small cell lung cancer (NSCLC) whose tumors have ≥50% 
PD-L1 expression. On November 8, 2022, the Food and Drug Administration approved 
cemiplimab in combination with platinum-based chemotherapy for adult patients with advanced 
NSCLC with no EGFR, ALK, or ROS1 aberrations. 

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Refer to the IB/approved labeling for detailed background information on cemiplimab 
(REGN2810). 
2.3. 
Benefit/Risk Assessment 
This is the first-in-human study of E-602, which is designed to evaluate the safety profile of the 
drug as a monotherapy and in combination with cemiplimab. Although E-602 has never been 
administered before to humans, the nonclinical research findings to date have not shown 
significant toxicities from administration of E-602 to non-human primates. The subjects treated in 
this study will have advanced cancers with limited or no other treatment options. Subjects will be 
closely monitored after receiving the study treatment, and dose-modification and discontinuation 
criteria are prespecified in the protocol. A safety data review committee will meet regularly to 
review the data and provide oversight in trial conduct and protection of patient safety.  
Although E-602 is not expected to significantly stimulate cytokine release in humans based on the 
preclinical data, precautions are recommended for any drug product that interacts with immune 
cells to monitor for and manage suspected cytokine or immune-related adverse reactions. This 
includes frequent assessment of vital signs, blood pressure, and observation for emergent 
symptoms consistent with cytokine release. Premedication including standard prophylaxis such as 
antihistamines and acetaminophen are recommended at doses ≥10 mg/kg of E-602 as infusion 
related reactions have been observed. As of 02-Dec-2022, preliminary data indicate that 12 of 26 
treated subjects had infusion related reactions at doses ≥10 mg/kg of E-602 which were primarily 
≤Grade 2 and manageable, resolving with concomitant medication and/or slowing of the infusion 
rate. An isolated Grade 3 infusion related reaction occurred in one subject at the 20 mg/kg E-602 
monotherapy dose level which resolved with concomitant medication and did not recur following 
premedication and slowing of the infusion rate. Two subjects have discontinued study treatment 
due to ≤Grade 2 recurrent infusion related reactions.  
More detailed information about the known and expected benefits, risks, and adverse events (AEs) 
of E-602 and cemiplimab may be found in the respective IBs.  

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4. 
Study Design 
4.1. 
Overall Design 
This is a Phase 1/2, first-in-human (FIH), open-label, dose escalation and dose expansion study of 
E-602, administered as a single agent and in combination with cemiplimab, to evaluate the safety, 
tolerability, PK, pharmacodynamics, and antitumor activity in subjects with advanced cancers. 
4.1.1. 
Study Design Overview 
Phase 1: Dose Escalation, Monotherapy and Combination Therapy 
Phase 1 of the study consists of 5 planned dose escalation cohorts of E-602 as a monotherapy and 
2 planned dose escalation cohorts of E-602 in combination with cemiplimab. Phase 1 monotherapy 
will treat eligible subjects with melanoma, ovarian cancer, non-small cell lung cancer (NSCLC), 
colorectal cancer, pancreatic cancer, breast cancer, gastric/EGJ cancer, head and neck cancer, or 
urothelial cancer. Phase 1 combination with cemiplimab will treat eligible subjects with melanoma, 
NSCLC, gastric/EGJ cancer, head and neck cancer or urothelial carcinoma. The safety of the dose 
regimens will be evaluated to identify the maximum tolerated dose (MTD) and recommended 
Phase 2 dose (RP2D) to be used during Phase 2. 
The cohorts of E-602 monotherapy will receive E-602 at the doses of 1, 3, 10, 20 and 30 mg/kg, 
respectively, via intravenous (IV) infusion once a week. Intermediate dosing cohorts may be added 
in Phase 1. The first subject dosed in a cohort will be a sentinel subject, with at least 24 hours until 
any subsequent subjects are dosed in the cohort. No intrasubject dose escalation of E-602 will be 
permitted. 
The cohorts of E-602 in combination with cemiplimab will be initiated at dose level(s) that have 
previously completed DLT assessments (Cycle 1) as monotherapy. Intermediate dosing cohorts 
may be added in Phase 1. Subjects in the combination cohorts will receive 20 mg/kg E-602 IV 
once a week (additional dose levels to be determined) and 350 mg cemiplimab IV once every 3 
weeks. The first subject dosed in a cohort will be a sentinel subject, with at least 24 hours until any 
subsequent subjects are dosed in the cohort. No intrasubject dose escalation of E-602 will be 
permitted. 
Each treatment cycle consists of 21 days. E-602 will be administered on Days 1, 8, and 15 of each 
cycle. Cemiplimab, if given, will be administered on Day 1 of each cycle. When the cemiplimab 
combination is administered, cemiplimab should be administered first and E-602 administered at 
least 30 minutes after the cemiplimab infusion is completed. Subjects receiving ≥10 mg/kg of E-
602 as monotherapy or in combination with cemiplimab should receive premedication including 
antihistamines and acetaminophen as indicated in the Pharmacy Manual. Corticosteroids should 
be used as premedication for subjects with previous infusion reaction(s) to E-602 as indicated in 
the Pharmacy Manual (see Pharmacy Manual, Section 10.5). 
Dose escalation guidelines for all Phase 1 dose cohorts will utilize a modified 3+3 design. 
Assessments of DLTs will occur during Cycle 1 (defined as a subject receiving 3 doses of E-602 
for monotherapy cohorts and 3 doses of E-602 and 1 dose of cemiplimab for combination therapy 
cohorts) for all dose cohorts. Safety monitoring for immune-related toxicities will continue for all 

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subjects for 90 days after treatment discontinuation unless a subsequent cancer therapy is started. 
All available data will be taken into consideration in selecting the RP2D. 
E-602 dose escalation will continue until the MTD is exceeded, unacceptable toxicity is reached, 
or the RP2D is determined. The Sponsor may terminate dose escalation at an RP2D prior to 
reaching the MTD based on emerging PK, pharmacodynamic, and safety data.   
Any Phase 1 cohort may be backfilled at the judgement of the Sponsor, up to a total of 15 subjects 
in the dose cohort (dose escalation and backfill) as needed to obtain additional safety, PK, and 
pharmacodynamic data at a particular dose level.  
In addition to DLTs, subjects will be evaluated for safety and tumor response as well as PK and 
pharmacodynamics, as listed in the Schedule of Activities (SoA) in Section 1.3. 
Phase 2: Dose Expansion, Monotherapy and Combination Therapy 
Phase 2 consists of dose expansion disease cohorts in subjects with 3 types of advanced tumors: 
melanoma, NSCLC, and the third type to be determined (ovarian, colorectal, pancreatic, breast, 
gastric/EGJ, head and neck, or urothelial) based on available data including the Phase 1 results. 
Phase 2 of the study will employ a 2-stage design, as outlined in Section 9.4. Each disease cohort 
will be analyzed separately. The E-602 dose(s), i.e., RP2D(s), chosen based on Phase 1 data will 
be used. E-602 as monotherapy and in combination with cemiplimab will be evaluated separately. 
Subjects will be evaluated for safety and tumor response as well as PK and pharmacodynamics, as 
listed in the Schedule of Activities (SoA) in Section 1.3. 
Study Duration and Visit Frequency 
• Study duration: approximately 2 years from screening of the first subject to the last visit of 
the last subject (end of study). 
• Treatment duration for individual subjects: 
o Screening period: up to 4 weeks before Cycle 1 Day 1 
o Treatment period: up to 1 year from Cycle 1 Day 1 regardless of treatment delays 
o Follow-up period: up to approximately 15 months from Cycle 1 Day 1 
• Visit frequency: approximately up to 7 visits in Cycle 1, up to 5 visits in Cycle 2 and from 
Cycle 3 onward, approximately weekly visits in each 21-day cycle. 
Number of Subjects 
The planned total number of subjects to be treated in Phase 1 of the study is up to 87 subjects 
including up to 42 subjects in dose escalation and 45 subjects in backfilled cohorts. The planned 
total number of subjects to be treated in Phase 2 of the study is up to 186 subjects. 
Total study treatment is up to 273 subjects. 
4.1.2. 
Continued Treatment Beyond Disease Progression 
Each subject will receive the study treatment for 1 year, unless the treatment is discontinued for 
any of the reasons listed in Section 7.1. 

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Treatment beyond progressive disease (PD) will be allowed as per iRECIST guidelines (Seymour 
2017). The following criteria must be met for continued use of the study treatment beyond PD: 
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in the Eastern Cooperative Oncology Group (ECOG) performance status 
• Absence of symptomatic rapid disease progression requiring urgent medical intervention 
(e.g., symptomatic pleural effusion, spinal cord compression). 
At the time of radiographic progression of disease, a subject will be reconsented with emphasis on 
the FDA-approved therapy and potential clinical benefit that the subject may be foregoing to 
continue treatment. 
4.1.3. 
Post-treatment Follow-up 
For subjects who complete the 1-year treatment, an end-of-treatment (EOT) visit will be conducted, 
and subjects will return for safety follow-up visits 30 and 90 days after the last dose of study 
treatment to monitor for safety, including late immune-related toxicities. If prior to completing the 
90-day safety follow-up period a subject begins a new cancer treatment, no further safety follow-
up is required.   
For subjects who discontinue treatment early, an EOT visit will be conducted, and subjects will 
return for safety follow-up visits 30 and 90 days after the last dose of study treatment. If prior to 
completing the 90-day safety follow-up period a subject begins a new cancer treatment, no further 
safety follow-up is required. These subjects will continue to be contacted once every 3 months for 
disease and survival status through approximately 15 months after the first dose of the study 
treatment unless the subject has died or withdrawn consent.  
4.1.4. 
Phase 1 Dose-escalation Guidelines 
The following modified 3+3 guidelines will be employed on the basis of the number of DLTs 
observed during Cycle 1 (3 doses of E-602 administered for monotherapy cohorts and 3 doses of 
E-602 and 1 dose of cemiplimab administered for combination therapy cohorts): 
• Each dose level cohort will initially treat 3-6 subjects. At each dose level, at least 3 subjects 
must be DLT-evaluable prior to dose escalation. 
• If 0 subjects experience a DLT, the next cohort will be treated at the next higher dose level. 
• If only 1 subject experiences a DLT in 6 DLT-evaluable subjects, the next cohort will be 
treated at the next higher dose level. 
• If 2 or more subjects in any cohort experience a DLT, the MTD will have been exceeded 
and no further subjects will be treated at this or higher dose levels. Additional subjects will 
be treated at the next lower dose level if needed to have at least 6 subjects treated at that 
prior dose level. If at least 6 subjects were previously treated at the prior dose level, that 
prior dose level will be considered the MTD. 
4.1.5. 
Dose-Limiting Toxicity (DLT) Definition 
The DLT window of observation for the purposes of dose escalation will be Cycle 1 defined as a 
subject receiving 3 doses of E-602 for monotherapy cohorts and 3 doses of E-602 and 1 dose of 
cemiplimab for combination therapy cohorts. Any of the following events will meet the definition 

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of a DLT if assessed by the investigator to be possibly, probably, or definitely related to study 
treatment: 
• Any death not clearly due to the underlying disease or extraneous causes 
• Hy’s law: 
o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3×the 
upper limit of normal (ULN) AND 
o Total bilirubin >2×ULN AND 
o Alkaline phosphatase <2×ULN AND 
o No other reason for liver injury 
• Neutropenic fever 
• Any Grade ≥3 non-hematologic toxicity (with exceptions noted below) 
• Grade 4 neutropenia or thrombocytopenia >7 days 
• Grade 3 thrombocytopenia with bleeding 
• Grade 4 vomiting or diarrhea of any duration 
• Grade 3 fatigue ≥7 days 
• Grade ≥3 electrolyte abnormality that lasts >72 hours, unless the subject has clinical 
symptoms, in which case all Grade ≥3 electrolyte abnormality regardless of duration will 
be a DLT. 
• For subjects with hepatic metastases, AST or ALT >8×ULN or AST or ALT >5×ULN for 
≥14 days 
• Recurrent Grade 3 infusion-related reaction despite pre-medication 
• Grade 4 infusion-related reaction on the first occurrence 
• Dose delay of >14 days for the study treatment due to an AE 
However, the following AEs are NOT considered a DLT:   
• Hematologic toxicity: 
o Grade 3 anemia 
o Grade 3 lymphopenia 
o Grade 3 or 4 neutropenia that is not associated with clinical sequelae and lasts <7 
days 
o Grade 3 or 4 thrombocytopenia without bleeding 
• Cardiovascular toxicity: 
o Grade 3 hypertension 
• Other toxicities: 
o Grade 3 fatigue lasting <7 days 
o Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate 
antiemetic and other supportive care 
o Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated and resolves spontaneously or responds to conventional medical 
interventions 
o Grade 3 or higher amylase or lipase that is not associated with symptoms or clinical 
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o Isolated Grade 3 infusion reaction  
o AEs that are clearly and incontrovertibly due to disease progression or extraneous 
causes. 
Subjects treated in the Phase 1 dose escalation part of the study will discontinue treatment if he/she 
experience DLT(s) during Cycle 1. 
4.2. 
Scientific Rationale for Study Design 
This study is a combination of a Phase 1, FIH, dose escalation study and a Phase 2, dose expansion 
study. Subjects to be treated in the study are those with advanced cancers, and a control group is 
not deemed appropriate.   
In this study, the effects of desialylation of immune and tumor cells on the antitumor immunity 
will be explored, with E-602 given as a monotherapy and together with a PD1-pathway inhibitor. 
The tumor types chosen to be studied are populations enriched for patients with tumors that have 
greater amounts of sialoglycan modifications with immunoinhibitory potential, such as melanoma 
(Prendergast 2021), lung, colon, pancreatic, ovarian, breast, gastric/EGJ, head and neck and 
urothelial cancers (data on file). 
In Phase 1 of the study, dose escalation (5 dose levels planned) will follow a modified 3+3 design 
for the E-602 monotherapy, and dose escalation (2 dose levels) for the combination therapy with 
cemiplimab will be carried out after the same dose level in monotherapy has been deemed 
tolerable. This design will assure protection of subject safety while identifying an MTD and an 
appropriate dose for dose expansion in Phase 2. Phase 1 cohorts can be backfilled at the judgement 
of the Sponsor in a dose cohort as needed to obtain additional safety, PK, and pharmacodynamic 
data at a particular dose level.  
The RP2D(s) for monotherapy and combination therapy will be selected separately based on the 
totality of data including safety, pharmacodynamic, and PK data collected during Phase 1.  
4.3. 
Justification for Dose 
4.3.1. 
Justification for E-602 Dose 
The starting dose in this FIH study is based on the maximum safe starting dose based on the highest 
non-severely toxic dose (HNSTD) or the no-observed-adverse-effect level (NOAEL) from the 
preclinical Good Laboratory Practice (GLP) toxicology studies and data from in vitro human 
cytokine release assays. The dose increment between cohorts is based on a modified Fibonacci 
pattern. Details for each method to estimate starting dose can be found in the IB. 
Since immune desialylation serves as both a critical pharmacodynamic indicator for the overall 
activity of E-602 and a logical surrogate marker for the potential of E-602 to cause immune-related 
toxicity, the EC20 for E-602 desialylation of human CD8 T cells in vitro was estimated to be 15.5 
µg/mL and 14.4 µg/mL for CD4 T cells (Table 1). Taken together, the EC20 for immune cell 
desialylation is approximately 15 µg/mL. 

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Table 1 
50% And 20% effective concentrations (EC50 and EC20) of E-602 for 
desialylation of human CD8 and CD4 T cells 
 
CD8+ T cells (µg/mL) 
CD4+ T cells (µg/mL) 
EC50 
62.0 
57.5 
EC20 
15.5 
14.4 
A human PK model was developed for E-602 based on the NHP data to estimate the amount of 
delivered E-602 that would yield a blood concentration of 15 µg/mL at Cmax. A range of 5 dose 
levels, 0.1, 0.5, 1, 1.5, and 3 mg/kg, were simulated to produce concentrations over a 21-day 
period, with weekly dose administration. The simulated concentrations of dose levels 1 and 1.5 
mg/kg produced a Cmax of 10 and 15 µg/mL, respectively.   
Thus, the human dose delivered that would likely produce the pharmacodynamic EC20 for 
desialylation of immune cells at the Cmax would be approximately 1.5 mg/kg. Based on these data, 
the first cohort dose level will be 1 mg/kg. 
An additional monotherapy dose escalation cohort of 30 mg/kg is planned for evaluation. As 
limited desialylation of peripheral immune cells has been observed at the 1 and 3 mg/kg dose 
levels, addition of 30 mg/kg dose level is expected to further inform the PK/PD relationship and 
identification of the recommended Phase 2 dose of E-602 monotherapy. The pharmacodynamic 
activity of E-602 in NHP GLP toxicology studies demonstrated a linear dose response of immune 
cell desialylation following E-602 administration across the dose range with maximum 
desialylation at 200 mg/kg (human equivalent dose of 60 mg/kg). The 30 mg/kg dose remains 
below the human equivalent dose (approximately 33 mg/kg) of the NHP NOAEL (100 mg/kg). 
Clinical experience (as of 23-September-2022) supports the tolerability of E-602 monotherapy. 
Doses up to 10 mg/kg of E-602 monotherapy have been evaluated with no DLTs reported and the 
20 mg/kg E-602 monotherapy dose level is currently enrolling. Preliminary data indicate that the 
adverse events are consistent with an advanced cancer population. No E-602 related serious 
adverse events have been reported. 
4.3.2. 
Justification for Cemiplimab Dose 
A 350 mg Q3W dose of cemiplimab was chosen based on the safety and anti-tumor activity 
observed across >20 clinical studies (see cemiplimab IB). Analysis of the 350 mg Q3W dose 
regimen demonstrated that median steady-state concentrations (CV%) of cemiplimab ranged 
between a maximum concentration (Cmax,ss) of 166 mg/L (28%) and a minimum concentration 
(Cmin,ss) of 59 mg/L (48%). Cemiplimab exposure in serum at the fixed dose of 350 mg Q3W is 
similar to that at the body weight adjusted dose of 3 mg/kg once every 2 weeks (Q2W). The dose 
of 350 mg Q3W is consistent with the current USPI (Libtayo® USPI, 2022). 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last subject in the study.  
A subject is considered to have completed the study if he/she has completed the final study visit 
or follow-up contact, whichever is later. 

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5. 
Study Population 
5.1. 
Inclusion Criteria 
1. Criteria for each cancer type are as follows: 
a. Melanoma:  
­ Histologically confirmed unresectable Stage III or Stage IV cutaneous or 
mucosal melanoma. 
­ Subject must have known BRAF genetic mutation status. 
o BRAF mutation-positive subjects are eligible without prior treatment or 
after failure of BRAF directed inhibitor therapy. 
­ Subjects must have had prior therapy with an anti-PD-(L)1 pathway therapy 
and been deemed resistant (had progression on therapy or within 3 months of 
discontinuation of therapy). 
b. Ovarian:  
­ Histologically or cytologically confirmed diagnosis of advanced, epithelial 
ovarian cancer (except carcinosarcoma), primary peritoneal, or fallopian tube 
cancer. 
­ Subject has received at least 1 line of platinum-containing therapy or must be 
platinum-intolerant. 
­ A subject with homologous repair deficiency (HRD) positive disease may 
participate if he/she has received prior polyadenosine diphosphate ribose 
polymerase (PARP) inhibitor therapy. 
­ Subject has no standard therapy options that are likely to convey clinical 
benefit. 
c. NSCLC:  
­ Histologically or cytologically documented Stage IV NSCLC not amenable to 
curative surgery or radiation. 
­ Subject must have progressed on standard therapy that includes platinum-based 
chemotherapy and anti-PD-(L)1 pathway therapy. 
o Subjects must have been deemed resistant (had progression on therapy 
or within 3 months of discontinuation of therapy) to an anti-PD-(L)1 
therapy. 
­ Subjects with known active driver mutations that confer insensitivity to immune 
checkpoint inhibitors are excluded, including those with driver mutations in 
EGFR, ALK, ROS-1, and RET.  
d. Colorectal cancer: 
­ Histologically or cytologically documented metastatic colorectal cancer.  
­ Subject must have been previously treated with chemotherapy regimens based 
on fluoropyrimidine, oxaliplatin, and irinotecan; and anti-VEGF biological 
therapy; and, if RAS wild-type, an anti-EGFR therapy. 
­ Subjects with microsatellite instability-high (MSI-H) or mismatch repair 
deficient tumors (dMMR) must have had prior therapy with an anti-PD-(L)1 

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pathway therapy and been deemed resistant (had progression on therapy or 
within 3 months of discontinuation of therapy). 
e. Pancreatic: 
­ Histologically 
or 
cytologically 
confirmed 
metastatic 
pancreatic 
adenocarcinoma.  
­ Subjects has no standard therapy options available that could be of benefit as 
per the treating investigator. 
f. Breast: 
­ Other than Triple-Negative Breast Cancer (TNBC): 
o Histologically or cytologically confirmed diagnosis of hormone 
receptor (HR) positive and/or human epidermal growth factor receptor-
2 (HER-2) positive breast cancer (Allison, 2020) not amenable to 
curative surgery or radiation.  
o Subject has received at least 2 lines of systemic therapy in the recurrent 
or metastatic setting:  
 Relapse within 6 months of completing neoadjuvant/adjuvant 
therapy can be considered 1 line of therapy  
 Regimens may include treatments such as anthracycline, 
platinum or taxane chemotherapy, aromatase inhibitor, 
endocrine therapy, PARPi, or, if HER-2+, HER-2-targeting 
agent.  
 If HR+, must have progressed on or was offered and deferred a 
cyclin-dependent kinase4/6 (CDK4/6) inhibitor.  
­ TNBC: 
o Histologically or cytologically confirmed diagnosis of triple-negative 
breast cancer (Allison, 2020) not amenable to curative surgery or 
radiation.  
o Subject has received at least 1 line of systemic therapy including an anti-
PD-(L)1 pathway therapy if PD-L1 Combined Positive Score (CPS) > 
10. Relapse within 6 months of completing neoadjuvant/adjuvant 
therapy can be considered 1 line of therapy. 
a. For subjects with CPS>10 receiving a PD-(L)1 pathway 
therapy, subjects must have been deemed resistant (had 
progression on therapy or within 3 months of discontinuation 
of therapy) to the anti-PD-(L)1 pathway therapy. 
g. Gastric/EGJ: 
­ Histologically or cytologically documented locally advanced or metastatic 
gastric/EGJ carcinoma not amenable to curative surgery.  
­ Subject must have been previously treated with chemotherapy regimens based 
on fluoropyrimidine and platinum. 
­ A subject with HER-2+ cancer must have progressed on or was offered and 
deferred a prior HER-2-targeting agent and/or if known NTRK gene fusion a 
tropomyosin receptor kinase (TRK) inhibitor. 

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­ Subjects with microsatellite instability-high (MSI-H) or mismatch repair 
deficient tumors (dMMR) or PD-L1 CPS > 5 must have had prior therapy with 
an anti-PD-(L)1 pathway therapy and been deemed resistant (had progression 
on therapy or within 3 months of discontinuation of therapy). 
h. Head and Neck cancer: 
­ Histologically or cytologically confirmed squamous or adenocarcinoma of the 
head and neck (oral cavity, oropharynx, hypopharynx and larynx), not 
amenable to local therapy with curative intent surgery or radiation therapy ± 
chemotherapy. Carcinomas of the nasopharynx, paranasal sinus, or salivary 
glands are excluded. 
­ Subject must have progressed on standard therapy that includes platinum-based 
chemotherapy and anti-PD-(L)1 pathway therapy. 
o Subjects must have been deemed resistant (had progression on therapy 
or within 3 months of discontinuation of therapy) to an anti-PD-(L)1 
pathway therapy. 
i. Urothelial Carcinoma: 
­ Histologically or cytologically documented locally advanced or metastatic 
(Stage IV) muscle invasive urothelial carcinoma not amenable to curative 
surgery or radiation. 
­ Subject must have progressed on standard therapy that includes platinum-based 
chemotherapy, and/or an anti-PD-(L)1 pathway therapy. 
o Subjects must have been deemed resistant (had progression on therapy 
or within 3 months of discontinuation of therapy) to an anti-PD-(L)1 
pathway therapy. 
­ Subject with known fibroblast growth factor receptor (e.g., FGFR2 or FGFR3) 
genetic alternations must have progressed on or was offered and deferred the 
standard treatments approved for these settings. 
2. Age ≥18 years old. 
3. Mentally competent and able to understand and sign the informed consent form. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  
5. Life expectancy of greater than 12 weeks per the investigator. 
6. Subject has disease that is measurable by Response Evaluation Criteria in Solid Tumors 
(RECIST) v.1.1. 
7. Female subjects of childbearing potential and male subjects are willing and able to use a 
highly effective method of contraception (see Appendix 10.4.2) from the first dose of study 
treatment through 6 months after the last dose.  
8. Laboratory values at screening meet the following criteria: 
a. Hematology: 
­ absolute neutrophil count ≥1,500 cells/mm3 
­ platelet count ≥100,000 cells/mm3  
­ hemoglobin ≥9.0 g/dL without packed red blood cell transfusion within the 
prior 2 weeks. Prior and concomitant erythropoietin is permitted.  
b. Renal: 
­ creatinine clearance ≥30 mL/min on the basis of the Cockcroft-Gault 
glomerular filtration rate estimation:  

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(140-age)×(weight in kg)×(0.85 if female)/[72× (serum creatinine in mg/dL)] 
c. Coagulation: 
­ International Normalized Ratio (INR) and prothrombin time (PT) ≤1.5×ULN 
or activated partial thromboplastin time (aPTT) ≤1.5×ULN, unless undergoing 
anticoagulation therapy  
d. Liver: 
­ AST and ALT ≤2×ULN or ≤2.5×ULN with liver metastasis 
­ Bilirubin ≤1.5×ULN, unless genetic cause of elevated bilirubin is known (such 
as Gilbert’s Syndrome).  
5.2. 
Exclusion Criteria  
1. For cohorts receiving E-602 and cemiplimab combination therapy: 
- 
Moderate or Severe hypersensitivity to cemiplimab or any of the following 
excipients that are used for formulation: histidine, sucrose, L-proline, polysorbate 
80. 
- 
Previous treatment with an anti-PD-(L)1 pathway therapy as a monotherapy and a 
history of ≥Grade 3 autoimmune complications or discontinuation due to toxicity, 
with the exception of asymptomatic Grade 3 elevations in lipase and/or amylase 
not associated with clinical manifestations of pancreatitis. 
- 
Subject has an active autoimmune disease. The following are not exclusionary: 
vitiligo, type 1 diabetes, autoimmune endocrinopathies that are stable on hormone 
replacement therapy, or psoriasis that does not require systemic treatment. 
- 
Previously received idelalisib. 
2. Cardiovascular exclusions: 
o Subject has a medical history of an arterial thrombotic event, stroke, or transient 
ischemia attack within the past 12 months. 
o A medical history of symptomatic congestive heart failure (CHF) (New York Heart 
Association classes II-IV) or a cardiac arrhythmia that requires treatment. 
o A medical history of myocardial infarction or unstable angina within 6 months 
before Cycle 1 Day 1. 
o QTc prolongation to >470 milliseconds (ms) based on a 12-lead electrocardiogram 
(ECG). 
3. History of age-related macular degeneration (AMD). 
4. Subject has been previously administered study treatment in this study. 
5. Subject is actively enrolled in another clinical study, unless it is an observational 
(noninterventional) clinical study or the follow-up component of an interventional study.  
6. Major surgery < 4 weeks from Cycle 1 Day 1.  
7. Use of another therapy within 4 weeks prior to Cycle 1 Day 1 or within 5 half-lives of the 
previous drug, whichever is shorter. Note: Subjects must have recovered from all AEs due 
to previous therapies to ≤ Grade 1 or baseline prior to Cycle 1 Day 1. Subjects with ≤ Grade 
2 neuropathy may be eligible. Subjects with endocrine-related AEs ≤ Grade 2 requiring 
treatment or hormone replacement may be eligible. 

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8. Evidence of active infection requiring antimicrobials (IV or oral) within 7 days prior to 
Cycle 1 Day 1. 
9. Active uncontrolled bleeding or a bleeding diathesis within 7 days before Cycle 1 Day 1. 
10. Serious or non-healing wound, fistula, skin ulcer, or non-healing bone fracture within 
7 days prior to Cycle 1 Day 1.   
11. Subject has had a vaccine within 14 days prior to Cycle 1 Day 1. 
12. Prior history of interstitial lung disease that required steroids or ≥ Grade 2 immune-related 
pneumonitis or has current non-infectious pneumonitis or interstitial lung disease. 
13. Known human immunodeficiency virus (HIV) infection, active hepatitis B infection, or 
active hepatitis C infection. 
14. Subjects with central nervous system (CNS) metastasis, and/or carcinomatous meningitis. 
However, subjects with CNS metastasis may participate if the subject has completed 
treatment of CNS metastasis and is: 
o >4 weeks from prior therapy for CNS metastasis (including radiation and/or 
surgery), 
o >2 weeks from receiving steroid therapy for treating CNS metastasis and are 
asymptomatic, and 
o clinically stable with respect to CNS metastasis at Screening. 
15. Subject is taking the equivalent of >10 mg/day oral prednisone or the equivalent systemic 
exposure by any other route of administration. 
16. Pregnant or breastfeeding woman. 
17. Subject is unwilling or unable to follow protocol requirements. 
18. Subject has had an allogeneic tissue or organ transplantation or is on systemic 
immunosuppressive therapy. 
19. Subject has a known additional malignancy that is progressing or has required active 
treatment within the past 3 years, with the following exceptions: 
o Subjects with history of basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin, non-muscle invasive bladder cancer, carcinoma in situ, or localized 
breast cancer previously treated with curative intent are not excluded.   
o Localized prostate cancer that has been treated with curative intent or which does 
not require active treatment is not excluded. 
20. Any condition or serious illness that, in the opinion of the investigator, would interfere 
with evaluation of the investigational product or interpretation of the subject’s safety or 
study results. 
21. History of thromboembolic event unless the event occurred > 6 months from Cycle 1 Day 
1 and the subject is on anti-coagulation treatment. Note: subjects with history of 
thromboembolic event which occurred >6 months from Day 1 of study treatment 
administration but who are not on anti-coagulation treatment may be allowed to participate 
if, in the judgment of the investigator, the thromboembolic event was provoked by a 
temporary factor that is resolved (e.g. by temporary immobility due to surgery) and the 
subject does not have a predisposition to or elevated risk of thromboembolic event. 

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22. Subject has received prior radiotherapy within 2 weeks of Cycle 1 Day 1, has a history of 
≥Grade 3 radiation pneumonitis, or Grade 2 radiation pneumonitis that has been active 
within the last 6 months. Note: Subjects must have recovered from all radiation-related 
toxicities and not require corticosteroids. A 1-week washout prior to Cycle 1 Day 1 is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. 
 
5.3. 
Lifestyle Considerations 
Partners (male and female) of subjects should use effective methods of contraception. 
5.4. 
Screen Failures 
A screen failure occurs when a subject who consents to participate in the study is not subsequently 
entered in the study. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure subjects to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened after discussion with Medical Monitor. Rescreened subjects should be assigned a new 
subject number. 

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6. 
Study Treatment and Concomitant Therapy 
6.1. 
Study Treatment Administered 
E-602 is supplied as a sterile solution for IV infusion in glass vials. Each container is filled with 
10 mL solution which contains 100 mg E-602 active ingredient in 20 mM glutamic acid-sodium 
hydroxide buffer with 8% (w/v) sucrose and 0.04% (w/v) polysorbate 80 at a pH value of 4.7. 
Cemiplimab is provided as a sterile solution (350 mg/7 ml vial) for IV infusion. 
For all subjects treated in the study, E-602 will be administered via IV infusion once a week at the 
assigned doses summarized below. For the combination therapy cohorts, 350 mg of cemiplimab 
will be administered via IV infusion once every 3 weeks. Subjects receiving ≥10 mg/kg of E-602 
as monotherapy or in combination with cemiplimab should receive premedication including 
antihistamines and acetaminophen as indicated in the Pharmacy Manual. Corticosteroids should 
be used as premedication for subjects with previous infusion reaction(s) to E-602 as indicated in 
the Pharmacy Manual (see Pharmacy Manual, Section 10.5). All procedures and assessments must 
be completed prior to the start of dosing. 
In each 21-day cycle, E-602 will be administered on Days 1, 8, and 15, and cemiplimab will be 
administered on Day 1.  When the cemiplimab combination will be administered, cemiplimab 
should be administered first and E-602 administered at least 30 minutes after the cemiplimab 
infusion is completed. No intrasubject dose escalation of E-602 will be permitted. Details of study 
treatment administration methods will be provided in the Pharmacy Manual.  
Cemiplimab should be administered in compliance with the manufacturer’s labeling information 
(Libtayo® Prescribing Information 2022). 
Phase 1 Treatment (Planned):  
Five escalating dose cohorts of E-602 monotherapy and 2 escalating dose cohorts of combination 
therapy will be treated. 
Cohort 
Number of 
Subjectsa 
Dose of E-602 
Frequency of E-
602 
Dose of 
Cemiplimab 
Frequency of 
Cemiplimab 
101 
3 – 6 
1 mg/kg 
once a week 
n/a 
n/a 
102 
3 – 6 
3 mg/kg 
once a week 
n/a 
n/a 
103 
3 – 6 
10 mg/kg 
once a week 
n/a 
n/a 
104 
3 – 6 
20 mg/kg 
once a week 
n/a 
n/a 
105 
3 – 6 
30 mg/kg 
once a week 
n/a 
n/a 
111 
3 – 6 
20 mg/kg 
once a week 
350 mg 
once every 3 weeks 
112 
3 – 6 
to be determined 
once a week 
350 mg 
once every 3 weeks 
a Phase 1 cohorts may be backfilled to a maximum of 15 subjects.  
The dose for E-602 in the combination therapy cohorts will be initiated at dose level(s) that have 
previously completed dosing and DLT assessments (Cycle 1) as monotherapy.   
Dose modifications will be made according to Section 6.5. 
Phase 2 Treatment (Planned): 

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Subjects in Phase 2 will receive the following treatment:  
Cohort 
Number 
of 
Subjects 
Advanced 
Disease 
Dose of E-602 
Frequency 
of E-602 
Dose of 
Cemiplimab 
Frequency of 
Cemiplimab 
201 
16 − 31 
melanoma 
monotherapy 
RP2D 
once a 
week 
n/a 
n/a 
202 
16 − 31 
NSCLC 
monotherapy 
RP2D 
once a 
week 
n/a 
n/a 
203 
16 − 31 
TBDa 
monotherapy 
RP2D 
once a 
week 
n/a 
n/a 
211 
16 − 31 
melanoma 
combination 
RP2D 
once a 
week 
350 mg 
once every 3 
weeks 
212 
16 − 31 
NSCLC 
combination 
RP2D 
once a 
week 
350 mg 
once every 3 
weeks 
213 
16 − 31 
TBDa 
combination 
RP2D 
once a 
week 
350 mg 
once every 3 
weeks 
a The third cohort will treat subjects with one of ovarian, colorectal, pancreatic, breast, gastric/EGJ, head and neck or 
urothelial cancers, based on available data including the Phase 1 results. 
The maximum duration of treatment for each subject will be 1 year, regardless of treatment delays. 
See Section 7.1 for early treatment discontinuation criteria. 
6.2. 
Preparation, Handling, Storage, and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received, and any discrepancies are reported and 
resolved before use of the study treatment. 
Only subjects consented to the study may receive study treatment, and only authorized site staff 
may supply or administer study treatment. All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatments are provided 
in the Pharmacy Manual. 
As E-602 is a large molecule, the drug product is supplied as a frozen liquid. E-602 should be 
handled and prepared by qualified study personnel using aseptic technique and administered 
through an IV infusion as described in the Pharmacy Manual. Details for the storage, handling, 
and preparation of E-602 will be provided in the Pharmacy Manual. 
Cemiplimab (manufactured by Regeneron Pharmaceuticals, Inc.) is supplied as a solution (350 
mg/7 mL) and administered via IV infusion. Cemiplimab should be prepared by qualified study 
personnel in accordance with the manufacturer’s labeling.  

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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable. This is an open-label study. No control group will be used.  
6.4. 
Study Treatment Compliance 
All study subjects will receive E-602 and cemiplimab (if assigned to a combination therapy cohort) 
at the study site and will receive the study treatment directly from the investigator or designee, 
under medical supervision. The date and time of each dose administered in the clinic will be 
recorded in the source documents. The dose of study treatment(s) and study subject identification 
will be confirmed at the time of treatment by a member of the study site staff other than the person 
administering the study treatment(s).  
6.5. 
Dose Modification 
To mitigate treatment-related toxicities, the following dosing modifications will be made for both 
E-602 monotherapy and for E-602 in combination with cemiplimab. When E-602 is used in 
combination, cemiplimab should be administered first and E-602 administered at least 30 minutes 
after the cemiplimab infusion is completed. Dose modifications for combination therapy apply to 
both E-602 and cemiplimab, and both study treatments must be held or restarted according to 
recommended dose modifications in Table 2. Dosing visits should not be skipped due to dose 
delays. 
All therapies should be permanently discontinued if the study treatment is not restarted within 12 
weeks after the last dose for the following: 
• treatment-related toxicity, per Dose Modification (Table 2), does not resolve to Grade 
0–1 
• corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day  
• any non-treatment related toxicity does not permit restarting study treatment 
 
Table 2 
Dose modifications for E-602 monotherapy and combination therapy with 
cemiplimab 
Adverse Reaction 
Severity (CTCAE v5.0) 
Dose Modification/ 
Action with study treatment 
Hematologic events 
Any Grade 3 except 
thrombocytopenia with bleeding 
as specified below 
Grade 4 neutropenia not 
associated with clinical sequelae 
Grade 4 thrombocytopenia 
without bleeding  
Withhold until adverse reaction 
recovers to Grade 0–1 
Grade 3 thrombocytopenia with 
bleeding 
Any Grade 4 unless specified 
above or recurrent Grade 3 
Neutropenic fever 
Permanently discontinue 

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Adverse Reaction 
Severity (CTCAE v5.0) 
Dose Modification/ 
Action with study treatment 
Non-hematologic 
events unless 
specified below 
Any Grade 3  
Grade 4 electrolyte abnormality 
without clinical complications 
Grade 4 amylase or lipase 
increases not associated with 
symptoms or clinical 
manifestations of pancreatitis  
Withhold until adverse reaction 
recovers to Grade 0–1 
Any Grade 4 unless specified 
above 
Permanently discontinue 
Pneumonitis  
Grade 2  
Withhold until adverse reaction 
recovers to Grade 0–1  
Grade 3 or 4, or recurrent Grade 2  
Permanently discontinue  
Diarrhea or Colitis 
Grade 2 or 3  
Withhold until adverse reaction 
recovers to Grade 0–1  
Grade 4 or recurrent Grade 3  
Permanently discontinue  
Nephritis (CTCAE 
grading according to 
increase creatinine or 
acute kidney injury) 
Grade 2 with creatinine >1.5 to 
≤3 times ULN 
Withhold until adverse reaction 
recovers to Grade 0–1  
Grade ≥3 with creatinine >3 
times ULN 
Permanently discontinue 
Endocrinopathies 
Grade 2 adrenal insufficiency or 
hypophysitis 
Withhold treatment until controlled 
by hormone replacement 
Grade 3 or 4 adrenal 
insufficiency or symptomatic 
hypophysitis  
 
Type 1 diabetes associated with 
Grade ≥3 hyperglycemia (glucose 
>250 mg/dL or >13.9 mmol/L) or 
associated with ketoacidosis 
Hyperthyroidism Grade ≥3 
Withhold until adverse reaction 
recovers to Grade 0–1  
For any subject with Grade 3 or 
Grade 4 endocrinopathy that 
improves to Grade 2 or lower and is 
controlled with hormone 
replacement, if indicated, 
continuation of study treatment may 
be considered after corticosteroid 
taper, if needed. Otherwise, treatment 
should be discontinued. 
Hypothyroidism 
Hypothyroidism may be managed 
with replacement therapy without 
treatment interruption. 
AST or ALT 
elevation or Increased 
Bilirubin 
Grade 2  
Withhold until adverse reaction 
recovers to Grade 0-1 
Grade ≥3  
Permanently discontinue 
In case of liver metastasis with 
baseline Grade 2 elevation of 
AST or ALT, hepatitis with AST 
or ALT increases ≥50% and lasts 
≥1 week 
Permanently discontinue 

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Adverse Reaction 
Severity (CTCAE v5.0) 
Dose Modification/ 
Action with study treatment 
Immune-mediated 
skin reactions 
Grade 3 or suspected Stevens-
Johnson syndrome (SJS) or toxic 
epidermal necrolysis (TEN) or 
drug rash eosinophilia and 
systemic symptoms (DRESS) 
Withhold until adverse reaction 
recovers to Grade 0–1 
Grade 4 or confirmed SJS or TEN 
or DRESS 
Permanently discontinue 
Myocarditis 
Asymptomatic cardiac enzyme 
elevation with clinical suspicion 
of myocarditis (previously 
CTCAE v4.0 Grade 1) 
Withhold until adverse reaction 
recovers to Grade 0–1 
Grade 2, 3 or 4 myocarditis 
Permanently discontinue 
Other immune-
related adverse 
reactions 
Based on severity and type of 
reaction (Grade 2 or Grade 3) 
Withhold until adverse reaction 
recovers to Grade 0–1 
Grade 3 or 4 encephalitis 
Grade 3 or 4 Guillain-Barré 
syndrome  
Grade 4 or recurrent Grade 3 
Permanently discontinue 
Infusion-related 
reactions 
Recurrent Grade 2 or isolated 
Grade 3 
Consider a one week study drug 
delay 
Recurrent Grade 3 despite pre-
medication or Grade 4  
Permanently discontinue 
6.6. 
Management of Infusion Reactions 
As a biologic product, infusion reaction is possible with E-602 and/or cemiplimab. Investigators 
should assess infusion reactions from the start of an infusion through one hour after the end of the 
infusion. See Appendix 10.5 for CTCAE version 5.0 severity grading and acute clinical 
management guidelines.  
6.7. 
Treatment of Overdose 
For this study, any dose of E-602 administered greater than the 125% assigned dose will be 
considered an overdose. No specific information is available on the treatment of an overdose. 
In the event of an overdose, the investigator should: 
• Contact the medical monitor immediately. 
• Evaluate the subject to determine, in consultation with the medical monitor, whether study 
treatment should be interrupted and/or delayed. 
• Closely monitor the subject for any AE/SAE and laboratory abnormalities. Appropriate 
supportive treatment should be provided if clinically indicated. 
• Document the quantity of the excess dose as well as the duration of the infusion.  

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6.8. 
Concomitant Therapy 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for any medication or vaccination specifically 
prohibited during the trial, discontinuation from study treatment may be required.   
Vaccines including those against the SARS-CoV-2 virus are allowed during the study, after the 
subject completes a minimum of 30 days on treatment or has discontinued treatment and is in 
follow-up. Vaccines should not be administered the same day (+2 days) as study treatment 
administration. 
Any medication or vaccine (including premedications, medications used to manage adverse events, 
over-the-counter or prescription medicines, recreational drugs, vitamins, and/or herbal 
supplements) that the subject is receiving from 28 days prior to Cycle 1 Day 1, until study treatment 
discontinuation must be recorded. Any medication to treat adverse events during the 90-day safety 
follow-up must also be recorded. The following information must be included: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
6.8.1. 
Rescue Medicine 
The study site will supply rescue medication that will be obtained locally to treat potential 
occurrence of anaphylaxis and/or severe allergic reactions. Local standard of care medications will 
be used in such emergency situations. 
The date and time of rescue medication administration as well as the name and dosage regimen of 
the rescue medication must be recorded. 
 

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7. 
Discontinuation of Study Treatment and Withdrawal of Consent 
7.1. 
Discontinuation of Study Treatment 
Subjects will permanently discontinue study treatment for any of the following: 
• PD (confirmed PD for subjects who continued treatment beyond PD, see Section 4.1.2) 
• Initiation of alternative cancer therapy 
• Unacceptable toxicity including permanent discontinuation criteria defined in Section 6.5 
• Subject’s decision to discontinue treatment 
• Withdrawal of consent 
• Investigator’s decision to discontinue treatment 
• Sponsor’s decision to discontinue treatment 
• Inability of the subject to comply with the requirements of the study 
• Completion of maximum treatment duration of 1 year from Cycle 1 Day 1 
If study treatment is permanently discontinued, the subject will return for an EOT visit as well as 
30 days and 90 days after the last dose for safety follow-up, as indicated in the SoA (Section 1.3). 
In addition, the subject will be contacted every 3 months for disease status (if the discontinuation 
is not due to progression of disease) and survival, until 15 months after Cycle 1 Day 1.  
Subjects treated in the Phase 1 dose escalation part of the study will discontinue treatment if he/she 
experience DLT(s) during Cycle 1 (see Section 4.1.5).  
For all subjects, see Section 6.5 for toxicity-related treatment-discontinuation criteria.  
For subjects receiving the combination therapy of E-602 and cemiplimab, both treatments should 
be discontinued simultaneously.  
7.1.1. 
Temporary Interruption of Study Treatment 
Temporary interruption of study treatment due to adverse drug reactions is permitted. See Section 
6.5 for guidelines.  
7.1.2. 
Subject Replacement 
During Phase 1 dose escalation, subjects who cannot be evaluated for DLT (e.g., discontinued 
before completing Cycle 1 for reasons other than study treatment-related toxicity) may be replaced. 
Backfill and Phase 2 subjects will not be replaced. 
7.1.3. 
Study Stopping Criteria 
The study will be stopped and an assessment of the risk/benefit for subjects evaluated if any of the 
following criteria are met: 
• Study treatment related deaths 
• Recommendation of the SDRC based on the risk/benefit no longer warranting continuation 
of the study 
The study may be restarted if appropriate measures to protect the safety of study subjects can be 
implemented.  

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7.2. 
Subject Withdrawal from the Study 
A subject may withdraw his or her consent for study participation at any time at his/her own request 
or may be withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons.  
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws consent from the study, he/she may request destruction of any blood or 
tissue samples taken and not tested, and the investigator must document this in the site study 
records. 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit schedule, 
and ascertain whether the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls, and if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study.  

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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor or designee as soon as possible 
upon occurrence or awareness to determine if the subject should continue or discontinue study 
treatment. 
Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria. The investigator will maintain a screening log to record details of all subjects 
screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Procedures conducted as part of the subject’s routine clinical management (eg, blood count) and 
obtained before signing of the ICF may be utilized for screening or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the timeframe defined 
in the SoA. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Study Periods 
Overall, this study encompasses the following periods:  
• Screening: up to 28 days  
• Treatment: from Cycle 1 Day 1 to End-of-Treatment (EOT) visit, up to 1 year, regardless 
of treatment delays 
• Post-treatment safety follow-up: up to 90 days after the last dose  
• Survival follow-up: up to approximately 15 months from Cycle 1 Day 1  
Written informed consent must be obtained before any study procedures are performed, unless the 
procedure is a part of routine care. The Eastern Cooperative Oncology Group (ECOG) 
performance status at screening should be evaluated within 7 days of informed consent. Screening 
tests should be completed within 28 days before Cycle 1 Day 1, and study personnel should ensure 
each subject meets the eligibility criteria before the initial dose of study treatment is administered. 
Radiology examinations during screening are permitted up to 35 days prior to Cycle 1, Day 1. 
8.1. 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA. 
Subjects will undergo radiological tumor assessment at baseline during screening (up to 35 days 
prior to Cycle 1, Day 1), 9 weeks (±1 week) after the first dose and every 9 weeks (±1 week) 
thereafter regardless of treatment delays until the EOT visit. An examination at EOT visit should 
be performed unless the subject already has radiographic confirmation of PD within 4 weeks of 
the EOT visit.  

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Tumor assessment should include contrast-enhanced computed tomography (CT, preferred) or 
magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis. The same method (positron 
emission tomography [PET]/CT, MRI, or CT) and the same technique should be used to 
characterize each identified and reported lesion throughout the study. Lesions in a previously 
irradiated field may be assessed as target lesions if progression since irradiation has been 
demonstrated.   
Response to treatment will be evaluated using the RECIST version 1.1 (Eisenhauer 2009) and 
iRECIST (Seymour 2017). Subject responses will be classified as progressive disease (PD), stable 
disease, partial response (PR), and complete response (CR). A per timepoint response of Stable 
Disease requires a minimum of 56 days between two measures. To assess a Best Overall Response 
(BOR) of CR or PR per RECIST version 1.1, confirmation of the CR or PR is required at the 
subsequent timepoint at least 4 weeks later.  
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, dermatologic, and neurological systems along with the lymph nodes, 
and liver. 
8.2.2. 
Vital Signs 
Vital signs will be assessed and include body temperature, pulse, blood pressure, and oxygen 
saturation via pulse oximetry and be assessed as outlined in the SOA (Section 1.3).  
8.2.3. 
Weight and Height 
Height will be measured during screening. Body weight will be measured at visits indicated in 
Section 1.3. 
8.2.4. 
Electrocardiograms 
A 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals. ECG should be conducted at screening. 
8.2.5. 
Clinical Safety Laboratory Tests 
See Appendix 10.2 for the list of clinical laboratory tests to be performed and the SoA (Section 
1.3) for the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any clinically 
significant changes occurring during the study as an AE. The laboratory reports must be filed with 
the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered clinically 
significant unless judged by the investigator to be more severe than expected for the subject’s 
condition. 

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All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 90 days after the last dose of study treatment should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor. If clinically significant values do not return to normal/baseline 
within a period of time judged reasonable by the investigator, the etiology should be identified, 
and the Sponsor notified. 
8.2.6. 
Pregnancy Testing 
Subjects who are women of childbearing potential are required to undergo either serum or urine 
pregnancy test, (choice of test at the investigator’s discretion), during the study at timepoints 
indicated in the SoA (Section 1.3). 
8.3. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 10.3. 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the subject’s 
legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all adverse events until resolved or clinical stable. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.3. 
Note: The causality of each AE should be assessed and recorded separately for E-602 and 
cemiplimab for subjects receiving combination therapy.  
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing the informed consent form (ICF) until the 
final safety follow-up visit at the timepoints specified in the SoA (Section 1.3). If prior to 
completing the 90-day safety follow-up period a subject begins a new cancer treatment, no further 
safety follow-up is required. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.3. The investigator will 
submit any updated SAE data to the Sponsor or designee within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must promptly 
notify the Sponsor or designee. 

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8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs and Adverse Events of Special Interest (AESI) (as defined in 
Section 8.3.7) will be followed until resolution, stabilization, the event is otherwise explained, or 
the subject is lost to follow-up (as defined in Section 7.3).  
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, institutional review boards (IRBs), and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the IB and will notify the IRB, if appropriate according to local requirements. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and forwarded to investigators. 
8.3.5. 
Pregnancy 
Details of all pregnancies in female subjects and female partners of male subjects will be collected 
from the first dose of study treatment until 6 months after the last dose (see Section 5.1). 
If a pregnancy is reported, the investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor or designee within 24 hours of learning of the female subject or 
female partner of male subject (after obtaining the necessary signed informed consent from the 
female partner) pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any subject/female partner who becomes pregnant during the study will be followed to determine 
the outcome of the pregnancy. The investigator will collect follow-up information on the 
subject/female partner, and the neonate and the information will be forwarded to the Sponsor or 
designee. 

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Any post-study pregnancy-related SAE considered reasonably related to the study treatment(s) by 
the investigator will be reported to the Sponsor or designee as described in Section 8.3.4. While 
the investigator is not obligated to actively seek this information in former study subjects/pregnant 
female partner, he or she may learn of an SAE through spontaneous reporting. 
Any female subject who becomes pregnant while participating in the study will discontinue all 
study treatments.  
8.3.6. 
Death Events 
After the safety follow-up visit, information on subjects’ survival status will be collected via 
telephone or other methods, including date and cause of death, during the post-treatment period 
(up to 15 months from Cycle 1 Day 1).  
8.3.7. 
Adverse Events of Special Interest 
The adverse events of special interest (AESI) in this study will be potential immune-related 
toxicities. The following assessments will be conducted throughout the study:  
• Clinical observation for immune-related signs and symptoms. 
• Select laboratory tests for endocrine, hepatic, or renal dysfunction.  
8.4. 
Pharmacokinetics 
Plasma samples will be collected for PK analysis of E-602 concentration at time points shown in 
Table 3.  Sample collection and handling instructions will be provided in the Laboratory Manual.  
Table 3 
Blood sample collection time points for pharmacokinetic analyses 
Cycle 
Day 
Timea 
PK 
1 
1 
predose 
X 
0.5 h (EOI) ± 5 minb   
X 
2 h ± 10 minc 
X 
4 h ± 30 min 
X 
6 h ± 30 mind 
X 
2 
24 h ± 2 h 
X 
3 
48 h ± 4 he 
X 
8 
predose  
X 
15 
predose 
X 
2 
1  
(Day 22) 
predose 
X 
0.5 h (EOI) ± 5 minb  
X 
8 
predose 
X 
0.5 h (EOI) ± 5 minb  
X 
2 h ± 10 minc 
X 
4 h ± 30 min 
X 
6 h ± 30 mind 
X 
9 
24 h ± 2 h 
X 
10 
48 h ± 4 he 
X 
15 
predose 
X 

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Cycle 
Day 
Timea 
PK 
≥ 3 
1 
predose 
X 
0.5 h (EOI) ± 5 minb 
X 
8 
predose  
X 
EOT Visit 
NA 
NA 
X 
Follow-up 30 day 
NA 
NA 
X 
aAll time points except predose are after the start of E-602 infusion. Predose should be collected prior to the start of 
any study treatment. 
bThe 0.5 h sample collection is ± 5 mins from the end of E-602 infusion. In instances when the infusion time is >30 
minutes, the ± 5 mins window still applies to the end of the infusion. 
cIn the event the E-602 infusion exceeds 2 hours, the 2 h timepoint will be permitted as a missed assessment.  
dThe 6 h sample is only required for Phase 1 E-602 monotherapy cohorts. 
eCycle 1 Day 3 and Cycle 2 Day 10 sample collection is not required for Phase 2. 
8.5. 
Biomarkers 
The samples collected for pharmacodynamic, genetic and biomarker research, and any additional 
samples derived from the original samples, may be analyzed and stored for up to 15 years after the 
study ends and the final results are reported. These samples may be used for scientific research to 
support this study protocol, to design or improve methods for analyzing, comparing or combining 
study data. The Sponsor and its authorized representatives will ensure that samples are destroyed 
at the end of the storage period.  
8.5.1. 
Pharmacodynamics 
Whole blood and serum samples will be collected according to SoA. The time points for sample 
collection are listed in Table 4 and  
Table 5. In addition, results for baseline biomarkers of disease will be performed locally up to 72 
hours prior to Day 1 as follows: carcinoembryonic antigen (CEA) and CA-125 for subjects with 
NSCLC, CEA and CA19-9 for subject with colorectal or pancreatic cancer, and CA-125 for 
subjects with ovarian cancer. 
The exploratory biomarker investigations include but are not limited to:  
• Immune cell desialylation using FACS  
• Immune cell content and activation status by FACS  
• Pro-inflammatory cytokine and chemokine levels, including but not limited to: IL-2, IL-6, 
TNFα, IFN-γ, IL-8, IP-10, monocyte chemoattractant proteins (MCP) 
• Complement C3a 
• Changes in the glycoproteomic profile 
These samples may also be used for other biomarker research to further elucidate E-602 
mechanism of action, identify potential resistance mechanisms, understand variability in response 
and/or adverse events, identify other biomarkers of response, and to better understand the disease 
understudy.  Analyses may include, but are not limited to protein, metabolite and antibody 
profiling methodologies. 
Additional exploratory biomarkers related to tumor and immune biology may be analyzed, using 
methods such as gene expression profiling, mutational, protein and tissue image analysis. 

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Details of sample collection, storage, and shipping instructions will be provided in the Laboratory 
Manual. 
Table 4 
Phase 1 E-602 monotherapy biomarker sample collection time points for 
pharmacodynamic, genetic and immunogenicity analyses  
Cycle 
Day 
Timea 
Cytokine 
Panels 
and C3a 
FACS 
(desialylation 
and 
activation) 
RNASeq 
(blood) 
Circulating 
Tumor 
DNA 
Tumor 
Biopsy 
ADA Glycoproteomic 
Profile 
Screening 
 
 
 
 
 
 
X 
 
 
1 
1 
predose 
Xb 
Xb 
Xb 
Xb 
 
X 
X 
2 
24 h ± 2 h 
X 
X 
X 
 
 
 
X 
3 
48 h ± 4 h 
X 
X 
X 
 
 
 
X 
8 
predose  
X 
X 
X 
 
 
 
X 
9 
24 h ± 2 h 
X 
X 
X 
 
 
 
X 
10 
48 h ± 4 h 
X 
X 
X 
 
 
 
X 
15 
predose 
X 
X 
X 
 
 
 
X 
2 
1 
(Day 
22) 
predose 
 
 
 
 
X 
X 
 
≥ 3 
1 
predose 
 
 
 
Xc 
 
X 
 
EOT 
NA 
NA 
 
 
 
 
 
X 
 
Follow-
up 30 day 
NA 
NA 
 
 
 
 
 
X 
 
aAll time points except predose are after the start of infusion. 
bTwo predose samples should be collected at least 1 hour apart and up to 72 hours prior to Cycle 1 Day 1. 
cCirculating tumor DNA samples will be collected with radiological assessments. 
 
Table 5 
Phase 1 combination and Phase 2 biomarker sample collection time points for 
pharmacodynamic, genetic and immunogenicity analyses 
Cycle 
Day 
Timea 
Cytokine 
Panels 
and C3a 
FACS 
(desialylation 
and 
activation) 
SNPs 
Circulating 
Tumor 
DNA 
Tumor 
Biopsy 
ADA Glycoproteomic 
Profile 
Screening 
 
 
 
 
 
 
Xd 
 
 
1 
1 
predose 
Xb 
Xb 
X 
Xb 
 
X 
X 
2 
24 h ± 2 h 
X 
X 
 
 
 
 
X 
8 
predose  
X 
X 
 
 
 
 
X 
9 
24 h ± 2 h 
X 
X 
 
 
 
 
X 
15 
predose 
X 
X 
 
 
 
 
X 

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Cycle 
Day 
Timea 
Cytokine 
Panels 
and C3a 
FACS 
(desialylation 
and 
activation) 
SNPs 
Circulating 
Tumor 
DNA 
Tumor 
Biopsy 
ADA Glycoproteomic 
Profile 
2 
1 
(Day 
22) 
predose 
 
 
 
 
Xd 
X 
 
8 
predose 
X 
X 
 
 
Xd 
X 
X 
9 
24 h ± 2 h 
X 
X 
 
 
 
 
X 
15 
predose 
X 
X 
 
 
 
 
X 
≥ 3 
1 
predose 
 
 
 
Xc 
 
X 
 
EOT 
N
A 
NA 
 
 
 
X 
 
X 
 
Follow-up 
30 day 
N
A 
NA 
 
 
 
 
 
X 
 
aAll time points except predose are after the start of any study treatment infusion. Predose should be collected prior to 
the start of any study treatment. 
bTwo predose samples (prior to start of any study treatment administration) should be collected at least 1 hour apart 
and up to 72 hours prior to Cycle 1 Day 1. 
cCirculating tumor DNA samples will be collected with radiological assessments and at EOT visit. 
dFresh tumor biopsy is required for all subjects in Phase 1 combination at screening and on Cycle 2 Day 1 post-dose 
(+4 days). Fresh tumor biopsy is required for all subjects in Phase 2 at screening and post dose on Cycle 2 Day 1 or 
Day 8. The biopsy should be performed on Day 2 or 3 if performed post Cycle 2 Day 1 E-602 administration or Day 
9 or 10 if performed post Cycle 2 Day 8 E-602 administration. An archive tissue sample is required for all subjects. 
8.5.2. 
Genetics 
Blood samples in the Phase 1 E-602 monotherapy portion of the study will be collected to analyze 
circulating tumor DNA for target gene expression and immune cell gene expression profiling 
(RNAseq) at timepoints specified in the SoA and in Table 4.  
Table 5 summarizes the blood sample collection in Phase 1 combination and Phase 2 including 
collection of samples for circulating tumor DNA assessment and a whole blood single nucleotide 
polymorphism (SNP) sample for DNA sequencing.   
The SNP sample will be used to assess genetic variation or single nucleotide polymorphisms in 
select genes, including and not limited to genes involved in the metabolism and catabolism of 
sialoglycans and glycoproteins (i.e., glycogenes) or other genes that may predispose subjects to 
E-602 benefit or adverse events. Additional uses of the DNA sequencing data from the whole 
blood SNP sample may include correlations with clinically-relevant biomarkers identified by other 
methodologies described in this section to identify genotypic associations, as well as for 
comparison to tumor mutation data to identify genetic variants specific to the tumor. 
These blood samples may also be used for other pharmacogenomic/biomarker research to further 
elucidate E-602 mechanism of action, identify potential resistance mechanisms, understand 
variability in response and/or adverse events, identify other biomarkers of response, and to better 
understand the disease under study. 

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Tissue samples (Section 8.5.3) may also be analyzed for immune cell gene expression profiling 
(RNAseq) and tumor mutational burden. 
8.5.3. 
Tumor Biopsy 
For subjects in Phase 1 monotherapy, tumor biopsy at screening and Cycle 2 Day 1 are optional. 
For subjects treated in Phase 1 combination and Phase 2, a tumor biopsy at screening and in Cycle 
2 as indicated in Table 5 are required. If the investigator considers that performing a tumor biopsy 
at Cycle 2 puts a subject at undue safety risk and the subject is otherwise eligible to continue study 
participation, the subject may be allowed to continue the study. Additionally for Phase 2, the 
Sponsor may elect to permit subjects on study who do not have lesions amenable to biopsy in the 
investigator’s judgement but would otherwise be eligible for the study following discussion with 
the investigator. The reason for not performing a required biopsy will be documented in the CRF.   
An archival tumor tissue sample is required for all subjects. A fresh tumor biopsy is permissible 
at screening if tumor tissue from a subject’s previous biopsy cannot be obtained. 
Table 6 
Collection time point requirements for tumor biopsy 
 
Phase 1 
monotherapy 
Phase 1 
combination 
Phase 2 
Archival Biopsy Sample 
X 
X 
X 
Screening 
Optional 
X 
X 
Cycle 2  
Optional: Cycle 2 
Day 1 post-dose + 
4 days 
Cycle 2 Day 1 
post-dose + 4 days 
Cycle 2 Day 1 or 
Day 8 post dosea 
aThe biopsy should be performed on Day 2 or 3 if performed post Cycle 2 Day 1 E-602 administration or Day 9 or 10 
if performed post Cycle 2 Day 8 E-602 administration. 
During screening and during Cycle 2 as indicated in Table 6, subjects who undergo a tumor biopsy 
will have a sample collected and preserved in a representative formalin-fixed paraffin-embedded 
(FFPE) block (preferred) or at least 20 unstained, freshly cut, serial sections (on slides) from an 
FFPE tumor specimen will be collected. The specimen should be accompanied by the associated 
pathology report. The following specimen types are acceptable: resections, core needle biopsies, 
excisional, incisional, or forceps biopsies.  For core needle biopsy specimens, preferably, at least 
3 cores embedded in a single paraffin block should be submitted for evaluation. Fine needle 
aspirate is not an acceptable tissue collection method. 
Tumor cells will be analyzed for immune modulation of different immune cell subtypes, including 
T cells, macrophages, dendritic cells, and neutrophils. The following analyses may include but is 
not limited to:  
• Tumor desialylation by immunohistochemistry (IHC)  
• Tumor IHC analysis for immune markers (PD-L1) and modulation of different immune 
cell subtypes (T cells, macrophages, DC, neutrophils) 
These samples may also be used for other biomarker research to further elucidate E-602 
mechanism of action, identify potential resistance mechanisms, understand variability in response 
and/or adverse events, identify other biomarkers of response, and to better understand the disease 

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under study. Additional exploratory biomarkers related to tumor and immune biology may be 
analyzed, using methods such as gene expression profiling, mutational, protein and tissue image 
analysis. 
8.6. 
Immunogenicity Assessments 
Antibodies to E-602 will be evaluated in plasma samples collected from all subjects according to 
the SoA. These samples will be collected pre-dose at the designated visits, including a pre-dose 
sample before the initial dose on Cycle 1 Day 1.  
The detection and characterization of the ADAs will be performed using a validated assay method.  

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9. 
Statistical Considerations 
The statistical analysis plan (SAP) will be finalized prior to database lock and will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints. 
9.1. 
Analysis Sets 
DLT Evaluable Set: 
Will include all subjects treated in the dose escalation part who have had a DLT within Cycle 1 on 
study or without a DLT but completed safety assessments through Cycle 1 (3 doses of E-602 
administered for monotherapy cohorts and 3 doses of E-602 and 1 dose of cemiplimab 
administered for combination therapy cohorts). The DLT Evaluable Set will be defined for each 
dose cohort. Subjects who discontinue prior to completing Cycle 1 (3 doses of E-602 administered 
for monotherapy cohorts and 3 doses of E-602 and 1 dose of cemiplimab administered for 
combination therapy cohorts) for reasons other than toxicity may be replaced.  
Safety Analysis Set: 
Will include all subjects who have received any dose of study treatment. The Safety Analysis Set 
will be used for safety analyses. Safety Analysis Set may be further defined by the phase of the 
study, dose, and tumor type. 
Efficacy Evaluable Set: 
Will include all subjects who receive any dose of study treatment, meet eligibility criteria, have 
measurable tumor lesions at baseline, and have at least one post-baseline disease assessment per 
RECIST v1.1. Efficacy Evaluable Set is defined for each cohort in the Phase 2 separately.  
Pharmacokinetics (PK) Analysis Set: 
Will include all subjects in the Safety Analysis Set for whom adequate data on E-602 plasma 
concentration are available. 
9.2. 
Statistical Analyses 
9.2.1. 
General Considerations 
The statistical analyses will generally be descriptive in nature. Data collected will be presented 
using summary tables, data listings, and figures. For continuous variables, descriptive summaries 
will include the mean, median, standard deviation, the first and third quartiles, minimum, and 
maximum.  For categorical variables, the number and percentage of subjects in each category will 
be presented.  
9.2.2. 
Subject Disposition 
The number and percent of subjects who have consented, treated, discontinued (including reasons 
for discontinuation), and completed the study will be summarized. The number of subjects for each 
analysis set will be tabulated. 

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9.2.3. 
Baseline Characteristics 
Descriptive summary statistics will be provided for demographic variables (age at consent, sex at 
birth, race, ethnicity) and baseline disease characteristics (e.g., ECOG performance status). 
Relevant medical history and prior anti-cancer therapies/medications will also be summarized. 
9.2.4. 
Safety Analyses 
9.2.4.1. 
Treatment Exposure 
Duration of treatment, cumulative dose administered, relative dose intensity, frequency of dose 
adjustment, and treatment discontinuation will be summarized. For the combination therapy 
cohorts, E-602 and cemiplimab doses will be summarized separately. 
9.2.4.2. 
Treatment Emergent Adverse Events 
All adverse events will be coded to a system organ class and a preferred term based on the Medical 
Dictionary for Regulatory Activities (MedDRA) version 24.0 or later.  
Treatment-emergent adverse events (TEAEs) are defined as AEs with an onset date on or after the 
date of first dose of study treatment until 90 days after the last dose.  
Subject incidence of all treatment-emergent adverse events, serious adverse events, adverse events 
leading to discontinuation of treatment, and fatal adverse events will be tabulated by system organ 
class and preferred term. 
The number and percent of subjects reporting TEAEs will be evaluated overall and by dose level 
and will also be tabulated by severity and relationship to study treatment. The severity of each 
adverse event will be graded using The Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 or later criteria. 
For the Phase 1 component of the study, DLTs (if any) will be summarized by dose and will be 
listed separately.  
9.2.4.3. 
Laboratory Values 
Descriptive statistics for laboratory test values and changes from baseline at each visit will be 
tabulated and, in some cases, presented graphically. Additional analyses based on shift from 
baseline in test values in multiples of the lower/upper limit of normal range (LLN/ULN) of a 
parameter will be detailed in the statistical analysis plan.  
9.2.4.4. 
Vital signs 
Vital sign parameters (blood pressure, pulse, and body temperature), oxygen saturation, and weight 
observed at each visit will be summarized along with the change values from baseline.  Clinically 
important physical exam findings will be listed and summarized. 
  

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9.2.5. 
Efficacy analysis 
The primary analysis for efficacy will be based on the cohort-specific efficacy evaluable analysis 
set. Sensitivity analysis may include pooling additional subjects treated in Phase 1 at the same dose 
level in the same tumor type.  
For objective response rate (ORR), the Clopper-Pearson 80% and 95% confidence intervals (CIs) 
will be provided. Confidence intervals adjusting for the 2-stage nature of the design may also be 
provided.  
Duration of response (DoR) will be calculated among responders (CR and PR). The Kaplan-Meier 
method will be used to estimate median DoR and the confidence intervals. Subjects who continue 
to respond at the time of the analysis will be censored at the last assessment of response.  
Progression-free survival (PFS) is measured from the date of first study treatment dose until the 
first date when progressive disease (PD) is objectively documented or death from any cause. 
Subjects without PD or death will be censored at the last available tumor assessment. PFS will be 
summarized using the Kaplan-Meier method. 
Overall survival (OS) is measured from the date of first study treatment dose until death. Subjects 
who are alive will be censored at the last known alive date. OS will be summarized using the 
Kaplan-Meier method.  
9.2.6. 
Pharmacokinetics and Immunogenicity 
Pharmacokinetics 
Individual and mean plasma E-602 concentration versus time data will be tabulated, summarized, 
and plotted by dose level. Noncompartmental PK parameters of E-602 including but not limited to 
AUC, Cmax, and Ctrough, will be tabulated and summarized (e.g., mean, standard deviation, and 
coefficient of variation). Inter-subject variability and drug accumulation may be evaluated. 
Immunogenicity 
The number and percentage of subjects who develop detectable ADA will be summarized by dose 
level. The impact of ADA on PK may be analyzed as appropriate.  
9.2.7. 
Exploratory Analysis: Pharmacodynamics 
Serum immune cell desialylation and ctDNA levels will be monitored for potential changes due to 
the various therapies tested in this study. 
9.2.8. 
 Covariates and Subgroup analysis 
Additional safety and efficacy subgroup analyses may be performed based on, but not limited to, 
the following covariates: 
• Age or age categories 
• Gender (sex at birth) 
• Prior anti-cancer treatment 
• Baseline PD-L1 expression levels 
 

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9.3. 
Interim Analysis 
During the phase 2 portion of the study, the safety data review committee will review both safety 
and efficacy data. Efficacy data at the end of Stage 1 of the Phase 2 portion will be used to 
determine Stage 2 expansion. Any additional interim analyses not built in as a part of the study 
design will be documented.  
9.4. 
Sample Size Determination 
Phase 1 Dose Escalation:  
Dose escalation for all cohorts will utilize a modified 3+3 design.  
A total of 5 dose escalation cohorts are planned for E-602 monotherapy for a total of up to 30 
subjects.  
A total of up to 2 dose cohorts are planned for the E-602 and cemiplimab combination therapy for 
a total of up to 12 subjects.  
Phase 1 Backfill: 
Any Phase 1 cohort may be backfilled up to a total of 15 subjects in a dose cohort (dose escalation 
and backfill) to obtain additional safety, PK and pharmacodynamic data at a particular dose level. 
Phase 2: 
For each cohort in Phase 2, Simon’s minimax 2-stage design will be used. Sixteen subjects will be 
treated in the first stage. If ≥2 of 16 subjects respond, Stage 2 will be opened to treat an additional 
15 subjects for a total of 31 subjects in the cohort. At the end of Stage 2, if ≥6 of 31 subjects 
respond, the treatment will be considered promising for further evaluation. Within each cohort, the 
design has 80% power and a type I error rate of 0.1 to test the null hypothesis that the response 
rate is ≤10% against the alternative hypothesis of ≥25%. 
 
 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB by the investigator and reviewed and approved 
by the IRB before the study is initiated. 
Any amendments to the protocol will require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
subjects.  
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study subjects. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB 
• Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB, European regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information by completing a financial disclosure form as requested to allow the Sponsor to submit 
complete and accurate financial certification or disclosure statements to the appropriate regulatory 
authorities. Investigators are responsible for providing information on financial interests during 
the course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the subject and answer all questions regarding the study. 

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Subjects must be informed that their participation is voluntary. Subjects will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and the IRB or study 
center. 
The medical record must include a statement that written informed consent was obtained before 
the subject underwent any study required procedures beyond standard of care and the date the 
written consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF. 
Subjects must be reconsented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the subject. 
Subjects can be rescreened if they are within the protocol-specified screening window and do not 
need to re-consent. If the subject falls outside of the protocol-specified screening window, the 
subject must re-sign the ICF and receive a new subject number. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples for 
optional exploratory research. The investigator or authorized designee will explain to each subject 
the objectives of the exploratory research. Subjects will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 
period.  
10.1.4. 
Data Protection 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
subject who will be required to give consent for their data to be used as described in the informed 
consent.  
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
A Safety Data Review Committee (SDRC) will be formed to oversee the study conduct and safety 
of subjects, including dose-escalation recommendations. The committee will consist of the 
principal investigators and members of the Sponsor.  
Details of committee structure and meetings will be described in the committee charter.  
10.1.6. 
Dissemination of Clinical Study Data 
The study protocol and results will be reported in compliance with US FDA regulations.  

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10.1.7. 
Data Quality Assurance 
All subject data relating to the study will be recorded on electronic CRFs unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the CRF. 
Guidance on completion of CRFs will be provided. 
The investigator must permit study-related monitoring, audits, IRB review, and regulatory agency 
inspections and provide direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
The Sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
10.1.8. 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical records 
must be available. 
Definition of what constitutes source data and its origin can be found in the monitoring plan. 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of subjects are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements. 

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10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of subjects 
and the site has all required documents in place prior to screening potential subjects. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are not 
limited to: 
For study termination: 
• Discontinuation of further development of E-602 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by 
the investigator 
• Total number of subjects included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IRBs, the regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the subject and should assure appropriate 
subject therapy and/or follow-up. 
10.1.10. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to discuss publication opportunities with the Sponsor for approval in 
advance. All agreed upon manuscripts or abstracts will be reviewed and approved by the Sponsor 
before submission.  
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a coordinating 
investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 

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Other screening 
tests 
• Follicle-stimulating hormone and estradiol (as needed in women of 
nonchildbearing potential only) 
• Coagulation: prothrombin time (PT), activated partial thromboplastin 
(aPTT), International Normalized Ratio (INR) 
aTest should be performed at screening only. 
bTest should be performed at screening and each restaging visit (Cycle 4 Day 1, Cycle 7 Day 1, etc.). 
cTest should be performed at screening and Day 1 of each cycle. 
Safety laboratory tests including pregnancy test for Cycle 1 Day 1 may be collected up to 72 hours 
prior to Day 1 to ensure results are available for review prior to dosing on Day 1. For all other 
dosing days, serum electrolytes, ALT/AST and hematology test results need to be reviewed prior 
to dosing.  
Investigators must document their review of each laboratory safety report. 
 
 

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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
• Following menarche 
• From the time of menarche until becoming postmenopausal unless permanently sterile (see 
below) 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle-stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. If the subject cannot meet these criteria as written, the subject will be 
considered to be WOCBP and pregnancy testing is required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
o Permanent sterilization methods (for the purpose of this study) include: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
- 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (eg, Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
o If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study treatment(s), additional evaluation 
should be considered. 

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10.4.2. 
Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of < 1% per year when 
used consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)c 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a to medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. Spermatogenesis cycle 
is approximately 90 days. 
Note: documentation of azoospermia for a male subject can come from the site personnel’s review 
of the subject’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent Failure rate of < 1% per year when used 
consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulationc 
− oral 
− intravaginal 
− transdermal 
− injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
− oral 
− injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment(s). The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject. 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use 
of contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ 
from those when used consistently and correctly. 
c) Male condoms must be used in addition to hormonal contraception. If locally required, in 
accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Male condom and female condom should not be used together (due to risk 
of failure with friction) 
 
 

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10.5. 
Appendix 5: Infusion Reaction Assessments and Management 
NCI CTCAE version 5.0 Grading Criteria for Infusion Reactions 
Infusion related reactions will be considered the adverse event and graded following the below CTCAE 
criteria.  
Grade 
Description 
1 
Mild transient reaction: infusion interruption not indicated; intervention not indicated 
2 
Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications 
indicated for ≤24 hours 
3 
Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
4 
Life-threatening consequences: urgent intervention indicated 
5 
Death 
Source: https://ctep.cancer.gov/protocoldevelopment/electronic applications/docs/ctcae v5 quick reference 5x7.pdf 
Clinical Management Guidelines for Infusion Reactions 
Unscheduled plasma PK, ADA and cytokine panel samples should be collected in the event of an infusion 
related reaction. 
Infusion Reactions 
Immediate Clinical Management 
Mild (Grade 1) 
Mild-transient reaction; infusion interruption is not 
indicated; intervention is not indicated. 
 
*Any of the following symptoms may be 
observed: 
• 
Mild chills 
• 
Mild flushing 
• 
Pruritus  
• 
Transient rash (covering less than 10% BSA 
with or without symptoms) 
• 
Dizziness (not interfering with activity) 
• 
Mild allergic rhinitis 
• 
Assess and monitor subject closely. 
• 
Ensure equipment and medication are readily 
available should the reaction progress. 
• 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
• 
Remain with subject until symptoms have 
resolved. 
If symptoms progress to Grade 2, proceed as 
described below. 
Moderate (Grade 2) 
Therapy or infusion interruption is indicated but 
subject responds promptly to treatment (such as 
NSAIDs, antihistamines, narcotics, IV fluids); 
Apply Grade 1 clinical management and: 
• 
Stop infusion. 
• 
Consider giving diphenhydramine 50 mg IV 
and/or hydrocortisone sodium succinate 100 
mg IV. 

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Infusion Reactions 
Immediate Clinical Management 
medications are indicated for less than or equal to 
24 hours. 
 
*Any of the following symptoms may be 
observed: 
• 
Moderate flushing 
• 
Pruritus 
• 
Mild to moderate chest discomfort 
• 
Mild to moderate back pain 
• 
Mild to moderate nausea, vomiting, and/or 
diarrhea 
• 
Transient rash (covering 10 to 30% BSA with 
or without symptoms) 
• 
Dizziness (moderate unsteadiness or sensation 
of movement) 
• 
Moderate dyspnea 
• 
Urticaria (lesions covering 10 to 30% BSA) 
• 
Moderate allergic rhinitis 
• 
Fever 39 to 40°C 
• 
Mild to moderate abdominal discomfort 
• 
Mild hypotension (less than or equal to 20 
mmHg drop from baseline) 
• 
Rigors 
• 
If symptoms resolve within 1 hour of stopping 
drug infusion, may resume infusion at the 
following rates at the investigator’s discretion: 
o 25% of the rate at time of reaction for 5 
minutes 
o 50% of the rate at time of reaction for 5 
minutes 
o 75% of the rate at time of reaction for 5 
minutes 
o 100% of the rate at time of reaction 
o Slowed infusion rates and durations 
beyond those above are permitted at the 
discretion of the investigator 
o Otherwise, dosing will be held until 
symptoms resolve and corticosteroids, 
dose at the discretion of the investigator, 
should be added to the premedication 
regimen for the next scheduled dose and at 
subsequent E-602 doses.  
 
Participants who develop recurrent Grade 2 
toxicity despite adequate premedication should 
be evaluated for individual risk/benefit prior to 
further study treatment. A one week study drug 
delay may be considered. 
Severe (Grade 3) 
Prolonged (i.e., not rapidly responsive to 
symptomatic 
medication 
and/or 
a 
brief 
interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization is 
indicated for clinical sequelae.  
 
*Any of the following symptoms may be 
observed: 
• 
Fever greater than 40°C 
• 
Hypoxia: decreased oxygen saturation at rest 
(e.g., pulse oximeter less than 88%) 
• 
Severe rash (covering greater than 30% BSA 
with or without associated symptoms) 
• 
Symptomatic bronchospasm with or without 
urticaria 
• 
One or more symptoms of respiratory distress 
requiring treatment (e.g., repetitive cough, 
wheeze, throat tightness/change in voice) 
• 
Generalized urticaria (covering greater than 
30% BSA) 
• 
Dizziness: severe unsteadiness or sensation of 
Apply Grade 1 clinical management and: 
• 
Stop infusion and do not restart. 
• 
Consider giving diphenhydramine 50 mg IV 
and/or hydrocortisone sodium succinate 100 
mg IV. 
• 
Consider giving normal saline if needed for 
hypotension. 
• 
Consider 
giving 
epinephrine 
0.5 
mg* 
intramuscularly STAT. Consider repeating 
epinephrine at 5-minute intervals twice more as 
needed (i.e., if breathing becomes more labored 
or level of consciousness decreases). 
• 
Consider giving oxygen if needed for dyspnea. 
• 
Consider giving bronchodilators if indicated. 
 
• 
Initiate 
Emergency 
Response 
Call 
as 
appropriate if subject condition warrants. 
• 
Hospitalization may be considered as indicated 
for clinical sequalae. 
• 
If isolated Grade 3, attempt to retreat on 
another occasion after premedication including 
corticosteroids using a slower infusion rate as 

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Infusion Reactions 
Immediate Clinical Management 
movement 
• 
Edema/angioedema 
• 
Uncontrolled hypotension (more than 20 
mmHg drop from baseline) requiring therapy  
• 
Severe nausea, vomiting, and/or diarrhea 
 
Severe (Grade 4) 
Life-threatening 
consequences: 
urgent 
intervention indicated 
 
*Any of the following symptoms may be 
observed: 
• 
Cyanosis 
• 
 Life-threatening 
hypoxia 
or 
airway 
compromise 
• 
Severe angioedema (periorbital/facial) 
• 
Altered level of consciousness 
indicated for Grade 2. 
• 
If Grade 4 or recurrent Grade 3, permanently 
discontinue study treatment. 
 
 
*Note: epinephrine 1:1,000 = 1 mg/mL and 
epinephrine 1:10,000 = 1 mg/10 mL 
 
*Symptoms noted are intended as potential examples at each grade. Severity grading of the 
infusion related reaction will be based on the investigator’s judgement per CTCAE v5.0. 

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10.6. 
Appendix 6: Abbreviations  
ADA 
antidrug antibody 
ADCC 
antibody-dependent cellular toxicity 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BOR 
best overall response 
BUN 
blood urea nitrogen 
CDK 
cyclin-dependent kinase 
CEA 
carcinoembryonic antigen 
CHF 
congestive heart failure 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum concentration 
CNS 
central nervous system 
CPS 
combined positive score 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DC 
dendritic cell 
dMMR 
mismatch repair deficient tumors 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DRESS 
drug rash with eosinophilia and systemic symptoms 
EC20 
20% effective concentration 
 
EC50 
50% effective concentration 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGJ 
esophagogastric junction 
EOI 
end of infusion 
EOT 
end of treatment 
FACS 
fluorescence-activated cell sorting 
FFPE 
formalin-fixed paraffin-embedded 
FIH 
first in human 
FGFR 
fibroblast growth factor receptor 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
hCG 
human chorionic gonadotropin 
HER-2 
human epidermal growth factor receptor 2 
HIV 
human immunodeficiency virus 
HR+ 
hormone receptor positive 

Phase 1/2 Clinical Study Protocol 
Protocol Number: PAL-E602-001 
Palleon Pharmaceuticals 
 
Version 8.0, 24 August 2023 
 
Confidential and Proprietary 
77/79 
 
HRD 
homologous repair deficiency 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IFN 
interferon 
IHC 
immunohistochemistry 
IL 
interleukin 
INR 
International Normalized Ratio 
IRB 
institutional review board 
iRECIST 
Immunotherapy Response Evaluation Criteria in Solid Tumors 
 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MCP 
monocyte chemoattractant proteins 
MCV 
mean corpuscular volume 
MLR 
mixed lymphocyte reaction 
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NHP 
nonhuman primate 
NOAEL 
no-observed-adverse-effect level 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PARP 
polyadenosine diphosphate ribose polymerase 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
prothrombin time 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SJS 
Stevens-Johnson syndrome 
SNP 
single nucleotide polymorphism 
SoA 
Schedule of Activities 
T1/2 
half-life 
T3 
triiodothyronine 
TEN 
toxic epidermal necrosis 
TNBC 
triple-negative breast cancer 

Phase 1/2 Clinical Study Protocol 
Protocol Number: PAL-E602-001 
Palleon Pharmaceuticals 
 
Version 8.0, 24 August 2023 
 
Confidential and Proprietary 
78/79 
 
TNF 
tumor necrosis factor 
TRK 
tropomyosin receptor kinase 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WOCBP 
Woman of Childbearing Potential  
 
 

Phase 1/2 Clinical Study Protocol 
Protocol Number: PAL-E602-001 
Palleon Pharmaceuticals 
 
Version 8.0, 24 August 2023 
 
Confidential and Proprietary 
79/79 
 
11. 
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