A Phase I Study of HCW9218, a Bifunctional TGF-B; Antagonist/IL-15 Protein Complex, in Select Advanced Solid Tumors After Failing at Least Two Prior Therapies
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Masonic Cancer Center, University of Minnesota

Masonic Cancer Center 
University of Minnesota 
 
 
A Phase I Study of HCW9218, a Bifunctional TGF-β Antagonist/IL-15 
Protein Complex, in Select Advanced Solid Tumors After Failing at 
Least Two Prior Therapies 
CPRC #2021LS143 
IND # 160084 
 
 
Principal Investigator/IND Sponsor: 
Melissa A Geller, MD 
Professor and Division Director, Gynecologic Oncology 
Department of Obstetrics, Gynecology and Women's Health (OBGYN) 
420 Delaware Street SE MMC 395 
Minneapolis, MN 55455 
Email: gelle005@umn.edu 
Phone: 612 626-3111  
 
 
Collaborators: 
Jeffrey S Miller, MD 
Manish Patel, DO 
 
 
Biostatistician: 
Qing Cao, MS 
UMN Biostatistical Core 
 
 
Version Date:  
March 29, 2023 
 
 
 
 
Confidential 
 
 
 
 

CPRC #2021LS143 – HCW9218 for Select Advanced Solid Tumors 
 
 
 
 
 
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Revision History 
 
Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
 
Dec 16 2021 
Original to the FDA 
n/a 
 
Jan 12 2022 
Full response to FDA clinical deficiencies and non-hold comments 
received Jan 11 2022. 
Other minors edits for consistency including Section 13.1  
Original to CPRC 
yes 
 
Feb 4 2022 
Edits and clarifications since the CCPM, original to IRB 
 Title page – add Qing Cao as the study statistician replacing Todd 
DeFor who has left the University  
 Synopsis and Section 1.3 – delete correlative objective to 
characterize blood cDNA, cytokine, chemokine and inflammatory 
marker levels (should have been deleted when a study expansion 
cohort was deleted prior to FDA submission) 
 Synopsis Study Design and Enrollment Plan reorganized for clarity 
(not tracked but available upon request) 
 Synopsis and Section 4.1.2 – only permit persons with measurable 
disease to be enrolled (delete evaluable as not relevant in RECIST 
1.1) – add Schwartz 2016 to references 
 Synopsis and Section 4.1 – delete inclusion criteria regarding prior 
RT to target lesion – move content to Section 4.1.2 (Section 4.2.5 of 
exclusion already addresses no prior RT in previous 14 days) 
 Synopsis and Section 4.1 – delete life expectancy of at least 12 
weeks as too subjective - ECOG PS of 0 or 1 is required eligibility 
 Synopsis and Section 4.2. 9 – after querying intent with HCW 
Biologics, rewrote for clarity as intent is to prohibit St. John’s wort and 
and/or other herbal CYP modulators   
 Synopsis and Section 4.1 – other minor edits to inclusion criteria for 
clarity 
 Schema and Section 6.3 – add any patient experiencing a DLT at any 
time is discontinued from study treatment, delete last line regarding 
DLT events only reported in the dose finding phase (should have 
been deleted when a study expansion cohort was deleted prior to 
FDA submission) 
 Synopsis and Section 6.3 – removed language in parentheses (due 
to treatment related re-distribution of immune cells) as felt 
undefinable per study clinical staff upon review  
 Section 4.2.3 and Section 6.1.1 – expand language around cardiac 
function and monitoring, add a footnote to table in Section 8.1 
 Section 4.2.6 – correct wording regarding prior malignancy to reflect 
schema 
 Section 5.2 – add language that if a patient does not start study 
treatment within 14 days of baseline bloodwork for eligibility they 
must be repeated and continue to meet criteria set in Section 4.1.6. 
 Section 6.1 and Section 9.4 – HCW9218 is administered as 2-3 
injections not 2-4 injections 
 Section 6.1 – simplify 1st bullet under may delay HCW9218 for 1 
week to read ongoing Grade 3 toxicity that is not a DLT – any 
occurrence of a DLT at any time permanently discontinues HCW9218 
 Section 6.1.2 – reiterate pre/post meds are as needed (prn). 
 Section 6.1.3 – add a reminder that during Cycle 1 and Cycle 2 Day 1 
a targeted toxicity worksheet is completed per the schedule in 
Section 10.2.2. 
yes 

CPRC #2021LS143 – HCW9218 for Select Advanced Solid Tumors 
 
 
 
 
 
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Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
 Section 6.1.4 – expand (repeat) dose delay language from Section 
6.1 and add a participant is discontinue from treatment if experiences 
a DLT at any time.  
 Section 6.4 (supportive care)  – move language for management of 
injection site reaction from Section 7.2  
 Section 6.5 (prohibited concomitant therapy), Section 6.6 (duration of 
treatment), Section 6.7 (duration of study participation – expand 
sections for clarity and content as included in other sections of the 
protocol 
 Section 7.2 – relabel as Most Common and Most Serious Side 
Effects Seen in Drugs Similar to HWE9218 and expand the section to 
include the AE events in the consent form sorted by common, 
occasional and rare. Reiterate that the Table in Appendix II should 
continue to be used when assigning for event documentation and 
reporting requirements. 
 Section 8 – further define acceptable windows, move all lab tests and 
ECG charged to research to the research activities table (Section 
8.2), rework footnotes in both tables. 
 Section 9.7 – potential side effects – rework section referring reader 
to Section 7.2 and Appendix II. 
 Section 10 – Copy language from Section 10.2 to introduction 
regarding the AE monitoring period. 
 Section 10.2 – make two new sub sections (exceptions to 
documentation and targeted toxicity) to allow hyperlinking from other 
protocol sections. edit table for clarity  
 Section 10.3 – update table for clarity 
 Section 11.1 – delete reference to REDCap as will not be used. 
 Section 12.2 – add “In a 3 patient cohort at least 14 days must 
separate the 1st and 2nd patients with no staggering required 
between the 2nd and 3rd patient. A minimum of 21 days must 
separate each 3 patient cohort.” 
 Section 14.1 – add protocol deviations must be report per Section 
10.3 
 Appendix IV – delete pruritus and rash rows as skin covered by other 
skin/subcutaneous 
1 
October 4 
2022 
 Schema and Section 4.1.6 inclusion criteria – require adequate organ 
function within 14 days prior to “Cycle 1 Day 1” rather than “study 
enrollment”  
 Synopsis and Section 6 – edit the DLT regarding inability to start 
Cycle 2 due to treatment related toxicity 
 Synopsis, Section 6.1 - Clarify weight calculation as done on weight 
taken Cycle 1 Day 1 or within 14 days prior as currently uses vague 
term of baseline weight 
 Section 6.1 - add details of how and when to recalculate the HCW 
dose based on a ≥10% weight change from the weight used for Cycle 
1 Day 1. If a 2nd dose recalculation is needed patient can either 
continue treatment (if weight is returning to Cycle 1 Day 1 weight) or 
discontinue treatment as a ≥20% weight change is a Grade 3 toxicity. 
 Section 6.1.4, Section 6.6 – Removed references from original 
protocol language that a patient who experiences a DLT or unable to 
receive treatment after a 1 week delay is taken off study.   
 Section 6.3 – Expand Definition of Dose Limiting Toxicity section and 
remind reader about fast track pre-defined events that do not meet 
the definition of DLT but trigger a change in the enrollment plan and 
remind the reader of monitoring for excessive toxicity by the study 
statistician regular review of DLT reported events. 
 Section 6.3, Section 8 - clarify the window for Cycle 2 Day 1 is +3 
days and that “the DLT period does not end until the patient is 
yes 

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Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
assessed on Cycle 2 Day 1 (+3 days) and the results of lab work 
drawn on Cycle 2 Day 1 (+3 days) confirms no new DLTs since the 
previous assessment and/or no ongoing DLT events”. (After cycle 2, 
the window for Day 1 is ±3 days.) 
 Section 6.4 - Permit palliative radiation therapy to non-target lesions 
(as defined by RECIST) 
 Section 8.1 SOC activities - add a row for eligibility assessment to 
prompt completion of the relevant checklist/eCRF, expand footnote 
one to permit consent signing at any time prior to the start of study 
related activities, permit disease assessments to be done within 42 
days of Cycle 1 Day 1 if not intervening anti-cancer therapy. Add x’s 
to the vitals, assessment and other activities during Cycles 1 and 2 
as not otherwise performed in CRU. Increased window for imaging 
studies from ± 1 week to ± 14 days.  
 Section 8.2 – Update schedule of research sample collection and 
tube type to match the administrative letter dated March 2022 
previously submitted to the IRB. Added language to optional biopsy 
footnote to indicate it is exempt from 28 day limit. 
Other minor edits and clarifications including: 
 Synopsis, Schema, Section 3 Expand HCW9218 is administered by 
subcutaneous injection in the outpatient setting once every 3 weeks 
for a minimum of 2 cycles adding unless medically contraindicated or 
patient refusal – a minimum of 2 cycles is felt needed to see any 
effect, but study uses intent-to-treat for efficacy and toxicity. 
 Synopsis -  Expanded exclusion criteria regarding use of St John’s 
Wort or other herbals CYP modulators to match Section 4.29 - 
Replace “courses” with “cycles” for consistency through-out the 
protocol 
 Synopsis, Section 6.6 Section 8 – End of Treatment visit – add 
flexibility to the EOT visit in the event decision to stop treatment 
occurs outside of the window from last dose and/or patient isn’t 
returning to the U. 
 Section 8.2 - add reference to the HCW provided IIT manual for 
sample collection, processing and shipping. 
 Section 9 - update HCW information based on the IIT manual 
provided by HCW 
 Section 10.2.2 - add a Day 2 assessment, but otherwise reduce the 
frequency for completion of the targeted toxicity worksheet to end at 
Day 5 
 Previous Section 10.3 regarding reporting death due to disease as an 
SAE as QA suggests adding a CRF for death reporting (date and 
cause)  
 Reformat the definition of DLT into table format for ease of reading  
 Synopsis - Refer to the study agent as an investigational product (IP), 
add IP to key abbreviations table. 
Other updates to match the MCC protocol template 
2 
February 14 
2023 
In response to IRB stipulations 
 Synopsis and Schema – remove remaining references that a 
participant is discontinued from treatment if they experience a DLT at 
any time. 
no 
3 
March 29 
2023 
 Synopsis, and Sections 4.2 and 6.5 – Added an exception for use of 
prednisone in persons with CT contrast allergies as it is necessary for 
persons with CT contrast allergies to receive high-dose prednisone 
prior to a CT. 
yes 

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Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
 Synopsis, Section 13 – Removed language requiring 14 days 
between the 1st and 2nd patients in a cohort of 3 patients as no DLTs 
have been observed from dose level 1 to dose level 4. 
 Sections 4.1.2 and 8.2 (footnote 10) – Added language to indicate if a 
biopsy is obtained prior to treatment start (any time after consent) and 
a patient is later deemed ineligible to receive treatment, the tumor 
sample will not be used for research purposes since the sample 
cannot determine the effect of HCW9218. 
 Section 8.2 – Updated text in footnotes 5-8 regarding the 3 hour post 
dose blood draw window to read “30 minutes” instead of “0.5 hour” to 
be consistent with how all other windows are written throughout the 
protocol. Removed blood volume and tube type content as that is 
captured in the study lab manual. 
 
 
 
 

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Table of Contents 
 
Revision History .......................................................................................................................................... 2 
Table of Contents ....................................................................................................................................... 6 
Key Abbreviations ...................................................................................................................................... 9 
Study Synopsis ......................................................................................................................................... 11 
Study Schema........................................................................................................................................... 13 
1 
Objectives ...................................................................................................................................... 16 
1.1 
Primary Objective ................................................................................................................. 16 
1.2 
Secondary Objectives .......................................................................................................... 16 
1.3 
Correlative Objectives.......................................................................................................... 16 
2 
Background and Rationale.......................................................................................................... 16 
2.1 
Advanced Solid Tumor Cancer Control after Failure of Initial Treatments .................. 16 
2.2 
Investigational Product - HCW9218 .................................................................................. 17 
2.2.1 
General Information on HCW9218 .................................................................................... 17 
2.2.2 
Summary of Nonclinical Clinical Findings ......................................................................... 17 
2.2.3 
Summary of Clinical Findings ............................................................................................. 22 
2.3 
Study Rationale .................................................................................................................... 22 
2.3.1 
TGF-β and Cancer ............................................................................................................... 22 
2.3.2 
Rational for HCW9218-based Immunotherapy ................................................................ 23 
2.3.3 
Rationale for the Starting Dose and Dose Range of HCW9218 in Humans ............... 23 
2.3.4 
Rationale that HCW9218 Plays a Role in Therapy Induced Senescence (TIS) ......... 24 
3 
Study Plan ..................................................................................................................................... 25 
4 
Patient Selection ........................................................................................................................... 26 
4.1 
Inclusion Criteria ................................................................................................................... 26 
4.2 
Exclusion Criteria.................................................................................................................. 27 
5 
Patient Screening and Study Enrollment .................................................................................. 28 
5.1 
Consent and Study Screening in UMN OnCore .............................................................. 28 
5.2 
Study Enrollment and Treatment Assignment ................................................................. 29 
5.3 
Inability to Begin Study Treatment ..................................................................................... 29 
6 
Treatment Plan ............................................................................................................................. 29 
6.1 
Administration of HCW9218 ............................................................................................... 29 
6.1.1 
Provider’s Assessment Prior to Each HCW9218 and Dose Delay ........................... 30 

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6.1.2 
Pre Medication .................................................................................................................. 31 
6.1.3 
Patient Monitoring Day of HCW9218 Dosing ............................................................... 31 
6.1.4 
HCW9218 Dosing Delay and Discontinuation ............................................................. 32 
6.2 
HCW9218 Dose Finding Enrollment Plan ........................................................................ 32 
6.2.1 
STAGE 1 STEP 1 - Fast-track design (1 patient per dose level) .............................. 32 
6.2.2 
STAGE 1 STEP 2 - Expand Current and Future DLs to 3 Patients.......................... 33 
6.2.3 
STAGE 2 Continual Reassessment Method (CRM) ................................................... 33 
6.3 
Monitoring for Dose Limiting Toxicities and Excessive Toxicity .................................... 33 
6.4 
Supportive Care and Concomitant Medications .............................................................. 35 
6.5 
Prohibited Concomitant Therapy ....................................................................................... 35 
6.6 
Duration of Study Treatment .............................................................................................. 35 
6.7 
Follow-Up for Disease Response and Survival (Duration of Study Participation) ...... 36 
7 
HCW9218 Potential Toxicities and Management .................................................................... 37 
7.1 
Clinical Profile ....................................................................................................................... 37 
7.2 
Most Common and Most Serious Side Effects Seen In Drugs Similar To HCW921838 
8 
Schedule of Patient Activities ..................................................................................................... 39 
8.1 
Standard of Care Activities ................................................................................................. 41 
8.2 
Research Related Activities ................................................................................................ 43 
9 
HCW9218 Description, Supply and Potential Toxicities ......................................................... 46 
9.1 
Formulation ........................................................................................................................... 46 
9.2 
How Supplied ........................................................................................................................ 46 
9.3 
Study Site Storage and Stability ........................................................................................ 47 
9.4 
HCW9218 Preparation for Injection ................................................................................... 47 
9.5 
Agent Accountability and Reordering ................................................................................ 48 
9.6 
Possible Interactions with Other Drugs ............................................................................. 48 
9.7 
Potential Side Effects ........................................................................................................... 48 
10 
Event Monitoring, Documentation, and Reporting .................................................................. 48 
10.1 
Definitions .............................................................................................................................. 49 
10.2 
Event Monitoring and Documentation ............................................................................... 50 
10.2.1 
Exceptions to AE Documentation in OnCore ............................................................... 50 
10.2.2 
Targeted Toxicity Worksheet .......................................................................................... 51 
10.3 
Required Reporting: IRB, HCW Biologics and FDA ....................................................... 52 
11 
Study Data Collection and Monitoring ....................................................................................... 52 

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11.1 
Data Management ................................................................................................................ 52 
11.2 
Case Report Forms .............................................................................................................. 52 
11.3 
Data and Safety Monitoring Plan ....................................................................................... 53 
11.4 
Regular Team Meetings to Review Safety ....................................................................... 53 
11.5 
Record Retention.................................................................................................................. 54 
12 
Study Endpoints ........................................................................................................................... 54 
12.1 
Primary Endpoint .................................................................................................................. 54 
12.2 
Secondary Endpoints ........................................................................................................... 54 
13 
Statistical Considerations ............................................................................................................ 55 
13.1 
Study Design, Objectives and Endpoints ......................................................................... 55 
13.2 
Statistical Analysis................................................................................................................ 56 
13.3 
Sample Size .......................................................................................................................... 56 
13.4 
Monitoring Guidelines for Stage 2 (Early Study Stopping Rules) ................................. 57 
14 
Conduct of the Study ................................................................................................................... 57 
14.1 
Protocol Deviations .............................................................................................................. 57 
14.2 
Good Clinical Practice ......................................................................................................... 58 
14.3 
Ethical Considerations ......................................................................................................... 58 
14.4 
Informed Consent ................................................................................................................. 58 
15 
References .................................................................................................................................... 59 
Appendix I – ECOG Performance Status ............................................................................................. 64 
Appendix II – Expected Adverse Events for HCW9218 ..................................................................... 65 
Appendix III – Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference (CTEP) 
 
 ........................................................................................................................................................ 69 
Appendix IV – Targeted Toxicity Worksheet ........................................................................................ 73 
Appendix V – FACT-G Quality of Life Questionnaire ......................................................................... 74 
Appendix VI – Skin Condition Questionnaire ....................................................................................... 76 
 
 
 

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Key Abbreviations 
Acronym 
Definition 
ADCC 
antibody-dependent cellular cytotoxicity 
ADL 
activities of daily living 
AE 
adverse event 
AGC 
absolute granulocyte count 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ALT-803 
IL-15 Mutein/IL-15RαSu-Fc Complex 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATPP 
activated partial thromboplastin time 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
C2D1 
Cycle 2 Day 1 
CBC 
complete blood count 
CMP 
complete metabolic panel 
CNS 
central nervous system 
CR 
complete response 
CRF 
Code of Federal Regulations 
CRF/eCRF 
case report form / electronic case report form 
CRP 
C Reactive Protein 
CT 
CT Computed Tomography 
dL 
decaliter 
DL 
dose level 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSMP 
data and safety monitoring plan 
ECG 
electrocardiogram 
ELISA 
enzyme-linked immunosorbent assay 
FACT-G 
The Functional Assessment of Cancer Therapy - General 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume 
FFPE 
formalin-fixed, paraffin embedded 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GFR 
glomerular filtration rate 
GLP 
good laboratory practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HCW9228 
TGF-β Antagonist/IL-15-Null Protein Complex 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IFN 
interferon 
IL 
interleukin 
IL-15RαSu 
Soluble (Sushi) Domain of IL-15 Receptor α 
IP 
Investigational Product 

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Acronym 
Definition 
IRB 
Institutional Review Board 
IV or i.v. 
intravenous 
kg 
kilogram 
L 
liters 
mg 
milligram 
MI 
myocardial infraction 
Min 
minute 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK 
natural killer 
ORR 
objective response rate 
OS 
overall survival 
PBS 
phosphate buffered saline 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression free survival 
PFT 
pulmonary function test 
PK 
pharmacokinetic 
PR 
partial response 
PS 
performance status 
QOL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors Committee 
S/I 
Sponsor/Investigator 
SAE 
Serious Adverse Event 
SC, s.c. or SQ 
subcutaneous 
SD 
stable disease 
SOC 
standard of care 
SOP 
standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TGF 
transforming growth factor 
TIS 
therapy induced senescence 
TME 
tumor microenvironment 
TNF 
tumor necrosis factor 
TTP 
time to progression 
ULN 
upper limit of normal 
UMN 
University of Minnesota 
 
 

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Study Synopsis 
A Phase I Study of HCW9218, a Bifunctional TGF-β Antagonist/IL-15 Protein Complex, in Select 
Advanced Solid Tumors After Failing at Least Two Prior Therapies 
Study Overview: 
This is a single center, Phase I dose finding study of HCW9218 for the treatment of select 
advanced solid tumor cancers, including, but not limited to breast, ovarian, prostate and 
colorectal. Pancreatic cancer is excluded due to a competing HCW9218 protocol. Primary brain 
tumors are not eligible.  
HCW9218 is a novel bi-functional fusion protein complex administered by subcutaneous (SC) 
injection. It is comprised of a soluble fusion of two human TGFβRII domains, human tissue 
factor, and human IL-15, and a second soluble fusion of two human TGFβRII domains and a 
sushi domain of human IL-15Rα. HCW9218 activates IL-15R signaling on effector immune cells 
and the dimeric TGFβRII functions as a “trap” for all three human TGF-β isoforms. 
HCW9218 is administered by subcutaneous injection in the outpatient setting once every 3 
weeks for a minimum of two cycles unless medically contraindicated or the participant wishes to 
discontinue. Treatment may continue until disease progression, unacceptable toxicity, patient 
refusal, or treatment is felt to be no longer of benefit. Patients are followed for 1 year from the 1st 
dose of HCW9218 to determine progression free survival (PFS) and overall survival (OS). The 
primary analysis will be intent-to-treat from the point of 1st injection of HCW9218 both for toxicity 
and efficacy. 
Up to 5 dose levels of HCW9218 will be tested (including a safety (-1) level in the event of 
unexpected toxicity) to identify the maximum tolerated dose (MTD) with a small expansion cohort 
of the MTD or Dose Level 4 if no dose limiting toxicity is encountered.  
Investigational 
Product (IP): 
HCW9218 provided by HCW Biologics, Inc. 
Study Rationale: 
HCW9218 potently activates natural killer (NK) cells and CD8+ T cells in vitro and in vivo to 
promote their proliferative and metabolic activities and enhance their cytotoxicity against tumor 
targets. The fusion complex also exhibits TGF-β neutralizing activity in vitro and sequesters 
plasma TGF-β in vivo. It is hypothesized that HCW9218 may serve as a novel therapeutic to 
simultaneously provide immunostimulation and lessen immunosuppression associated with solid 
tumors. 
Primary Objective: 
The primary objective of this study is to determine the maximum tolerated dose (MTD) of 
HCW9218 as monotherapy in advanced solid tumor cancers except pancreatic cancer and 
primary brain tumors. 
Secondary 
Objectives: 
Secondary objectives are: 
 Determine safety and feasibility of repeat dosing of HCW9218 as outlined by incidence of 
adverse events (AEs) based on CTCAE v5. 
 Estimate response rate at 3 months, 6 months and 12 months, progression-free survival (PFS) 
and overall survival (OS) at 6 months and 1 year from 1st dose of HCW9218. 
Correlative 
Objectives: 
Correlative objectives include: 
 Characterize the immunogenicity and pharmacokinetic (PK) profiles of HCW9218  
 Evaluate lymphocyte number, phenotype and function  
 Flow cytometry analysis to include surface markers that define lymphocyte subsets (NK, 
NKT, B, and T cells, both CD4 and CD8), as well as intracellular markers that define 
regulatory T cells (Foxp3) and proliferating cells (Ki67) 
 Immunohistochemistry analysis and genomic, transcriptomic and proteomic molecular profiling 
on available tumor biopsies 
 Evaluate effect on quality of life using patient completed FACT-G and skin condition 
questionnaires 

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Treatment 
Overview: 
Upon signing of consent and confirmation of eligibility, the patient is assigned to the currently enrolling 
dose level of HCW9218.  
HCW9218 at the assigned dose level is administered as a subcutaneous injection once every 3 
weeks for a minimum of 2 treatment cycles unless medically contraindicated or participant wishes to 
discontinue. Patients may continue until disease progression, unacceptable toxicity (an AE meeting 
the definition of a DLT) or other reason detailed in Section 6.6.  
Dosing is initially calculated on the patient’s weight taken on Cycle 1 Day 1 or within 14 days prior to 
Cycle 1 Day 1. The dose is recalculated in subsequent cycles in the event of a weight change of 
±10% or greater. 
An End of Treatment (EOT) visit occurs approximately 3 weeks after the last dose of HCW9218; 
however refer to Section 6.6 for exceptions. The patient transitions to the study required follow-up for 
disease response (if discontinued treatment for a reason other than disease progression) and survival 
for 1 year from the 1st dose of HCW9218. 
Study Design: 
Dose Level  
(DL) Cohort 
HCW9218 
Dose (mg/kg) 
Enrollment Plan 
-1 
0.1 
Administer HCW9218 as monotherapy at assigned dose by SC injection 
once every 3 weeks.  
All patients are assessed for AEs and dose limiting toxicities (DLT). A 
minimum of 21 days must separate each dose cohort.  
Refer to enrollment plan below. 
1 (start) 
0.25 
2 
0.5 
3 
0.8 
4 
1.2 
 
Enrollment Plan: 
Dose limiting Toxicity (DLT) is defined in the Schema and Section 6.3.  
STAGE 1 STEP 1 Fast-track design (1 patient per dose level) 
Start at DL1, enroll 1 patient per DL separated by a minimum of 21 days (DLT period) until the:  
 1st pre-defined adverse event defined as any of the following treatment emergent Grade 2 
events lasting >72 hours within 5 days of 1st dose of HCW9218: fatigue, flu-like symptoms or 
injection site reaction  
  and the patient completes the 21 day DLT period with no DLT- Activate Stage 1 Step 2 
OR  
 1st DLT event within 21 days after the 1st dose of HCW9218 as defined in the Schema and in 
Section 6.3 - Activate Stage 2 (Stage 1 Step 2 is not used)  
OR 
 9 patients are treated at the DL4 (This completes enrollment - Stage 1 Step 2 and Stage 2 are 
not used) 
STAGE 1 STEP 2 Expand current DL and subsequent DLs to 3 patients 
The cohort size increases from 1 to 3 patients with 2 additional patients added to the current cohort. 
A minimum of 21 days must separate each dose cohort. Continue dose escalation until: 
 1st DLT event as defined in the Schema and Section 6.3 - Activate Stage 2 
OR 
 9 patients are treated at the DL4 (This completes enrollment and Stage 2 is not used.) 
STAGE 2 Continual Reassessment Method (CRM) 
The study design changes to an application of the continual reassessment method (CRM). Enrollment 
occurs in cohorts of 3. Within a 3 patient dose cohort, a minimum of 14 days must separate the 1st 
and 2nd patient with no staggering of enrollment required between and 2nd and 3rd patient. Once the 
3rd patient in a cohort reaches Day 21 (DLT period), a new cohort of 3 patients is sequentially 
assigned to the most appropriate dose by the study statistician based on the updated toxicity 
probabilities. The goal will be to identify one of the 4 dose levels corresponding to the desired 
maximum toxicity rate of ≤25%. The MTD will be identified by the minimum of the following criteria: (1) 
the total Stage 2 sample size of 24 is exhausted or (2) 9 consecutive patients are enrolled at the 
same dose. 
Key Inclusion 
Criteria: 
 Histologically or cytologically confirmed advanced/metastatic solid tumor cancer (except pancreatic 
and primary brain cancers), has failed at least 2 prior lines of therapy given either in the recurrent or 
metastatic setting and must be refractory to or intolerant of existing therapy(ies) known to provide 
clinical benefit for their condition. 

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 Measurable disease per RECIST v 1.1. 
 Acute effects of any prior therapy must have resolved to baseline or Grade ≤1 NCI CTCAE v5 
except for AEs not constituting a safety risk in the opinion of the enrolling Investigator. 
 Age 18 years or older at the time of consent.  
 ECOG Performance Status 0 or 1.  
 Evidence of adequate organ function within 14 days prior to treatment on Cycle 1 Day 1 as defined 
in Section 4.1.6. 
 Adequate pulmonary function with PFTs >50% FEV1 if symptomatic or known impairment. 
 Sexually active persons of child-bearing potential or persons with partners of childbearing potential 
must agree to use (or agree to their partners’ use of) a highly effective form of contraception (refer to 
Section 4.1.10 for acceptable methods) for at least 28 days after the last dose of HCW9218.  
 Provides voluntary written consent prior to the performance of any research related activity. 
Key Exclusion 
Criteria: 
 Pregnant or breastfeeding.  
 History of clinically significant vascular disease, including any of the following within 6 months prior 
to start of study treatment: MI or unstable angina, percutaneous coronary intervention, bypass 
grafting, ventricular arrhythmia requiring medication, stroke or transient ischemic attack, 
symptomatic peripheral arterial disease. 
 Marked baseline prolongation of QT/QTc interval (e.g., demonstration of a QTc interval greater or 
equal to 470 milliseconds by Fridericia correction). 
 Known or suspected untreated CNS metastases.   
 Anti-cancer treatment including surgery, radiotherapy, chemotherapy, other immunotherapy, or 
investigational therapy within 14 days before treatment start. 
 Other prior malignancy except for the following: adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the subject is 
currently in complete remission, or any other cancer from which the subject has been disease-free 
for 3 years after surgical treatment. 
 Known hypersensitivity or history of allergic reactions attributed to compounds of similar chemical or 
biologic composition to the agents used in the study. 
 Prior therapy with TGF-β antagonist, IL-15 or analogs. 
 Ongoing use of St. John’s Wort and/or other herbal CYP modulators as certain cytokines, including 
IL-2 and TGF-β, have been found to suppress the activities of cytochrome P450 enzymes. The 
participant may be considered for the study if they discontinued the herbal CYP modulator at least 7 
days before the 1st dose of HCW9218 and agree not resume it until after the EOT visit. 
 Known autoimmune disease requiring active treatment. Persons with a condition requiring systemic 
treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 14 days of enrollment, with the exception of use for persons 
with CT contrast allergies. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 
mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 
 Active systemic infection requiring parenteral antibiotic therapy. All prior systemic infections must 
have resolved following optimal therapy. 
 Prior organ allograft or allogeneic transplantation. 
 Known HIV-positive or AIDS. 
 Psychiatric illness/social situations that would limit compliance with study requirements. 
 Other illness or a medical issue that in the opinion of the Investigator would exclude the subject 
from participating in this study 
Enrollment Goal: 
A minimum of 12 patients or a maximum of 24 if DLT is encountered. 
Study Schema 
 
1 cycle = 3 weeks (21 days) with a 2-cycle minimum unless medically contraindicated. 

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Monitoring for Excessive Toxicity Stage 2 Only: A stopping rule is in place during this study to stop the trial in case 
there are excessive DLTs. At the end of the 21-day evaluation period after each cohort of 3 patients is enrolled, the study 
statistician calculates an updated posterior probability for each dose. The trial will be stopped if the posterior probability 
that the lowest dose is unacceptably toxic (> 25% of patients) is greater than 80%.  

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1 Objectives 
1.1 Primary Objective 
The primary objective of the dose finding component is to determine the maximum 
tolerated dose (MTD) of HCW9218 as monotherapy in advanced solid tumor cancers 
except pancreatic cancer and primary brain tumors. 
1.2 Secondary Objectives  
Secondary objectives of this protocol are: 
 Determine safety and feasibility of repeat dosing of HCW9218 as outlined by 
incidence of adverse events (AEs) based on CTCAE v5. 
 Estimate response rate (complete response (CR), partial response (PR) or stable 
disease (SD)) as a primary efficacy objective. 
 Estimate progression free survival (PFS) and overall survival (OS) at 6 months and 
1 year from 1st dose of HCW9218. 
1.3 Correlative Objectives 
Correlative objectives include: 
 Characterize the immunogenicity and pharmacokinetic (PK) profiles of HCW9218.  
 Evaluate lymphocyte number, phenotype, and function.  
 Flow cytometry analysis to include surface markers that define lymphocyte subsets 
(NK, NKT, B, and T cells, both CD4 and CD8), as well as intracellular markers that 
define regulatory T cells (Foxp3) and proliferating cells (Ki67). 
 Immunohistochemistry analysis and genomic, transcriptomic and proteomic 
molecular profiling on available tumor biopsies. 
 Evaluate effect on quality of life using patient completed FACT-G and skin 
condition questionnaires.   
2 Background and Rationale 
2.1 Advanced Solid Tumor Cancer Control after Failure of Initial Treatments 
The immunosuppressive tumor microenvironment limits the success of current 
immunotherapies. The response rates to immune based treatments in some solid 
tumors has revolutionized the way these cancers are treated. Unfortunately, in most 
recurrent solid tumors the response to immune based therapy remains inadequate. 
For example, a cross-sectional study found that the estimated percentage of US 
patients with cancer who are eligible for checkpoint inhibitor drugs increased from 
1.54% in 2011 to 43.63% in 2018 (Hasam 2019). The percentage of patients 
estimated to respond to checkpoint inhibitor drugs was 0.14% in 2011 and has 

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increased to 12.46% in 2018 meaning that the estimated percentages of patients who 
are eligible for and who respond to checkpoint inhibitor drugs remain modest. This 
data speaks to the critical need for novel immune based therapies in recurrent solid 
tumors.  
2.2 Investigational Product - HCW9218  
2.2.1 General Information on HCW9218 
HCW9218 is a soluble bifunctional protein complex comprised of dimeric 
extracellular domains of the human transforming growth factor beta (TGF-β) 
receptor II (2*TGFβRII) and human interleukin-15 (IL-15) in a complex with the 
sushi domain of human IL-15 receptor α (IL15RαSu). These domains are linked 
through a protein scaffold consisting of the truncated extracellular domain of 
human tissue factor (TF). HCW9218 is produced by recombinant DNA technology 
in Chinese Hamster Ovary (CHO) cell suspension culture (animal derived 
component free) and purified through a series of chromatography and viral 
removal/inactivation steps. Based on the amino acid sequence, HCW9218 has a 
calculated molecular weight of 108 kDa. Additionally, HCW9218 is a highly 
glycosylated protein complex (Liu et al, 2021). HCW9218 drug product is a sterile, 
preservative-free solution in single-use vials. Each 1 mL vial contains 20 mg of 
HCW9218 and is formulated in potassium phosphate monobasic (KH2PO4, 1.36 
mg), sodium phosphate dibasic anhydrous (Na2HPO4, 1.43 mg), and sodium 
chloride (NaCl, 8.18 mg), with a pH of 7.4.  
2.2.2 Summary of Nonclinical Clinical Findings  
Immunotherapeutics, either as immunostimulants or inhibitors of tumor-induced 
immunosuppression, are promising anti-neoplastic agents and have revolutionized 
cancer therapy (Robert, 2020; Waldman et al, 2020; Leonard et al, 2019). 
Additionally, combination approaches with these agents have been demonstrated 
to additively or synergistically enhance antitumor activities (Wrangle et al, 2018; 
Fujii et al, 2018). Bifunctional fusion protein approaches, which eliminate the need 
for complicated multiagent treatment regimens, are also gaining considerable 
interest (Lan et al, 2018). HCW9218 is a bifunctional protein complex that contains 
TGF-β antagonist (i.e., dimeric TGFβRII) activity and IL-15/IL-15RαSu 
immunostimulatory activity. The proposed mechanisms-of-action of HCW9218 are 
to 1) activate immune effector cells through binding of the IL-15 domain to cell-
expressed 
IL-15βγ 
receptors 
and 
2) 
sequester 
(or 
trap) 
soluble 
immunosuppressive TGF-β isoforms via binding to the dimeric TGFβRII domains 
(Liu et al, 2021). As detailed in the Investigator’s Brochure (IB), in vitro studies 
verified the binding and functional activities of the IL-15/IL-15RαSu and dimeric 
TGFβRII domains of HCW9218 using ELISA, surface plasmon resonance (SPR) 
and cell-based activity assays. Binding studies also revealed that HCW9218 

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interacts with both latent and active forms of TGF-β, which may represent an 
efficient pathway for HCW9218 to sequester TGF-β activity and to out compete 
membrane-associated receptors for TGF-β binding. In contrast to the activities of 
the IL-15/IL-15RαSu and dimeric TGFβRII domains, the TF scaffold of HCW9218 
had little or no procoagulant activity in prothrombin time (PT) assays with soluble 
or cell-bound HCW9218 (Liu et al, 2021), consistent with previous published 
reports with truncated TF (Martin et al, 1995). Studies also demonstrated that 
HCW9218 potently activates mouse and cynomolgus monkey natural killer (NK) 
cells and CD8+ T cells in vitro and in vivo to enhance cell proliferation, metabolism 
and antitumor cytotoxic activities. Similarly, human immune cells become activated 
with increased cytotoxicity (and antibody-dependent cellular cytotoxicity (ADCC)) 
against tumor cells following incubation with HCW9218. This fusion complex also 
exhibits TGF-β neutralizing activity in vitro and sequesters plasma TGF-β isoforms 
in mice and cynomolgus monkeys. Comparative studies with a dimeric TGFβRII 
fusion protein lacking IL-15 activity (HCW9228) indicated that both TGFβRII and 
IL-15 domains of HCW9218 act together to enhance stimulation of immune cells 
in vitro and in vitro (Liu et al, 2021). The antitumor efficacy and mechanism-of-
action of HCW9218 was evaluated in C57BL/6 mice with subcutaneous (s.c.) 
B16F10 melanoma tumors. Subcutaneous treatment of B16F10 tumor-bearing 
mice with HCW9218 alone was found to significantly reduce tumor growth and 
prolonged survival when compared to control treatment (Liu et al, 2021). Similar 
antitumor activity was observed in B16F10 tumor bearing mice treated with 
HCW9218 in combination with the anti-TYRP-1 antibody TA99 which specifically 
recognizes B16F10 tumor cells. Immune cell depletion studies in B16F10 tumor-
bearing mice indicated that both CD8+ T cells and NK cells play a role in 
HCW9218-mediated activity against melanoma tumors. These results are 
supported by studies showing that HCW9218 treatment promoted an increase in 
NK cell and CD8+ T cell infiltration into B16F10 tumors in vivo (Liu et al, 2021). A 
series of mouse tumor efficacy studies were conducted to evaluate the effects of 
HCW9218 in combination with chemotherapy and antibody-based therapy, 
specifically assessing activity against tumor and normal tissue cells that become 
senescent following chemotherapy (Chaturvedi et al, 2020). Initial in vitro and in 
vivo studies demonstrated the murine B16F10 melanoma cells and human 
SW1990 pancreatic tumor cells could be induced to enter senescence and secrete 
pro-inflammatory factors, termed the senescence associated secretory phenotype 
(SASP), in response to docetaxel (DTX) and gemcitabine plus nab-paclitaxel 
(G+A) chemotherapy, respectively. These therapy-induced senescent (TIS) tumor 
cells could re-enter the cell cycle with greatly enhanced invasiveness and 
stemness characteristics and were susceptible to HCW9218-activated NK cell 
cytotoxicity. HCW9218 treatment (alone or in combination with TA99 antibody) 

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enhanced the antitumor activity of DTX in B16F10 tumor-bearing C57BL/6 mice 
and eliminated TIS cells in the tumors and normal tissues. Immune cell depletion 
and tumor infiltration studies showed that both NK and CD8+ T cells play a role in 
HCW9218+TA99-mediated effects on tumor growth with NK cells predominately 
acting to eliminate the TIS tumor cells. HCW9218-mediated immune cell infiltration 
into DTX treated B16F10 tumors, reduced the immunosuppression of the tumor 
microenvironment (TME), and enhanced the efficacy of anti-PD-L1 therapy. These 
findings collectively suggest that combination of HCW9218 with chemotherapy, 
tumor-targeted antibody, and immune checkpoint blockade therapies could 
promoted increased immune activity in the TME leading to effective tumor control 
while reducing TIS-mediated adverse effects on normal tissues. Further studies 
demonstrated that treatment of B6.Cg-Prkdcscid/SzJ mice (B6 SCID mice) bearing 
subcutaneous SW1990 human pancreatic tumors with HCW9218 alone and in 
combination with gemcitabine and nab-paclitaxel (G+A) chemotherapy resulted in 
reduced tumor burden and, in the case of the combination therapy, prolonged 
survival when compared to control treatment and chemotherapy alone. Thus, 
HCW9218 has potential as immunotherapy in combination with chemotherapy for 
treatment of pancreatic cancer. In vitro dose-response studies with human, 
cynomolgus monkey and murine immune cells indicated that HCW9218 induced 
similar levels of cell activation, proliferation and cytokine release for human and 
cynomolgus monkey cells. HCW9218 mediated responses in immune cells from 
C57BL/6 mice were also observed but at >2-fold higher EC50 values than human 
immune cells. However, HCW9218 did not induce a broad-based cytokine release 
or “cytokine storm” by human, cynomolgus monkey or murine immune cells. This 
activity is associated with severe pro-inflammatory responses observed with 
certain other immunotherapies. Together, the results of these studies support the 
use of C57BL/6 mice and cynomolgus monkeys as relevant animal models to 
evaluate the toxicity, pharmacodynamic and PK profiles of HCW9218. An initial 
non-GLP pilot dose-finding toxicity study was conducted in C57BL/6 mice treated 
with HCW9218 as a single (at 3, 10, 50, 100, 200, and 400 mg/kg) or two (at 3, 10, 
50, and 200 mg/kg, separated by 2 weeks) s.c. doses. Mice receiving a single dose 
of HCW9218 at 200 and 400 mg/kg exhibited body weight loss beginning 3 days 
after the injection (study day (SD) 0) and reaching a nadir on SD7 before returning 
to pre-dose levels by SD11 post treatment. Mortality was observed at SD10 in one 
of 3 mice receiving 200 mg/kg HCW9218. There were no apparent treatment-
mediated effects on body weight or other clinical signs in any other dose group or 
in mice receiving a second dose at up to 200 mg/kg two weeks after the first dose. 
Compared to the PBS group, mice receiving 200 mg/kg HCW9218 exhibited a 25-
fold increase in WBC counts at SD7 post treatment, which remained 5-fold higher 
7 days after the second 200 mg/kg HCW9218 dose (SD21). WBC subset analysis 

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revealed a 16-fold increase in absolute lymphocyte counts and >50-fold increases 
in neutrophil, monocyte, eosinophil, and basophil counts at SD7 in the 200 mg/kg 
HCW9218 group. These changes were not observed at lower HCW9218 dose 
levels but were expected as they were similar to those reported for C57BL/6 mice 
treated subcutaneously with IL-15/IL15Rα complexes (Liu et al, 2018). HCW9218-
mediated effects were greatest 7 days after the first dose and were reduced after 
the second dose, consistent with previous studies showing decreased immune 
responses in mice following repeat dosing with IL-15/IL15Rα (Frutoso et al, 2018; 
Elpek et al, 2010). Based on the lack of test article-related changes on body weight, 
clinical signs, hematology with complete blood count, and plasma chemistry, one 
and two s.c. doses of HCW9218 at up to 50 mg/kg were well tolerated by C57BL/6 
mice. This dose range is significantly higher than the HCW9218 dose level (3 
mg/kg) shown to be immunostimulatory and efficacious in normal and tumor-
bearing mice, respectively. Thus, the dose range of repeated s.c. HCW9218 
administration between 3 and 100 mg/kg was selected for evaluation in a GLP 
toxicity study in C57BL/6 mice. In a follow-up GLP toxicity study in C57BL/6 mice, 
s.c. administration of HCW9218 at 5, 25, and 100 mg/kg in two doses on Day 1 
and Day 15 was well tolerated. No early termination/mortality in any animal was 
noted. Additionally, no test article related changes were noted in clinical signs; 
injection 
site 
observations; 
ophthalmology; 
clinical 
pathology 
including 
hematology, coagulation parameters, clinical chemistry and urinalysis; and 
pathology including organ weights and coefficients and macroscopic and 
microscopic examinations. The only test article related effects were transient 
decreases in body weight and food consumption for the 100 mg/kg group during 
the first week of the dosing period. Therefore, the NOAEL (No Observed Adverse 
Effect Level) in this study was considered to be 100 mg/kg. Toxicokinetic (TK) 
analysis of C57BL/6 mice receiving a single s.c. dose of 25 mg/kg HCW9218 
demonstrated a maximal serum concentration (Cmax) in males and females of 
5.97 µg/mL (55 nM) and 5.63 µg/mL (52 nM) post treatment, respectively. The time 
to Cmax (Tmax) was 8 h for males and 16 h for females. Assuming a 50 mL/kg 
serum volume in mice (Davies and Morris, 1993), the average Cmax represents a 
serum recovery of about 1.2% for the subcutaneously administered 25 mg/kg 
HCW9218 dose. The terminal half-life (t1/2) of s.c. HCW9218 in mice averaged 
about 15 hours, the area under the concentration-time curve extrapolated to infinity 
(AUC0-∞) was approximately 230 h*µg/mL, the apparent clearance (Cl) was about 
109 mL/h/kg and the volume of distribution (Vz) averaged about 2,350 mL/kg. No 
obvious gender differences in the TK parameters of HCW9218 were noted. In a 
GLP toxicology study in cynomolgus monkeys, s.c. administration of HCW9218 at 
1, 3, and 10 mg/kg in two doses on Day 1 and Day 15 was tolerated. One male 
monkey treated with two doses of HCW9218 at 3 mg/kg was found dead on Day 

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19, mainly due to lung inflammation that was not noted for other study animals. 
Therefore, this death may not be test article related. There were no test article 
related changes in clinical signs, body weight, ophthalmology, ECG, blood 
pressure, or gross pathology. Test article related non-adverse changes included 
transient decreases in food consumption, decreases in erythroid cell, neutrophil 
and eosinophil parameters, albumin and albumin/globin ratio, increases in 
basophil, monocyte, and lymphocyte parameters and weights of spleen, 
spleen/body weight ratio and spleen/brain ratio, and fluctuations of platelet, 
reticulocyte and cytokine parameters. Dose-dependent related increases of MCP-
1 and decreases of TGFβ1 and TGFβ2 in the serum were observed, which may 
relate to pharmacodynamics of the test article. Immunophenotyping indicated that 
HCW9218 induced dose-dependent increases in the percentage of Ki67 positive 
cells and absolute cell numbers of CD4, CD8, Treg and CD16+ NK cells. Clinical 
pathological and organ weight changes may be related to inflammatory cell 
infiltration in adrenal gland, heart, kidney, liver, dosing site, and increased 
cellularity in the red pulp of the spleen and decreased lymphocytes in the cortex of 
the thymus. Due to the tendency of these changes to recover and the expected 
immunostimulatory mechanism-of-action of the test article, these changes were 
not considered to be adverse. Therefore, the NOAEL in this study was considered 
to be 10 mg/kg. Companion TK analysis of the cynomolgus monkey toxicology 
study showed an average Cmax after the first dose of 0.19 µg/mL (Tmax 20 h), 
1.2 µg/mL (Tmax 30 h), and 3.4 µg/mL (Tmax 24 h) for 1, 3, and 10 mg/kg 
HCW9218, respectively. The average Cmax after the second dose was 0.24 µg/mL 
(Tmax 8 h), 1.8 µg/mL (Tmax 8 h), and 3.2 µg/mL at (Tmax 8 h) for 1, 3, and 10 
mg/kg HCW9218, respectively. Similar to the results reported in mice, the 
averaged Cmax values after the first dose represent maximum serum recoveries 
of 0.7%, 1.5%, and 1.1% for subcutaneously administered doses of 1, 3 and 10 
mg/kg, respectively, assuming a 36 mL/kg serum volume in cynomolgus monkeys 
(Ageyama et al, 2001). The average t1/2 values after the first dose of 1, 3, and 10 
mg/kg s.c. HCW9218 were 21, 11.5, and 11.5 h, respectively. The results confirm 
that exposures to HCW9218 increased in a dose-dependent manner and that no 
apparent gender differences in the TK parameters of HCW9218 were observed. 
Additionally, there was no apparent accumulation of HCW9218 with repeated 
dosing every 14 days. While the serum Cmax levels were low, the findings were 
consistent with the results reported in nonclinical monkey studies and clinical trials 
of other IL-15 and IL-15/IL-15Rα product candidates where the Cmax observed for 
s.c. administration was ~200-fold less than that for the intravenous (i.v.) route and 
s.c. bioavailability (based on AUC0-t) was ~3% (Margolin et al, 2018; Romee et al, 
2018; Sneller et al, 2011). In these early phase clinical trials, s.c. administration 
was found to be advantageous in reducing i.v. IL-15-related constitutional adverse 

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events while maintaining immunostimulatory activity (Margolin et al, 2018; Romee 
et al, 2018).  
2.2.3 Summary of Clinical Findings  
HCW9128 has not yet been evaluated in human clinical studies. The published 
adverse event (AE) profiles of related immunotherapeutics, including recombinant 
IL-2, recombinant human IL-15 (rhIL-15), IL-15 mutein/IL-15RαSu-Fc complex 
(ALT-803, nogapendekin alfa inbakicept), TGFβRII-Fc fusion (AVID200), 
TGFβRII-anti-PD-L1 IgG1 fusion (M7824, bintrafusp alfa) and anti-TGF-β antibody 
(fresolimumab), are provided in Appendix II. These agents contain protein domains 
that are similar in structure and/or mechanism-of-action as those of HCW9218. 
See additional information in the IB.  
2.3 
Study Rationale  
2.3.1 TGF-β and Cancer 
TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent 
manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-
β pathway enhances cell proliferation, migratory invasion, metastatic spread within 
the tumor microenvironment and suppresses immunosurveillance (Moses 2016, 
Massague 2008). Collectively, the pleiotropic nature of TGF-β signaling 
contributes to drug resistance, tumor escape and undermines clinical response to 
therapy. Activation of the TGF-β signaling pathway can elicit either tumor-
suppressing or tumor-promoting effects in a cell- and context-dependent manner. 
In normal tissues, these effects maintain homeostasis and prevent the early stages 
of tumor formation (Smith 2012). In cancer cells, the TGF-β signaling pathway is 
deregulated or mutated, and TGF-β no longer controls proliferation. As a result of 
mutations or epigenetic modifications introduced during cancer progression, 
tumors can become resistant to the suppressive effects of TGF-β signaling 
(Ikushima and Miyazono 2010). Based on current human TCGA datasets, 
esophageal, gastric colorectal (CRC), and pancreatic (PDA) adenocarcinomas 
contain mutations or deletions in TGF-β receptor genes in 25%–50% of cases. 
Head and neck, bladder, and endometrial adenocarcinomas and cervical and lung 
squamous carcinomas harbor such mutations in 10%–20% of cases.  
TGF-β has been shown to play a major role in promoting immunosuppressive 
responses and fibrosis in the TME as well as inducing epithelial–mesenchymal 
transition (EMT) of tumor cells, which facilitates their migratory and invasive 
capabilities (Ciardiello et al, 2020; Principe et al, 2016). As a result, elevated serum 
TGF-β levels have been shown to correlate with a poor prognosis in patients with 
solid tumors (Huang and Blobe 2016). Early phase clinical studies have provided 
evidence that strategies to decrease TGF-β levels or signaling can provide clinical 
benefit, including objective responses and prolonged survival, in certain patients 

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with advanced/metastatic cancer (Lind et al, 2020; Melisi et al, 2018). Recently, 
several approaches have also been proposed to combine TGF-β antagonists with 
immunostimulatory agents, such as cytokines or immune checkpoint inhibitors, to 
improve infiltration and activation of effector CD8+ T cells and NK cells in the TME 
(Lind et al, 2020; Ganesh and Massague, 2018; Ng et al, 2016; Alvarez et al, 
2014). Additionally, studies in mouse tumor models support evaluation of 
combination therapies including chemotherapy to enhance antigen presentation 
by tumors, TGF-β antagonists to reduce TME immunosuppression, and 
immunostimulatory agents to augment antitumor T cells responses (Principe et al, 
2020).  
2.3.2 Rational for HCW9218-based Immunotherapy  
As described above, the tumor microenvironment of solid tumor cancer patients is 
immunosuppressive and resistant to chemotherapy due to a variety of 
mechanisms (Bazzichetto et al, 2020; Binnewies et al, 2018). HCW9218 has been 
designed to overcome immunosuppression in the immunosuppressive effects of 
the TME by 1) activating and promoting tumor infiltration of immune effector cells 
through binding of the IL-15 domain to cell-expressed IL-15βγ receptors and 2) 
sequestering soluble immunosuppressive TGF-β isoforms via binding to the 
dimeric TGFβRII domains. As a result, HCW9218 is expected to promote antitumor 
immune responses in solid tumor cancer patients.  
2.3.3 Rationale for the Starting Dose and Dose Range of HCW9218 in 
Humans 
Since HCW9218 comprises immunostimulatory agonist (IL-15/IL-15RαSu domain) 
and TGF-β antagonist (dimeric TGFβRII domain) components, the activities of 
both of these components as well as the extracellular TF scaffold domain were 
evaluated in nonclinical studies to determine the safe starting dose and dose range 
for subcutaneously administered HCW9218 in the first-in-human clinical study in 
persons with advanced/metastatic malignancies. In calculating the safe starting 
dose for an immune activating product in patients with advanced pancreatic 
cancer, the minimum anticipated biological effect level (MABEL) approach, 
including considerations of receptor and ligand occupancy, the biological activity 
of HCW9218 in vitro and in vivo, and the toxicity and pharmacokinetic profiles of 
HCW9218 in relevant animal models, was used (Saber et al, 2016), and findings 
compared to starting and recommended phase 2 dose (RP2D) levels of other 
clinical-stage immunotherapeutics comprising IL-15/IL-15RαSu and TGFβRII 
domains. Details of this analysis are provided in the IB. Based on these 
considerations, a s.c. dose of 0.25 mg/kg HCW9218 is expected to be a safe 
starting dose for patients with advanced solid tumors. This dose is expected to 
have immunostimulatory activity without causing significant adverse events. The 

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plan is for every 3-week dosing based on ease of administration of HCW9218 in 
combination with other therapies which are most commonly administered on an 
every 3-week basis. De-escalation to 0.1 mg/kg will be carried out if excessive 
toxicity is observed per Section 6.2.1. HCW9218 will be evaluated in planned dose 
escalation to 1.2 mg/kg. The tolerability of HCW9218 in patients will be closely 
monitored and its dose-dependent stimulatory effects on patients’ immune system 
will be evaluated based on correlative studies, as described in this protocol.  
2.3.4 Rationale that HCW9218 Plays a Role in Therapy Induced Senescence 
(TIS) 
Senescence is a tumor suppressor mechanism that is activated in response to 
stress and results in cell cycle arrest and leads to a secretory phenotype that is 
pro-inflammatory and tissue damaging (Zhu 2015). The accumulation of senescent 
cells is considered a hallmark of aging and thought to contribute to the aging 
pathologies. Senolytics are able to delay or attenuate age-related diseases (Baker 
2015). TGF-β exerts potent growth inhibitory activities in various cell types, and 
multiple growth regulatory mechanisms have reportedly been linked to the 
phenotypes of cellular senescence and stem cell aging in previous studies. There 
is increasing evidence that there is a multifaceted association between TGF-β 
signaling and aging-associated disorders, including Alzheimer’s disease, muscle 
atrophy, and obesity. TGF-β reportedly induces reactive oxygen species in the 
mitochondria in several cell types including hepatocytes and lung epithelial cells 
(Albright 2003, Yoon 2005). In addition, TGF-β suppresses telomerase activities 
by downregulating the expression of telomerase reverse transcriptase (TERT) in 
various cell types including rat fibroblasts and human breast cancer cells (Hu 2006, 
Li 2006). A recent report showed that TGF-β signaling can compromise DNA 
damage repair and promote senescence. This pathway contributed to cardiac 
aging in vivo, and the inhibition of TGF-β signaling restored H4K20me3 (an 
epigenetic modification to the DNA packaging protein Histone H4) and improved 
cardiac function in older mice (Lyu 2018). TGF-β induces the expression of 
inhibitory Smads (I-Smads), Smad6 and Smad7, thus incorporating negative 
feedback mechanisms. In bronchial epithelial cells, TGF-β causes senescence by 
inducing p21 (Minagawa 2011). Immune cells appear to senesce with age and are 
characterized by increased levels of p16INK4a (CDKN2A) and p21CIP1 
(CDKN1A) and a senescence-associated secretory phenotype (SASP).  A recent 
study showed that immunosenescence is a phenomenon that is characterized by 
attrition and senescence of immune cells in mice subjected to increased 
endogenous DNA damage. Markers of senescence (p16 and p21) were 
significantly increased in the DNA repair protein knock out (Ercc1) mice in the 
following immune cells: B cells (B220+ CD19+), T cells (CD3+), natural killer cells 
(CD3− NK1.1+) and macrophages (CD11b+ F4/80+) compared to the wild-type mice 

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(Yousefrzadeh, et al. 2021). Inhibiting senescence in the immune compartment 
may have a profound effect on the cytotoxic functions of both innate and adaptive 
immune cells. We propose to examine markers of senescence on immune cells 
obtained from blood throughout the proposed trial. We hypothesize that  
HCW9218 will act as a senolytic by “trapping” excess TGF-β, therefore inhibiting 
its ability to promote senescence.  We believe that this combined with the immune 
activating effect of IL-15 will be a biologically relevant therapeutic with potential to 
at least partially reverse therapy induced senescence (TIS) or in the future, 
perhaps have an effect even on physiologic aging. 
3 Study Plan 
This is a single center Phase I dose finding study of HCW9218 for the treatment of select 
advanced solid tumor cancers, including, but not limited to breast, ovarian, prostate and 
colorectal. Pancreatic cancer is excluded due to a competing HCW9218 protocol. Primary 
brain tumors are not eligible.  
HCW9218 is a novel bi-functional fusion protein complex administered by subcutaneous 
(SC) injection. It is comprised of a soluble fusion of two human TGFβRII domains, human 
tissue factor, and human IL-15, and a second soluble fusion of two human TGFβRII 
domains and a sushi domain of human IL-15Rα. HCW9218 activates IL-15R signaling on 
effector immune cells and the dimeric TGFβRII functions as a “trap” for all three human 
TGF-β isoforms. 
HCW9218 is administered by subcutaneous injection in the outpatient setting once every 
3 weeks for a minimum of two cycles unless medically contraindicated or the participant 
wishes to discontinue treatment as detailed in Section 6.6. Treatment may continue until 
disease progression, unacceptable toxicity, patient refusal, or treatment is felt to be no 
longer of benefit. Patients are followed for 12 months from the 1st dose of HCW9218 to 
determine progression free survival (PFS) and overall survival (OS). 
Dose 
Level (DL) 
Cohort 
HCW9218 
Dose 
(mg/kg) 
Enrollment Plan 
-1 
0.1 
Administer HCW9218 as monotherapy at assigned dose by 
SC injection once every 3 weeks.  
All patients are assessed for AEs and dose limiting toxicities 
(DLT). A minimum of 21 days must separate each dose 
cohort. Within a 3 patient dose cohort, a minimum of 14 days 
must separate the 1st and 2nd patient. 
1 (start) 
0.25 
2 
0.5 
3 
0.8 
4 
1.2 
 
The maximum sample size will be 24 patients.   

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4 Patient Selection 
Study entry is open to those 18 years of age and older regardless of gender, race, or 
ethnic background. While there will be every effort to seek out and include minority 
patients, the patient population is expected to be no different than that of other advanced 
solid tumor studies at the University of Minnesota. 
A potential participant must meet all of the inclusion and none of the exclusion criteria to 
be considered eligible for study participation. 
4.1 Inclusion Criteria 
4.1.1 Any histologically or cytologically confirmed advanced/metastatic solid 
tumor cancer (except pancreatic cancer and primary brain tumor), that has 
failed at least 2 prior lines of therapy given either in the recurrent or 
metastatic setting and must be refractory to or intolerant of existing 
therapy(ies) known to provide clinical benefit for their condition. 
4.1.2 Measurable disease per RECIST v 1.1. A single target lesion is considered 
measurable disease provided the lesion meets the definition of 
measurability as described in RECIST 1.1 (Schwartz 2016). If a target lesion 
has been surgically removed or treated with radiotherapy, it is not evaluable 
for response. Although not a requirement for eligibility, patients with tumor 
assessable may be asked if willing to undergo an optional research related 
biopsy prior to treatment start and prior to the 3rd treatment course – 
interested participants would provide consent through a separate optional 
biopsy consent form. Note: If a biopsy is obtained prior to treatment start 
(any time after consent) and a patient is later deemed ineligible to receive 
treatment, the tumor sample will not be used for research purposes.  
4.1.3 Resolved acute effects of any prior therapy to baseline or Grade ≤1 NCI 
CTCAE v5 except for AEs not constituting a safety risk in the opinion of the 
enrolling Investigator. 
4.1.4 Age 18 years or older at the time of consent. 
4.1.5 ECOG Performance Status 0 or 1. (Refer to Appendix I). 
4.1.6 Evidence of adequate organ function within 14 days prior to treatment on 
Cycle 1 Day 1 defined as: 
 hemoglobin ≥9 g/dL (may be transfused not more than 2 units of pRBCs 
within previous 2 week to meet this requirement)  
 absolute neutrophil count (ANC) ≥1500/ul 
 platelets ≥100 x 10^9/L (may be transfused not more than 1 unit of 
platelets within previous 2 week to meet this requirement) 
 estimated glomerular filtration rate (eGFR) >40 mL/min or creatinine: 
≤1.5 x upper limit of institutional normal (ULN)  
 ALT, AST and ALP ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases  

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4.1.7 Adequate pulmonary function with PFTs >50% FEV1 if symptomatic or 
known impairment. 
4.1.8 Sexually active persons of child-bearing potential or persons with partners 
of childbearing potential must agree to use (or agree to their partners’ use 
of) a highly effective form of contraception for at least 28 days after the last 
dose of HCW9218. Non-childbearing is defined as >1 year post-
menopausal or surgically sterilized.  
Examples of highly effective birth control methods include but are not limited 
to the following:  
 Using twice the normal protection of birth control (i.e., double-barrier) by 
using a condom AND spermicidal jelly or foam, or a diaphragm AND 
spermicidal jelly or foam. A spermicidal jelly or foam must be used in 
addition to a barrier method (e.g., condom or diaphragm).  
 Oral contraceptive pills  
 Depot or injectable birth control  
 Intrauterine Device (IUD)  
 Transdermal contraceptive patch  
 Vaginal contraceptive ring 
 Contraceptive implants 
Note: Rhythm method or abstinence alone is not considered to be an 
adequate method of contraception. 
4.1.9 Provides voluntary written consent prior to the performance of any research 
related activity. 
4.2 Exclusion Criteria 
4.2.1 Pregnant or breastfeeding. Persons of child-bearing potential must have a 
negative pregnancy test (serum or urine) within 14 days of treatment start. 
4.2.2 History of clinically significant vascular disease, including any of the 
following within 6 months prior to start of study treatment: MI or unstable 
angina, percutaneous coronary intervention, bypass grafting, ventricular 
arrhythmia requiring medication, stroke or transient ischemic attack, 
symptomatic peripheral arterial disease.  
4.2.3 Marked baseline prolongation of QT/QTc interval (e.g., demonstration of a 
QTc interval ≥470 milliseconds by Fridericia correction). If undiagnosed 
MI(s) appear on ECG, work up as medically warranted and determine 
eligibility based on findings. Cardiac function should be monitored by clinical 
examination and assessment of vital signs for hypotension, arrhythmia, 
angina, and myocardial infarction during the study period per Section 6.1.1.  
4.2.4 Known or suspected untreated CNS metastases are excluded. Persons are 
eligible if CNS metastases are treated and they are neurologically stable for 
at least 2 weeks prior to enrollment. In addition, must be either off 

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corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent).    
4.2.5 Anti-cancer treatment including surgery, radiotherapy, chemotherapy, other 
immunotherapy, or investigational therapy within 14 days before treatment 
start. 
4.2.6 Prior malignancy except for the following: adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, adequately treated Stage 
I or II cancer currently in complete remission, or any other cancer from which 
the patient has been disease-free for 3 years after surgical treatment. 
4.2.7 Known hypersensitivity or history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to the agents used 
in the study. 
4.2.8 Prior therapy with TGF-β antagonist, IL-15 or analogs. 
4.2.9 Ongoing use of St. John’s Wort and/or other herbal CYP modulators as 
certain cytokines, including IL-2 and TGF-β, have been found to suppress 
the activities of cytochrome P450 enzymes. The participant may be 
considered for the study if they discontinued the herbal CYP modulator at 
least 7 days before the 1st dose of HCW9218 and agree not resume it until 
after the End of Treatment visit. 
4.2.10 Known autoimmune disease requiring active treatment. Persons with a 
condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications 
within 14 days of enrollment, with the exception of use for persons with CT 
contrast allergies. Inhaled or topical steroids, and adrenal replacement 
steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the 
absence of active autoimmune disease. 
4.2.11 Active systemic infection requiring parenteral antibiotic therapy. All prior 
systemic infections must have resolved following optimal therapy. 
4.2.12 Prior organ allograft or allogeneic transplantation. 
4.2.13 Known HIV-positive or AIDS. 
4.2.14 Psychiatric illness/social situations that would limit compliance with study 
requirements. 
4.2.15 Other illness or a medical issue that in the opinion of the Investigator would 
exclude the subject from participating in this study.  
5 Patient Screening and Study Enrollment 
Written consent must be obtained prior to the performance of any research related 
tests or procedures.  
5.1 Consent and Study Screening in UMN OnCore  

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Any patient who has been consented is to be entered in OnCore by the Study 
Coordinator or designee. If a patient is consented but is not enrolled in the study 
treatment, the patient’s record is updated in OnCore as a screen failure and reason 
for exclusion recorded.  
5.2 Study Enrollment and Treatment Assignment 
To be eligible for this study, the patient must sign the treatment consent and meet 
each inclusion criteria and none of the exclusion criteria listed on the eligibility 
checklist based on the eligibility assessment documented in the patient’s medical 
record.  
If a patient is not starting study treatment within 14 days of baseline eligibility lab 
work, the blood work in Section 4.1.6 must be repeated within 14 days prior to 
treatment on Cycle 1 Day 1 to confirm continuing eligibility. If one or more of the 
lab results do not meet the criteria the patient is taken off study per Section 5.3. 
The Study Coordinator or designee updates OnCore with the assigned HCW9218 
dose level to complete study enrollment. 
5.3 Inability to Begin Study Treatment 
If a patient is enrolled to the study and is later found not able to begin study 
treatment, for whatever reason, the patient will be taken off study and treated at 
the physician’s discretion. The Study Coordinator or designee will update OnCore 
of the patient’s non-treatment status. The patient will be replaced to fulfill 
enrollment requirements and will not be included in the outcome analysis.  
6 Treatment Plan 
6.1 Administration of HCW9218 
HCW9218 is given as a subcutaneous (SC) injection at the patient assigned dose 
once every 3 weeks until disease progression, unacceptable toxicity or 
continuation of treatment is longer of benefit. 
HCW9218 dose calculation is based on patient’s assigned dose level and actual 
body weight recorded at Cycle 1 Day 1 (or within 14 days prior).  
This dose is used for the duration of the study treatment unless there is a ±10% or 
greater change on a subsequent cycle’s “Day 1” weight from the weight used to 
calculate the Cycle 1 Day 1 dose. In this situation, the HCW9218 dose is 
recalculated using the more recent weight. The new dose is used for subsequent 
HCW9218 injections, unless a ≥10% weight change occurs based on the newer 
weight. Depending on the following:  

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 The 10% weight change is because their weight returned to around their 
Cycle 1 Day 1 weight – dose may be recalculated and the patient continue 
HCW9218 
 The 10% weight change represents a ≥20% weight change from the Cycle 
1 Day 1 (representing a Grade 3 weight change based on CTCAE v 5) 
meeting the criteria for discontinuing treatment per Section 6.6. 
If the total subcutaneous (SC) dose is greater than 1.5 mL, the dose will be divided 
by IDS into 2-3 SC injections as needed. Injections are given in the abdominal 
area. The injection site should be rotated per institutional guidelines and each 
injection site separated by at least 1 inch. 
HCW9218 can be administered on an outpatient basis, or if the patient is in the 
hospital for another reason, as inpatient treatment.  
6.1.1 Provider’s Assessment Prior to Each HCW9218 and Dose Delay 
In order to proceed with a planned HCW9218 injection, a provider must 
assess the patient prior to each HCW9218 dose to rule-out any of the 
following contraindications for dosing: 
 the previous injection site reaction is not showing signs of resolving 
(improving) based on measurement or intensity 
 signs or symptoms of a new infection 
 fever > 101°F (38.3 °C) 
 cardiac function by clinical exam and assessment of vitals for signs 
hypotension, arrhythmia, angina and myocardial infarction or symptoms 
of chest pain, murmurs, gallops, irregular rhythm, or palpitations with 
further assessment as clinically indicated. 
The HCW9218 dose will be delayed for up to 1 week if one or more of the 
above conditions are present. 
 
In addition, HCW9218 may be delayed for up to 1 week on the day of a 
planned dose for either of the following situations: 
 Any ongoing treatment related toxicity.  
 If in the opinion of the treating physician, holding HCW9218 would be of 
benefit to the patient.   
 
If after a 1 week rest: 
 The patient meets the above criteria for treatment, the patient may 
receive HCW9218. The patient calendar would be adjusted (reset) and 
the patient returns in 3 weeks for the next course of treatment. 

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 The patient does not meet the above criteria for treatment or the 
Investigator feels holding treatment would be of benefit to the patient, 
the dosing may be skipped. The patient would return for reassessment 
at the time of next planned dose (i.e. in 3 weeks). A decision is made at 
that time whether to treat or discontinue HCW9218 permanently. If Cycle 
2 cannot be given (is skipped) due to treatment related toxicity, a DLT 
event must be reported.   
Refer to Section 6.3 for additional information regarding DLTs. 
6.1.2 Pre Medication  
Use of pre-medications is at the discretion of the treating physician on an 
individual patient basis. Acetaminophen may be given prior to the injection 
to reduce the intensity of the fever that often occurs a few hours later. 
The HCW9218 intervention guidelines described below may be 
implemented or modified by the Investigator as medically necessary or as 
appropriate without requiring a protocol amendment or being considered a 
protocol deviation.  
HCW9218 Intervention Guidelines  
Condition 
Agents 
Dose  
Route 
When 
Fever/Chills 
Antipyretic* 
 
 
 
Acetaminophen 
up to 650 mg; or 
10 to 15 mg/kg 
recipient weight 
Orally 
Prior to each dose & repeat 4 hours after dosing 
prn.  
Repeat every 4-6 hours if fever present. 
Ibuprofen 
up to 400 mg; or 
10 mg/kg 
recipient weight 
Orally 
Prior to each dose & repeat 4 hours after dosing 
prn.  
Repeat every 4-6 hours if fever present 
Naproxen 
up to 440 mg 
Orally 
Prior to each dose & repeat 8 hours after dosing 
prn.  
Repeat every 8-12 hours if fever present. 
*Antipyretic medication including acetaminophen, ibuprofen, or naproxen may be given per physician 
discretion following the recommended dosing thresholds:  
Acetaminophen: not to exceed 3000 mg (3 grams) in 24 hours  
Ibuprofen: not to exceed 2400 mg in 24 hours  
Naproxen: not to exceed 1100 mg in 24 hours 
 
H1 and H2 blockers may be given prior to administration of HCW9218 per 
Investigator’s discretion and/or Institution’s standard of care related to 
protein-based therapeutics. 
6.1.3 Patient Monitoring Day of HCW9218 Dosing 
For Cycle 1 participants are observed for a minimum of 6 hours after 
HCW9218 dosing for immediate adverse events.  

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For Cycle 2 participants are observed for a minimum of 3 hours after 
HCW9218 dosing for immediate adverse events. Vital signs (body 
temperature, heart rate, respiratory rate, systolic and diastolic blood 
pressure) are documented prior to each HCW9218 dose and then after 
dosing at 15 minutes (±5 min), 30 minutes (± 5 min), 60 minutes (±10 min) 
and 120 minutes (±15 min) minutes then hourly (±15 min) until discharge 
from the clinic.  
In addition, during Cycle 1 only, the targeted toxicity worksheet is 
completed as detailed in Section 10.2.2. 
For subsequent doses (i.e., Cycle 3 and subsequent cycles), if the 
participant did not experience any severe side effects from the previous 
doses, they may be discharged from the treatment center 30 minutes after 
the HCW9218 injection at the discretion of the treating Investigator. Vital 
signs (body temperature, heart rate, respiratory rate, systolic and diastolic 
blood pressure) are documented prior to each HCW9218 dose and then 
after dosing at 15 minutes (±5 min) and at 30 minutes (±5 min).  
6.1.4 HCW9218 Dosing Delay and Discontinuation 
No dose reductions are permitted (except for HCW9218 dose recalculation 
for weight change in Section 6.1).  
A dose delay is permitted per Section 6.1.1.  
All attempts should be made to stay within the allotted timeframes although 
altering the schedule, if determined to be medically necessary by the 
Investigator, will not be a protocol deviation. 
6.2 HCW9218 Dose Finding Enrollment Plan 
Dose limiting Toxicity (DLT) is defined in Section 6.3.  
6.2.1 STAGE 1 STEP 1 - Fast-track design (1 patient per dose level) 
Start at DL1, enroll 1 patient per DL separated by a minimum of 21 days 
(DLT period) until the:  
 1st pre-defined adverse event - Any of the following treatment 
emergent Grade 2 events lasting >72 hours within 5 days of 1st dose of 
HCW9218: fatigue, flu-like symptoms or injection site reaction.   
  And the patient completes the 21 day DLT period with no DLT- Activate 
Stage 1 Step 2 in Section 6.2.2. 
OR  

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 1st DLT event within 21 days after the 1st dose of HCW9218 - Activate 
Stage 2 in Section 6.2.3 - Stage 1 Step 2 is not used.  
OR 
 9 patients are treated at the DL4 - This completes enrollment - Stage 
1 Step 2 and Stage 2 are not used. 
6.2.2 STAGE 1 STEP 2 - Expand Current and Future DLs to 3 Patients 
The cohort size increases from 1 to 3 patients with 2 additional patients 
added to the current cohort. A minimum of 21 days must separate each 
dose cohort. Continue dose escalation until: 
 1st DLT event - Activate Stage 2 in Section 6.2.3. 
OR  
 9 patients are treated at the DL4 - This completes enrollment and Stage 
2 is not used. 
6.2.3 STAGE 2 Continual Reassessment Method (CRM) 
The study design changes to an application of the continual reassessment 
method (CRM). Enrollment occurs in cohorts of three with a minimum of 14 
days between the 1st and 2nd patient. Each new cohort of three patients are 
sequentially assigned to the most appropriate dose by the study statistician 
based on the updated toxicity probabilities once the 3rd patient in a cohort 
reaches Day 21 (DLT period). The goal will be to identify one of the 4 dose 
level strategies corresponding to the desired maximum toxicity rate of ≤25%. 
The MTD will be identified by the minimum of the following criteria: (1) the 
total Stage 2 sample size of 24 is exhausted or (2) 9 consecutive patients 
are enrolled at the same dose. 
6.3 Monitoring for Dose Limiting Toxicities and Excessive Toxicity 
Toxicity and adverse events are classified and graded according to NCI's Common 
Terminology Criteria for Adverse Events V 5.0 (CTCAE) unless otherwise noted in 
Section 10.  
Note during the fast-track dose escalation only (Stage 1, Step 1), patients also 
are monitored for the pre-defined treatment emergent events defined in Section 
6.2.1.  
 
Dose Limiting Toxicity (DLT) is defined as any of the following treatment 
emergent adverse events using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0 within the 21 days after the 1st dose of HCW9218: 

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DLT event 
Exceptions: 
Any Grade 4 hematologic event 
o Grade 4 lymphopenia  hat resolves to Grade 1 or lower 
(or to Baseline or lower, if pre-existing Grade 2 or 
higher) within 7 days  
o Grade 4 leukopenia that resolves to Grade 1 or lower 
(or to Baseline or lower, if pre-existing Grade 2 or 
higher) within 7 days 
Any Grade 3 or Grade 4 febrile neutropenia 
 
Any Grade 3 thrombocytopenia with bleeding 
 
Any Grade 3 or higher non-hematologic adverse 
event 
o Grade 3 nausea, vomiting and/or diarrhea that last < 72 
hours  
o Grade 3 or higher electrolyte abnormality that lasts < 72 
hours, is not clinically complicated, and resolves 
spontaneously or responds to conventional medical 
interventions  
o Isolated Grade 3 elevation of ALT and/or AST that 
resolves to Grade 1 or lower (or to Baseline or lower, if 
pre-existing Grade 2 or higher) within 7 days  
o Grade 3 amylase or lipase that is not associated with 
symptoms or clinical manifestations of pancreatitis  
o Grade 3 fatigue, not due to disease progression, that 
lasts < 1 week 
Hy’s Law case (i.e., alanine aminotransferase/ 
aspartate aminotransferase (ALT/AST) >3 x 
ULN in combination with total bilirubin level 
(TBL) > 2 x ULN in the absence of cholestatic 
injury (ALP < 2 x ULN (Ricart, 2017; FDA, 
2009)) and no other cause identified) after 
excluding biliary tract obstruction and liver 
metastasis 
 
Inability to receive Cycle 2 dosing due to 
treatment related toxicity   
 
 
The Dose Limiting Toxicity (DLT) Observation Period is defined as 21 days after 
the first dose of HCW9218. The DLT period does not end until the patient is 
assessed on Cycle 2 Day 1 (+3 days) and the results of lab work drawn on Cycle 
2 Day 1 (+3 days) confirms no new DLTs since the previous assessment.  
Monitoring for Excessive DLT’s (Stage 2 patients only): 
A stopping rule is in place to stop the trial in case there are excessive DLTs based 
on Monitoring Guidelines in place for excessive toxicity. At the end of the 21-day 
DLT period for each cohort of patients, the study statistician or designee updates 
posterior probability that the lowest dose is unacceptably toxic. Refer to Section 
13.4 for complete details. 

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6.4 Supportive Care and Concomitant Medications 
Supportive care will be provided per institutional guidelines. Guidelines may be 
updated based on current data/drugs without requiring a protocol amendment or 
be considered a protocol deviation.  
If a rash occurs and the rash area surrounding the HCW9218 injection site is > 6 
cm and symptomatic (painful and/or itchy), it may be treated (at the discretion of 
the treating physician) with topical 0.05% clobetasol propionate (i.e., 0.05% 
Cormax) or 0.1% triamcinolone (i.e., Kenalog) cream.  
Diphenhydramine may be administered pre- (25-50 mg TID orally) and post-dosing 
(25-50 mg TID orally x 2 days) of HCW9218 at the discretion of the treating 
physician. Diphenhydramine should be eliminated if not tolerated.  
Red blood cell and/or platelet transfusions can be administered as clinically 
indicated.  
Palliative “standard of care” radiation therapy is permitted to non-target tumor(s) 
such as bony lesions at the discretion of the treating investigator.  
6.5 Prohibited Concomitant Therapy 
Unless the patient discontinues the study treatment, no investigational or 
commercial anti-cancer agents or anti-cancer therapies other than HCW9218 and 
supportive care therapies (i.e., topical steroids) may be administered. Palliative 
radiation therapy is permitted as described in Section 6.4. 
The use of systemic corticosteroids medications may result in loss of therapeutic 
effects of the investigational product and should be avoided; however, in the event 
of a life-threatening inflammatory reaction to HCW9218, the administration of 
dexamethasone or other corticosteroids-based medication is warranted. 
Prednisone should be avoided, with the exception of use in patients with CT 
contrast allergies. 
Certain cytokines, including IL-2 and TGF-β, have been found to suppress the 
activities of cytochrome P450 enzymes. This may potentially indirectly affect the 
metabolism of other medications resulting in significant toxicities in some cases. 
Since the effects of HCW9218 on human cytochrome P450 enzymes are not yet 
known, use of cyclosporine, statins, or warfarin (Coumadin) should be avoided in 
participants receiving HCW9218. 
6.6 Duration of Study Treatment 

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A minimum of two treatment cycles is planned and HCW9218 may continue until 
disease progression unless any one of the following occurs sooner: 
 Patient requests to discontinue treatment early – if in agreement, follow-up 
would continue as in Section 6.7 unless the patient also withdraws consent. 
 In the judgement of the treating Investigator and documented in the medical 
record, study treatment is no longer in the best interest of the participant. 
An End of Treatment (EOT) visit occurs 3 weeks (±1 week) after the last dose of 
HCW9218 to confirm no ongoing side effects/toxicity. If ongoing toxicity at the EOT 
visit, it should be managed as medically appropriate and documented, it if meets 
the criteria for documenting as an AE be followed until resolution or stabilization. 
In the situation where a patient’s EOT visit falls outside of the visit window due to 
a prolonged period before the decision to discontinue treatment is made, the EOT 
related activities may be retrospectively abstracted from the medical record from 
around the time the EOT would have occurred and/or delayed until the next 
standard of care visit. Missing items / research samples will not be considered a 
deviation.  
6.7 Follow-Up for Disease Response and Survival (Duration of Study 
Participation) 
After the End of Treatment visit follow up continues for 12 months from the 1st dose 
of HCW9218 to fulfill the secondary endpoints of disease status at 3, 6 and 12 
months and progression free survival / overall survival at 6 and 12 months.  
If a patient discontinued treatment for a reason other than disease progression, 
disease status is documented per standard of care reassessments until 
progression, and then for survival only until the end of the 12 month follow-up 
period.  
Follow-up assessments may be in person, by medical record review, or local 
medical doctor if patient is no longer seen at the treating institution. In person 
follow-up visits solely for this research study are not required and may be linked 
with a standard of care visit. Refer to Section 8 for allowable time related windows 
around each follow-up time points. 
Follow-up may end early if any of the following apply: 
 The patient is discharged to hospice 
 The patient withdraws consent 
 The patient is lost to follow-up (defined as 3 missed appointments/attempts 
to contact) 
If a patient dies before the end of the study defined follow-up, record the date of 
death as the off-study date and reason off study as death and add the date of 

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death. Refer to Section 10.3 regarding reporting of deaths while a patient is on 
study. 
If a person ends follow-up before the 12 month study period (i.e. withdraws 
consent, lost to follow-up), public records will be searched for survival information 
for the endpoints of survival at 6 and 12 months. 
7 HCW9218 Potential Toxicities and Management 
7.1 Clinical Profile 
The adverse event (AE) profile of HCW9218 has not yet been evaluated in human 
subjects.  
The HCW9218 protein complex comprises an IL-15 domain, which is a common γ 
chain cytokine that may have similar immunostimulatory properties as IL-2. 
HCW9218 treatment, particularly at high-dose levels, could potentially cause 
similar side effects, including severe cytokine release syndrome or capillary leak 
syndrome, as commercially available IL-2, Proleukin® (Clinigen, Inc. Yardley, PA) 
that is approved for use at high doses in advanced melanoma and advanced renal 
cell carcinoma. Therefore, in general, the Investigator may refer to the approved 
product package insert for Proleukin® (aldesleukin) for Injection and other 
published literature describing the management of IL-2-related AEs (Dutcher et al, 
2014). Details of these AEs are provided in Appendix II.  
Additionally, expected AEs based on the published clinical experience of 
monotherapy with the related product candidates, including recombinant human 
IL-15 (rhIL-15) (Conlon et al, 2019; Miller et al, 2018; Conlon et al, 2015), IL-15 
mutein/IL-15RαSu-Fc complex (ALT-803, nogapendekin alfa inbakicept) (Margolin 
et al, 2018; Romee et al, 2018), TGFβRII-Fc fusion (AVID200) (Lafyatis et al, 2020; 
Mascarenhas et al, 2020; Yap et al, 2020) and TGFβRII-anti-PD-L1 IgG1 fusion 
(M7824, bintrafusp alfa) (Tan et al, 2021; Khasraw et al, 2021; Kang et al, 2020; 
Strauss et al, 2020), are provided in Appendix II. These agents contain protein 
domains that are similar to those of HCW9218. Information on the AEs reported in 
clinical studies of anti-TGF-β antibody therapy (Lacouture et al, 2015; Morris et al, 
2014), assumed to have a similar mechanism-of-action as the HCW9218 TGFβRII 
domain, also is included in Appendix II.  
In general, treatment with ALT-803 monotherapy at up to 0.02 mg/kg was well-
tolerated and no DLTs were reported. Dose-dependent transient flu-like 
constitutional AEs were observed following i.v. administration whereas s.c. 
delivery resulted in self-limited injection site rashes infiltrated with lymphocytes 
without acute constitutional symptoms. Treatment with immunotherapies 

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containing the TGFβRII domain were also well-tolerated at i.v. dose levels up to 
15 mg/kg with reported treatment-emergent skin lesions and mucosal bleeding 
being 
associated 
with 
TGF-β 
inhibition. 
The 
combination 
of 
IL-15 
immunostimulatory and TGF-β antagonist activities in HCW9218 may result in 
additional and/or more frequent or severe AEs. 
7.2 Most Common and Most Serious Side Effects Seen In Drugs Similar To 
HCW9218 
 
HCW9128 has not yet been evaluated in human clinical studies. Thus, the 
expected AEs are based on the published clinical experience with other related 
immunotherapies, including recombinant human IL-2, recombinant human IL-15, 
TGFβRII-Fc fusion and anti-TGF-β antibody.  
All adverse events listed in Appendix II are defined as "Expected" for the purpose 
of event documentation and reporting requirements. 
The tables below show the most common and most serious side effects seen in 
drugs similar to HCW9218. This language matches the treatment consent form. 
COMMON, SOME MAY BE 
SERIOUS  
In 100 people receiving a drug 
similar to HCW9218, more 
than 20 and up to 100 may 
have:  
OCCASSIONAL, SOME MAY BE 
SERIOUS In 100 people receiving 
a drug similar to HCW9218, from 
4 – 20 people may have:  
RARE, AND SERIOUS  
In 100 people receiving a drug 
similar to HCW9218, 3 or 
fewer may have: 
• redness, itching and pain or 
swelling at the injection site  
• infection, especially when 
white blood cell count is low  
• anemia, which may require a 
blood transfusion  
• bruising, bleeding  
• nose-bleed  
• fever, chills, pain  
• flu like symptoms  
• swelling in arms and legs  
• pain in belly  
• pain in joints  
• loss of appetite  
• diarrhea  
• dizziness  
• shortness of breath  
• chest pain  
• skin rash  
• abnormal eye movement  
• constipation  
• bloating  
• cough  
• headache  
• sores in mouth  
• depression  
• anxiety/ worry  
• extreme sleepiness  
• weight gain  
• abnormal heartbeat  
• blurred vision 
• skin lesions  
• allergic reaction  
• fluid in the organs  
• heart attack  
• internal bleeding  
• severe blood infection  
• damage to multiple organs, 
heart, kidney, liver, others  
• swelling, tenderness and/or 
redness of the veins  
• stroke  

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COMMON, SOME MAY BE 
SERIOUS  
In 100 people receiving a drug 
similar to HCW9218, more 
than 20 and up to 100 may 
have:  
OCCASSIONAL, SOME MAY BE 
SERIOUS In 100 people receiving 
a drug similar to HCW9218, from 
4 – 20 people may have:  
RARE, AND SERIOUS  
In 100 people receiving a drug 
similar to HCW9218, 3 or 
fewer may have: 
• fatigue/ tiredness  
• high blood pressure which 
may cause headaches  
• increase/ decrease in 
urination  
• drop in blood pressure  
• itching  
• dry skin  
• nausea, vomiting  
• abnormal lab results  
• blood clot  
• confusion 
8 Schedule of Patient Activities 
Virtual visits may replace in person clinic visits as relevant. Lab work and disease 
reassessments must be performed at the enrolling site, unless other arrangements are 
permitted as discussed with the study PI. 
For flexibility “windows” are built into the study calendar to allow for scheduling issues 
(i.e. holidays, inclement weather, patient request) and may be used as needed. Each time 
point and its associated window is an independent event and does not affect future time 
points or the study calendar. This contrasts with treatment delays for toxicity written into 
the study plan – Refer to Section 6.1.1 
 
Permitted window for scheduling issues: 
 A ±1 day window is permitted for visits after Day 1 for Cycles 1 and 2. 
 Safety labs may be performed up to 48 hours prior to administration of HCW9218 
except for Cycle 2 Day 1 (end of DLT period).  
 Beginning with Cycle 3, a ±3 day window is permitted around Day 1 as long as a 
minimum of 2 weeks separate each HCW9218 in event of a dose delay per Section 
6.1.4. 
 Imaging studies and tumor markers are performed per standard of care (every 4 
cycles (12 weeks) or per SOC if more frequent) – windows do not apply. 

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 End of Treatment (EOT) visit ± 1 week (refer to Section 6.6 for options if the 
decision to stop treatment is made > 4 weeks after the last dose of HCW9218). 
 Follow-up assessments ± 1 month 
 
In addition, a treatment day may be adjusted by the treating Investigator on an individual 
patient basis if the change is in the best interest of the patient. This may require reporting 
the change as a study deviation. Contact the study’s Regulatory Specialist or Program 
Manager for guidance. Refer to Section 14.1 for the definition of protocol deviations. 

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8.1 Standard of Care Activities 
Standard of care assessments and procedures are part of good clinical care and are charged to the patient and their health insurance. 
 
 
 
 
 
 
Study day 
window 
Baseline / 
screening 
Within 28 days of 
Cycle 1 Day 1 
unless o/w noted1 
Cycle 1 
Cycle 2 
Cycle 3 and 
subsequent 
cycles 
Every 4 
cycles (12 
weeks) or 
per SOC if 
more 
frequent 
until PD 
End of 
treatment 
(EOT) visit  
3 weeks after 
the last dose 
of HCW9218 
After EOT visit: 
Follow-up for 
response until 
PD, then survival 
only every 3 mon 
for 12 months 
from C1D1  
-28 to -1  
(no Day 0) 
1 
2 
3 
5 
8 
15 
1 
2 
5 
8 
15 
1 
Not applicable 
±1 day using Day 1 as the anchor  
+3 days for Day 1 then  ±1 day 
±3 days 
± 14 days 
± 1 week 
± 1 month 
Written consent 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess for eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history including prior 
cancer treatment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Physical exam6 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
Provider assessment 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
X 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
Vitals signs 
X 
X3 
X 
X 
X 
X 
X 
X3 
X 
X 
X 
X 
X4 
 
X 
 
Weight5 plus height at baseline only 
X 
X5 
 
 
 
X 
 
X 
 
 
 
X 
X 
 
X 
 
CBC with differential 
X1 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X2 
 
X 
 
Complete metabolic panel7 
X1 
X2 
 
 
 
X 
 
X 
 
 
 
 
X2 
 
X 
 
CRP, ferritin, amylase, lipase, LDH, 
mg, phos 
X8 
 
 
 
 
X8 
 
 
 
 
 
 
 
 
 
 
Diagnosis related biomarker (e.g., 
CA125, PSA) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Pulmonary function testing only if 
clinically indicated 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment by disease 
appropriate methods 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Disease response based on RECIST 
1.1 (until disease progression) 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Survival/follow-up  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1. Baseline/Screening – within 14 days of study treatment start for labs required for eligibility; prior disease assessments may be used if they were performed within 42 days of the 1st HCW9218 dose in the 
absence of intervening anti-cancer therapy. Consent is exempt from 28 day limit and may be performed at any time prior to starting study related activities. If more than 14 days pass between lab work for 
eligibility (found in Section 4.1.6) and Cycle 1 Day 1, the pre Cycle 1 lab results must continue to meet the criteria in Section 4.1.6.  
2. Safety labs can be collected up to 72 hours prior to administration of HCW9218 except for C2 D1 where labs cannot be collected sooner than Cycle 1 Day 22 / Cycle 2 Day 1 (the end of DLT period).  
3. C1D1 and C2D1: Vital signs (body temperature, heart rate, respiratory rate, systolic and diastolic blood pressure) are documented before each HCW9218 dose and then after dosing at 15 min (± 5 min), 
30 min (± 5 min), 60 min (± 10 min) and 120 min (± 15 min) then hourly (± 15 min) until discharge from the clinic or at completion of dose monitoring.  
4. For C3D1 and subsequent doses: Vital signs (body temperature, heart rate, respiratory rate, systolic / diastolic blood pressure) are documented before each HCW9218 dose and then after dosing at 15 min (± 
5 min) and 30 min (± 5 min).  

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5. HCW9218 dose calculation is based on patient’s dose level and actual body weight recorded at Day 1 (or within 14 days prior). Dose adjustments occur only if weight changes by ±10% or greater from 
weight used to calculate original dose per Section 4.1. 
6. Cardiac function should be monitored by clinical examination and assessment of vital signs for hypotension, arrhythmia, angina and myocardial infarction. During the study, participants with signs or 
symptoms of chest pain, murmurs, gallops, irregular rhythm, or palpitations must be further assessed if clinically indicated, including the need for hospitalization  
7. Complete metabolic panel includes: albumin, alkaline phosphatase, ALT, Anion gap, AST, bilirubin (total), calcium, chloride, CO2, creatinine, glucose, potassium, protein (total), sodium, urea nitrogen 
8. Baseline and Day 8 measures, repeat only if clinically indicated. 
 
 

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8.2 Research Related Activities 
Activities directly related to participation in the research study are paid for by study funding and not charged to the patient or their 
health plan/health insurance. Research related activities are linked to a standard of care (SOC) visit and may be adjusted to stay with 
the SOC visit unless otherwise noted. 
Tests and procedures 
 
 
Study day 
Baseline/ 
Screening 
 
Cycle 1 
Cycle 2 
Cycle 3 and all 
subsequent 
cycles  
Every 4 Cycles 
(every 12 
weeks)  
At End of 
Treatment 
(EOT visit)  
1 
2 
3 
5 
8 
15 
1 
2 
5 
8 
15 
Day 1 
 
 
Coagulation studies (INR/PTT)1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECG and cardiac monitoring2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing (serum or urine) for females 
of child-bearing potential3 
X 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCW9218 administration (refer to Section 6.1 for 
dose adjustment based on weight change) 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Targeted toxicity worksheet (Appendix IV) in 
addition to AE assessment per Section 10.2.2 
 
X4 
X4 
X4 
X4 
 
 
 
 
 
 
 
 
 
 
Blood sample for pharmacokinetics (PK)9 
 
Pre and 
post 5  
X5 
X5 
X5 
X5 
 
Pre and 
post7 
X7 
X7 
X7 
 
 
 
X 
Blood sample for correlative marker (CM) 
analysis9 
 
Pre and 
post 6  
X6 
X6 
X6 
X6 
X6 
Pre and 
post8 
X8 
X8 
X8 
X8 
 
 
 
Blood sample for immunogenicity (IMG)9 
 
X (prior 
to dose) 
 
 
 
 
 
X (prior 
to dose) 
 
 
 
 
X (prior to dose) 
 
X 
Blood sample for immune cell analysis and 
TIS biomarkers (p16 and p21)  
(at least 10 mL collected in Heparin tube)  
 
X (prior 
to dose) 
 
 
 
X 
X 
x (prior to 
dose) 
 
 
 
 
X (prior to dose) 
 
 
Blood sample for UMN research related 
testing (at least 30 mL collected in 3 Heparin 
tubes) 
 
X (prior 
to dose) 
X 
X 
X 
X 
X 
x (prior to 
dose) 
 
X 
X 
X 
X (prior to dose) 
 
 
FACT-G QOL questionnaire (Appendix V) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Skin condition questionnaire (Appendix VI) 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Tumor biopsy (optional refer to Section 4.1.2)  
X10 
 
 
 
 
 
 
 
 
 
 
 
X (prior to cycle 3 
dose only) 
 
 
1- Coagulation studies are performed in FV labs as usual but charge to research, collect prior to day’s dose if applicable 
2- An ECG as usual will be performed at baseline/screening but charged to research.  
3- A negative serum or urine pregnancy test is required within 14 days prior to enrollment to confirm eligibility for women with childbearing potential (non-
childbearing is defined as > 1 year postmenopausal or surgically sterilized). The pregnant test must be repeated (and remain negative) if the baseline 
testing occurred more than 14 days before Cycle 1 Day 1. 

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4- Targeted toxicity worksheet is completed at the following timepoints per Section 10.2.2: Prior HCW9218 injection on Cycle1 Day 1 (within 1 hour prior to 
HCW9218), at 3 hours (±15 minutes) and at 6 hours (±15 minutes) post injection, Cycle 1 Day 2, Cycle 1 Day 3, and Cycle 1 Day 5. The completion of the 
targeted toxicity worksheet aligns with in person visits and may be shifted to align with the actual day a visit occurs or skipped if a visit is not occurred.  
5- Cycle 1 Blood samples for PK analysis will be collected in association with the first dose of HCW9218: Baseline sample collected within 24 hours prior 
to HCW9218 dosing, at 30 minutes ± 5 min and 3 hours ± 30 minutes (C1D1), 24 hours ± 6 hours (C1D2), 48 hours ± 6 hours (C1D3), 96 hours ± 24 hours 
(C1D5) and C1D8 ± 24 hours. 
6- Cycle 1 Blood samples for CM analysis will be collected in association with the first dose of HCW9218: Baseline sample collected within 24 hours prior 
to HCW9218 dosing, at 30 minutes ± 5 min and 3 hours ± 30 minutes (C1D1), 24 hours ± 6 hours (C1D2), 48 hours ± 6 hours (C1D3), 96 hours ± 24 hours 
(C1D5), then on C1D8 ± 24 hours and Day 15 ± 24 hours.  
7- Cycle 2 Blood samples for PK analysis of HCW9218 will be collected in association with the second dose of HCW9218: Baseline sample collected within 
24 hours prior to dose 2 of HCW9218 dosing and at 3 hours ± 30 minutes, 24 hours ± 6 hours (C2D2), 96 hours ± 24 hours (C2D5) and C2D8 ± 24 hours. 
8- Cycle 2 Blood samples for CM analysis will be collected in association with the second dose of HCW9218: Baseline sample collected within 24 hours 
prior to dose 2 of HCW9218 dosing and at 3 hours ± 30 minutes, 24 hours ± 6 hours (C2D2), 96 hours ± 24 hours (C2D5) then on C1D8 ± 24 hours and Day 
15 ± 24 hours.  
9- Refer to the HCW Biologics Investigator Initiated Trial (IIT) Manual for sample collection, processing, and shipping details. 
10- Patients with accessible tumor and who sign the separate consent for a fresh tumor biopsy collected prior to the 1st HCW9218 dose (any time after consent) 
and before the 3rd dose of HCW9218. Biopsy collection is exempt from the 28 day limit and may be performed at any time after consent and prior to HCW9218 
dose. If a biopsy is obtained prior to the 1st HCW9218 dose and a patient is later deemed ineligible to receive treatment, the tumor sample will not be used 
for research purposes. 
 

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Research related sample collection and activities are linked to a standard of care 
(SOC) visit and may be adjusted to stay with the SOC visit unless otherwise noted.  
Up to 3 additional research samples for each test type may be collected at other 
time points (i.e., at time of AE, disease progression or response) during the study 
period. 
All research samples go to the Masonic Cancer Center Translational Therapy Lab 
(TTL) except fresh biopsy or surgical samples are handled as described in the 
contract with BioNet.   
Residual samples (and study data) may be used by HCW Biologics Inc. and shared 
with University of Minnesota investigators for research studies of additional 
biomarkers and correlative assessments. Results will not influence a patient’s 
treatment nor will the results be provided to the patient or placed in their medical 
record.  
The following testing is performed at HCW Biologics or their designee lab.  
Pharmacokinetic (PK) analysis – Detection of HCW9218 levels over time. If 
appropriate, PK may also be performed using the same samples as 
immunogenicity and correlative marker analysis.  
Immunogenicity (IMG) - Detection of Anti-HCW9218 Antibodies will be performed 
at HCW Biologics Inc.  
Correlative Marker (CM) Assessments - These tests will be performed at HCW 
Biologics as research studies using de-identified samples. Serum samples will be 
collected to evaluate the levels of serum cytokines, chemokines and inflammatory 
markers, typically but not limited to TGF-β isoforms, IL1α, IL-1β, IL-6, IFN-γ, TNF-
α, MCP-1, resistin and CRP.  
Residual samples (and study data) may be used by HCW Biologics Inc. and shared 
with University of Minnesota investigators for research studies of additional 
biomarkers and correlative assessments. Results will not influence a patient’s 
treatment nor will the results be provided to the patient or placed in their medical 
record.  
The following testing is performed at the University of Minnesota.   
Blood Immune Cell Analyses - Flow and/or mass cytometry analysis of blood 
cells may be conducted to detect surface markers that define immune cell and 
lymphocyte subsets (such as NK, NKT, B, and T cells, both CD4 and CD8), as well 
as intracellular markers that define additional parameters (such as regulatory T 

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cells (Foxp3) and proliferating cells (Ki67)). RNA sequence analysis may also be 
conducted to assess the gene expression profile in immune cells.  
Quality of Life Assessments Exploratory Research Assessments will be 
performed on various quality of life parameters. Assessments are completed by 
the participant or, through oral response to a member of the research team 
administering the assessment. The Functional Assessment of Cancer Therapy - 
General (FACT-G) is a validated 27-item questionnaire designed to measure four 
domains of health related quality of life in cancer patients: physical, social, 
emotional, and functional well-being using a 5 point Likert-type score based on 
patient recall of the last 7 days.  
The Skin Condition Questionnaire is a 3 question binary (Y/N) survey created 
by HCW Biologics asking about skin changes at the injection site and overall 
changes in the skin noted by the participant. For yes responses, the participant is 
asked to describe the changes. 
Tumor Biopsies (Optional) Patients will be approached based on safety and 
feasibility of accessible tumor tissue. A separate research biopsy consent is 
required. Biopsy samples will be stored for future research studies. 
Immunohistochemistry analysis and genomic, transcriptomic and proteomic 
molecular profiling may be performed on fresh/frozen and/or formalin-fixed, 
paraffin embedded (FFPE) tumor tissue. All such analyses will be retrospective 
and exploratory. Biopsies will be performed according to the institution’s standard 
procedures. Tumors used for biopsy should not be lesions used as RECIST target 
lesions unless there are no other lesions suitable for biopsy.  
9 HCW9218 Description, Supply and Potential Toxicities 
9.1 Formulation 
The inactive ingredients of HCW9218 drug product are the formulation buffer 
(PBS) comprised of 1.36 g/L of potassium phosphate monobasic (KH2PO4), 1.43 
g/L of sodium phosphate dibasic anhydrous (Na2HPO4), and 8.18 g/L of sodium 
chloride (NaCl), pH 7.4. 
9.2 How Supplied 
HCW9218 is an investigational drug product supplied to Investigators by HCW 
Biologics Inc. at Miramar, Florida. Sufficient HCW9218 drug product will be 
available for this protocol to treat all of the projected enrolled subjects.  
The clinical lot of HCW9218 drug product for use in the study will be provided in 2 
mL vials containing 1.0 mL of HCW9218 at a concentration of approximately 20 
mg/mL (20 mg HCW9218 in 1 mL phosphate buffered solution). These vials will 

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be packaged in appropriately sized cartons. HCW9218 drug product vials will be 
labeled, in accordance with 21 CFR §312.6.   
HCW9218 drug product will be packed in a temperature-controlled box and 
shipped to the study site maintained at a temperature between 2°C to 8°C. 
9.3 Study Site Storage and Stability 
HCW9218 will be received by, stored in, and dispensed by the University of 
Minnesota, Fairview Investigational Drug Services (IDS) Pharmacy, a secure, 
limited access facility. Refer to the HCW Biologics Investigator Initiated Trial (IIT) 
Manual for receipt of the investigational product.   
HCW9218 drug product vials will be maintained at a temperature between 2°C and 
8°C, protected from excessive light and heat. 
Refer to the HCW Biologics Investigator Initiated Trial (IIT) Manual for the reporting 
of product excursions including storage temperature outside of the recommended 
temperature range (2ºC – 8ºC) and/or broken or missing vials.  
Note: The Investigator or designee(s) must report excursions by email to HCW by 
the end of the following business day following the identification and followed by 
event documentation using the Drug Product Excursion Form (DPEF). 
9.4 HCW9218 Preparation for Injection 
There are no particular hazards associated with HCW9218 and no specific 
considerations are necessary when handling the vialed product other than 
handling with gloves.  
HCW9218 dose calculation is based on the patient’s assigned dose level and 
actual body weight done on Cycle 1 Day 1 or within the 14 days prior. Dose 
adjustments occur only if a weight changes by ±10% or greater from the weight 
used to calculate the Cycle 1 dosing. See Section 6.1. 
The calculated amount of HCW9218 will be drawn into a syringe for subcutaneous 
(SC) injection. The stock concentration is 20 mg/mL, doses will be drawn directly 
into the syringe for injection.  
If the total SC dose is greater than 1.5 mL, the dose will be divided into 2-3 SC 
injections as needed. Injection sites should be rotated per institutional guidelines 
and each injection site separated by at least 1 inch. 
 
 

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9.5 Investigational Product Accountability and Reordering 
IDS, on behalf the study Investigator, will maintain the records of receipt and 
disposition of the HCW9218 drug product including patient related dates, dose, 
and quantities administered. IDS tracks the HCW9218 inventory, including 
expiration dates, and facilitates reordering. 
All partially used and unused HCW9218 drug product vials will be destroyed at the 
IDS per their standard procedures or returned to the HCW according to the 
established procedures.  
Refer to the HCW Biologics Investigator Initiated Trial (IIT) Manual for instructions 
on reordering the drug product and the return of unused vials at the end of the 
study. 
9.6 Possible Interactions with Other Drugs 
Potential drug-drug interactions with HCW9218 have not yet been defined. 
9.7 Potential Side Effects 
HCW9128 has not yet been evaluated in human clinical studies. 
Thus, the expected AEs are based on the published clinical experience with other 
related immunotherapies, including recombinant human IL-2, recombinant human 
IL-15, TGFβRII-Fc fusion and anti-TGF-β antibody.  
All adverse events listed in Appendix II are defined as "Expected" for the purpose 
of event documentation and reporting requirements. 
Section 7.2 presents the most common and most serious side effects seen in drugs 
similar to HCW9218 in table format organized by frequency (common, occasional, 
and rare) as presented in the treatment consent form. 
For additional information refer to the Investigator Brochure. 
10 Event Monitoring, Documentation, and Reporting 
Toxicity and adverse events will be classified according to NCI's Common Terminology 
Criteria for Adverse Events version 5 (CTCAE v5). A copy of the CTCAE can be 
downloaded from the CTEP home page at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_5x7.pdf  
The investigational product in this study is the HCW9218.  
Event monitoring and documentation begins at the time of the 1st HCW9218 dose and 
continues through the End of Treatment visit. Active monitoring for adverse events ends 

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with the End of Treatment visit unless there are ongoing study related toxicity. After the 
End of Treatment visit through 12 months after the 1st dose of HCW9218, events are 
documented upon knowledge. Refer to the table in Section 10.2. 
10.1 Definitions 
The following definitions are based on the Code of Federal Regulations Title 21 
Part 312.32 (21CFR312.32(a)). 
Adverse Event:  Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  
Suspected Adverse Reaction:  Any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. 
Life-Threatening Adverse Event or Life-Threatening Suspected Adverse 
Reaction: An adverse event or suspected adverse reaction is considered 
“life-threatening” if, in the view of either the Investigator or Sponsor, its occurrence 
places the patient or subject at immediate risk of death. It does not include an 
adverse event or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
Serious Adverse Event or Serious Suspected Adverse Reaction:  An adverse 
event or suspected adverse reaction is considered “serious” if, in the view of either 
the Investigator or Sponsor, it results in any of the following outcomes:  
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 A congenital anomaly/birth defect 
 An important medical event 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction: An 
adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that 
has been observed; or, if an investigator brochure is not required or available, is 
not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application, as amended.  
Note: An IB for HCW9128 is provided by HCW Biologics.    
Expedited (Rapid) Reporting: Certain events may require rapid notification to 
entities providing patient safety oversight (e.g. IRB). Refer to Section 10.3. 

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10.2 Event Monitoring and Documentation 
Event monitoring and documentation begins at the time of the 1st HCW9218 dose 
and continues through the End of Treatment visit. Active monitoring for adverse 
events ends with the End of Treatment visit unless there are ongoing study related 
toxicity. After the EOT through 12 months from Cycle 1 Day 1 (follow-up for 
response and survival), events are documented upon knowledge. Refer to the 
table below: 
 
Event  
Active Treatment Period 
During follow-up for 
12 months from 
Cycle 1 Day 1 
(events are 
documented upon 
knowledge) 
Cycle 1 Day 1 through 
the end of DLT 
observation period and 
the DLT assessment is 
completed  
Cycle 2 Day 1 through 
though End of 
Treatment (EOT) visit 
Any event meeting the definition of serious 
regardless of attribution or expectedness 
X 
X 
X1 
Any death (date and cause) 
X 
X 
X 
1st incidence of a pre-defined adverse event 
during Fast-track enrollment per Section 6.2.1 
X2 
 
 
Any event meeting the definition of a Dose 
Limiting Toxicity (DLT) 
X3 
 
 
All ≥Grade 2 AEs regardless of attribution (see 
exceptions in Section 10.2.1) 
X 
X 
 
Targeted Toxicity Worksheet (Appendix IV) – 
record all AE grades 
X (refer to schedule in 
Section 10.2.2) 
 
 
1. Events are documented upon knowledge if they are unexpected and at least possible related to 
HCW9218. 
2. Used only once to trigger change from 1 patient cohort to 3 patient cohort and move to Stage 1 Step 
2 or Stage 2 (if a DLT also occurs). 
3. Stage 1: Any event meeting the definition of DLT is in association with the 1st treatment cycle (through 
the end of the DLT period) is also be reported as a DLT event contributing to subsequent dose cohort 
decisions per Section 12. Stage 2 (CRM component) event Section 13.4. 
 
10.2.1 Exceptions to AE Documentation in OnCore 
Laboratory abnormalities (e.g., clinical chemistry, hematology, and 
urinalysis) without clinical significance are not recorded as AEs or SAEs 
with the exception of abnormalities that meet the definition of DLT per 
Section 6.3.  
 
Other abnormal assessments (e.g., vital signs, ECG, X-rays) that are not 
associated with signs or are considered of no clinical significance do not 
need to be recorded unless they are a targeted toxicity.  
 

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Clinical significance is defined as requiring medical or surgical intervention 
or leading to a study treatment delay or discontinuation. Any laboratory or 
other assessments meeting the definition of clinically significant must be 
recorded as an AE, as well as an SAE, if applicable.  
10.2.2 Targeted Toxicity Worksheet 
The targeted toxicity worksheet is done in addition to AE documentation as 
described in the table in Section 10.2. It is a focused assessment during the 
DLT period. The highest grade of toxicity since the last assessment is 
recorded (which for outpatients may be patient reported). The targeted 
toxicity worksheet is completed at each of the following timepoints based 
on an in person assessment at that timepoint: 
 Cycle 1 Day 1 
o Prior HCW9218 injection (within 1 hour prior) 
o At 3 hours (±15 minutes) post injection  
o At 6 hours (±15 minutes) post injection  
 Cycle 1 Day 2 
 Cycle 1 Day 3 
 Cycle 1 Day 5 
The completion of the targeted toxicity worksheet aligns with in person visits 
and may be shifted to align with the actual day a visit occurs or skipped if a 
visit is not occurred.  
 
 

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10.3 Required Reporting: IRB, HCW Biologics and FDA 
Certain events or situations require rapid (expedited) reporting as summarized in 
the table below as well as reporting to the FDA as a part of the IND annual report. 
Agency 
reporting to 
Criteria for reporting 
Timeframe 
Form to Use 
Submit to 
U of MN IRB  
Unanticipated death of a locally enrolled 
subject(s); New or increased risk; Any 
adverse event that requires a change to 
the protocol or consent form – refer to 
the IRB website for complete details  
5 Business 
Days 
RNI 
 
ETHOS 
Deviations that occur at UMN as defined 
in Section 14.1 
Per current IRB 
requirements 
OnCore 
Deviation Form 
and IRB Report 
Form 
FDA 
Unexpected and fatal or unexpected and 
life threatening suspected adverse 
reaction 
No later than 
7 Calendar 
Days 
University of 
Minnesota SAE 
Report 
Submit to FDA as an amendment to IND  
with a copy to HCW Safety Reporting 
<safetyreporting@hcwbiologics.com> 
 
1) Serious, unexpected, and suspected 
adverse reaction or 
2) Increased occurrence of serious 
suspected adverse reactions over that 
listed in the investigator brochure or 
3) Findings from other sources (other 
studies, animal or in vitro testing) – not 
applicable for this study  
No later than 
15 Calendar 
Days 
All other events per CFR 312.32 
At time of 
annual 
report 
FDA Annual 
report 
Submit to FDA as an amendment to IND 
HCW 
Biologics 
Any event meeting the definition of an 
SAE 
Within 24 
hours of 
study team 
knowledge 
University of 
Minnesota SAE 
Report 
Submit to: HCW Safety Reporting 
<safetyreporting@hcwbiologics.com> 
11 Study Data Collection and Monitoring 
11.1 Data Management 
This study will collect regulatory and clinical data using University of Minnesota 
CTSI’s instance of OnCore® (Online Enterprise Research Management 
Environment). The OnCore database resides on dedicated secure and PHI 
compliant hardware. Key study personnel are trained on the use of OnCore and 
will comply with protocol specific instructions embedded within the OnCore. 
Additional immune monitoring data about correlative laboratory samples 
generated by the Masonic Cancer Center Translational Therapy Laboratory (TTL) 
from the protocol-directed correlative research samples is stored in their 
Laboratory Information Management System (LIMS). The LIMS database 
application is also stored on a production server located in the UMN datacenter 
(WBOB) and is managed by the Academic Health Center 
11.2 Case Report Forms 

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Participant data will be collected using protocol specific electronic case report 
forms (e-CRF) developed within the University of Minnesota OnCore based on its 
library of standardized forms. The e-CRFs will be approved by the Principal 
Investigator and the Biostatistician prior to release for use. The Study Coordinator 
or designee will be responsible for registering the patient into OnCore at time of 
study entry, completing e-CRF based on the patient specific calendar, and 
updating the patient record until patient death or end of required study 
participation.  
11.3 Data and Safety Monitoring Plan 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan 
(DSMP), which can be accessed at https://z.umn.edu/dsmp. 
For the purposes of data and safety monitoring, this study is classified as high risk 
(Phase I under a locally sponsored IND). Therefore the following requirements will 
be fulfilled: 
 The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will 
review the study’s progress quarterly with the understanding the Cancer 
Protocol Review Committee (CPRC). 
 The Masonic Cancer Center PI will comply with at least twice yearly monitoring 
of the project by the Masonic Cancer Center monitoring services.  
11.4 Regular Team Meetings to Review Safety  
Regular meetings will be held to facilitate communication regarding the study’s 
progress in terms of individual patient safety including events meeting the definition 
of dose limiting toxicity, excessive toxicity (early study stopping rule for CRM only), 
serious adverse events (SAEs) and overall impact on future enrollment.  
At a minimum each patient is reviewed at the end the 1st 21 days to document the 
DLT status and to confirm the timing and dose level for the next patient cohort 
enrolled.  
The outcome of these discussion will be documented in the meeting minutes and 
the statistician or designee will send out a confirmatory email summarizing the 
discussion which will become part of the regulatory record.  
Other issues for discussion may include pending patients, patient updates, 
summary of safety reports, and case report form completion.  
The CRC or CRC-RN or designee is responsible for arranging these meetings and 
preparing the agenda. Meetings will occur every 2 weeks; however, these may be 
scheduled more or less frequently at the discretion of the PI and/or study staff. The 

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safety discussion may be part of the regular PI meeting but must be documented 
as above (in study minutes and post-meeting email from the statistician or 
designee).  
Expected participation includes the Principal Investigator, the study statistician or 
designee and relevant CTO staff (CRC-RN, CRC, Regulatory Specialist, and 
Program Manager) or appropriate designee.  
In the situation of a patient completing the DLT period between scheduled 
meetings, communication via email may be used in lieu of a meeting provided the 
patient was discussed at the prior meeting and will be included on the next 
meeting’s agenda. 
11.5 Record Retention 
The Investigator will retain study records including source data, copies of case 
report form, consent forms, HIPAA authorizations, and all study correspondence 
in a secured facility until notified by the Masonic Cancer Center Clinical Trials 
Office that the study records may be destroyed. 
12 Study Endpoints  
12.1 Primary Endpoint 
The primary endpoint is identification of the maximum tolerated dose (MTD) for 
HCW9218. 
12.2 Secondary Endpoints 
The safety of repeat dosing of HCW9218 is adverse events (AEs) based on 
CTCAE v5. 
Response and progression endpoints are based on the Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1. 
 Response rate (CR, PR or SD) at 3 months, 6 months and 12 months 
 Progression-free survival (PFS) by 6 month and 1 year is defined as the duration 
of time from start of treatment to time of progression or death, whichever occurs 
first  
 Overall survival (OS) at 6 month and 1 year from 1st dose of HCW9218 is 
defined as patients alive at 1 year 
 
 

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13 Statistical Considerations 
13.1 Study Design, Objectives and Endpoints 
The purpose of this Phase I open-label study will be to identify the maximum 
tolerated dose (MTD) in a combined study group of all solid tumor cancers (except 
pancreatic cancer) and provide preliminary estimates of the response for future 
studies.  
The primary endpoint is to provide the MTD of HCW9218 in advanced solid tumor 
cancers. The primary analysis will be intent-to-treat from the point of 1st injection 
of HCW9218 both for toxicity and efficacy. Patients who discontinue therapy prior 
to injection #1 will be replaced. We expect that the number of patients coming off 
therapy prior to injection #1 will be minimal/none.  
There are 5 potential dose levels defined for Phase I. The trial will be conducted 
with no intra-patient escalation. The starting dose will be 0.25 mg/kg HCW9218 
with a safety dose of 0.1 mg/kg HCW9218. The subsequent planned cohorts will 
be 0.5 mg/kg HCW9218, 0.8 mg/kg HCW9218 and 1.2 mg/kg HCW9218 (Table 
1). Given that little to no toxicity is expected, the MTD will be determined using an 
adaptation of the continual reassessment method (CRM) (O’Quigley, 1996) 
starting with 1 patient cohorts.  
Table 1. 
Phase I HCW9218 Dose Levels 
Dose Level 
HCW9218 dose 
-1 
0.1 mg/kg 
1 (start) 
0.25 mg/kg 
2 
0.5 mg/kg 
3 
0.8 mg/kg 
4 
1.2 mg/kg 
This Phase I study will be conducted in two consecutive stages (non-CRM and 
CRM). A minimum of 21 days must separate each cohort. All patients are assessed 
for Dose Limiting Toxicity (DLT) per Section 6.3 as defined in the schema below: 
 
Stage 1 Step 1 uses a fast-track design (1 patient per cohort) with a minimum of 
21 days between each patient until one of the following occurs:  
The 1st occurrence of a pre-defined treatment emergent adverse event within 
21 days of the 1st HCW injection (Section 6.2.1) at which point the study moves to 
Step 2 and the cohort size increases from 1 to 3 patients with 2 additional patients 
added to the current cohort. A minimum of 21 days must separate each 3 patient 
cohort 

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 Escalation in Step 2 continues until the 1st DLT event at which point Stage 2 
(CRM) is activated. If Cohort 4 is completed without a DLT, Stage 2 (CRM) is not 
used. 
 The 1st occurrence of a DLT at which point the study moves directly to Stage 2 
(CRM) as detailed below and Step 2 is not used. 
 Cohort 4 is completed without a pre-defined AE or a DLT – neither Step 2 nor 
Stage 2 is used if a total of 9 patients are enrolled in Cohort 4 to complete the 
study. 
 
Stage 2 is initiated at the 1st DLT. The study design changes to an application 
of the continual reassessment method (CRM) with an informative skeleton based 
on constrained maximum likelihood estimation (Iasonos & O'Quigley, 2012). 
Enrollment occurs in cohorts of three patients. Each new cohort of three patients 
are sequentially assigned to the most appropriate dose by the study statistician 
based on the updated toxicity probabilities once the 3rd patient in a cohort 
reaches Day 21 (DLT period). The goal will be to identify one of the 5 dose level 
strategies corresponding to the desired maximum toxicity rate of ≤25%. The MTD 
will be identified by the minimum of the following criteria: (1) the total Stage 2 
sample size of 24 is exhausted or (2) 9 consecutive patients are enrolled at the 
same dose. The function ‘crm’ from the R package ‘dfcrm’ will calculate posterior 
means of toxicity probabilities. Dose escalation of more than one level is not 
permitted with this design.  
13.2 Statistical Analysis  
The primary analysis study population will be intent-to-treat in that all patients 
receiving the 1st injection of HCW9218 will be evaluable for toxicity and efficacy.  
Primary Endpoint 
The MTD will be determined by design.  
Secondary Endpoints 
If there are sufficient numbers, the secondary endpoints of overall survival and 
progression-free survival by 6 months and 1 year will be estimated with Kaplan-
Meier curves. The primary efficacy endpoint of response rate will be estimated by 
a simple proportion with 95% confidence limits if sufficient numbers exist. Safety 
will be estimated by the proportion of adverse events based on CTCAE v5. Further 
descriptive statistics and plots such as boxplots, spaghetti plots and swimmer plots 
will be used to assess kinetics and other markers of efficacy such as immune 
based monitoring and toxicity.  
13.3 Sample Size 

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A maximum of 24 patients will be enrolled with a target DLT rate of ≤25%. Based 
on the simulations from Table 2, this should be sufficient and safe to define the 
MTD. Although complete skeleton estimates will not be determined until Stage 2, 
Table 2 is calculated based on hypothesized values. 
1. SAE’s without a DLT trigger step 2 in stage 1, DLT’s regardless of SAE’s trigger stage 2 
2. Expected/Excessive values are the hypothesized true values under the simulation 
3. Probability of dose chosen as the MTD using the Adaptive-CRM design 
4. The hypothesized number of patients enrolled at each dose during the trial under the assumed 
hypothesized “true” probabilities  
13.4 Monitoring Guidelines for Stage 2 (Early Study Stopping Rules) 
A stopping rule is in place to stop the trial in case there are excessive DLTs (Stage 
2) as defined by updated posterior probabilities throughout the trial. At the end of 
the 21-day evaluation period after each cohort of patients is enrolled, new posterior 
probabilities will be calculated for each dose. The trial will be stopped if the 
posterior probability that the lowest dose is unacceptably toxic (> 25% of patients) 
is greater than 80%. (Zohar & Chevret, 2001).  
14 Conduct of the Study 
14.1 Protocol Deviations 
The following definitions are from the Masonic Cancer Center’s Standard 
Operating Procedure (SOP) Deviation Reporting: 
Major Deviation: A deviation or violation that impacts the risks and benefits of the 
research; may impact subject safety, affect the integrity of research data and/or 
affect a subject’s willingness to participate in the research. Deviations that place a 
subject at risk, but do not result in harm are considered to be major deviations. 
Minor Deviation: A deviation or violation that does not impact subject safety, 
compromise the integrity of research data and/or affect a subject’s willingness to 
participate in the research. 
Deviations on University of Minnesota participants must be reported to the IRB as 
detailed in Section 10.3. One exception to the reporting of protocol deviations is 
Table 2. Operating characteristics for Adaptive-CRM 
 
HCW9218 Dose 
Levels 
Expected DLT, Expected SAE1,2 
Excessive DLT, Excessive SAE 
True 
Probability 
Prob. of 
dose3 
N4 
True 
Probability 
Probability 
of dose 
N 
0.1 mg/kg (-1) 
0.5%, 0.5% 
0% 
0 
5%, 18% 
3% 
3 
0.25 mg/kg (1, start) 
0.75%, 1.5% 
0% 
1 
10%, 29% 
18% 
6 
0.5 mg/kg (2) 
1.5%, 3% 
0% 
1 
25%, 50% 
44% 
9 
0.8 mg/kg (3) 
3%, 5% 
0% 
1 
40%, 66% 
34% 
5 
1.2 mg/kg (4) 
7%, 7.5%  
100% 
9 
55%, 77% 
1% 
1 

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noncompliance with timeframes that are subject to clinical judgement or do not 
impact subject safety or data integrity. Timeframes indicated throughout this 
protocol are intended to be targeted timeframes unless “must” is specified. 
14.2 Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s). Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected. Master files should be 
established at the beginning of the study, maintained for the duration of the study 
and retained according to the appropriate regulations.  
14.3 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The IRB will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients. The study will 
only be conducted at sites where IRB approval has been obtained. The protocol, 
consent, written information given to the patients, safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB by the 
Investigator.  
14.4 Informed Consent 
All potential study participants will be given a copy of the IRB-approved consent to 
review. The Investigator or designee will explain all aspects of the study in lay 
language and answer all questions regarding the study. If the participant decides 
to participate in the study, he/she will be asked to sign and date the consent 
document. Patients who refuse to participate or who withdraw from the study will 
be treated without prejudice. 
 
 

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Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer 
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Principe DR, Narbutis M, Kumar S, et al. Long-Term Gemcitabine Treatment Reshapes the 
Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination 
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Ricart AD. Drug-induced liver injury in Oncology. Ann Oncol.2017;28(8):2013-2020.  
Robert C. A decade of immune-checkpoint inhibitors in cancer therapy'. Nat Commun. 
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Romee R, Cooley S, Berrien-Elliott MM, et al. First-in-human phase 1 clinical study of the IL-15 
superagonist complex ALT-803 to treat relapse after transplantation. Blood.2018;131(23):2515-
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Saber H, Gudi R, Manning M, Wearne E, Leighton JK. An FDA oncology analysis of immune 
activating products and first-in-human dose selection. Regul Toxicol Pharmacol.2016;81:448-
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Smith AL, Robin TP, Ford HL. Molecular Pathways: Targeting the TGF-β Pathway for Cancer 
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Sneller MC, Kopp WC, Engelke KJ, et al. IL-15 administered by continuous infusion to rhesus 
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Strauss J, Gatti-Mays ME, Cho BC, et al. Bintrafusp alfa, a bifunctional fusion protein targeting 
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Immunother Cancer.2020;8(2). 
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Biomedicine 72 (2003) 117-125. 
 
 

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Appendix I – ECOG Performance Status 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair.* 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am 
J Clin Oncol. 1982;5:649-655. 

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Appendix II – Expected Adverse Events for HCW9218 
HCW9128 has not yet been evaluated in human clinical studies. Thus, the expected AEs are based on the published clinical 
experience with other related immunotherapies, including recombinant human IL-2 (Dutcher et al, 2014), recombinant 
human IL-15 (rhIL-15) (Conlon et al, 2019; Miller et al, 2018; Conlon et al, 2015), IL-15 mutein/IL15RαSu-Fc complex (ALT-
803, nogapendekin alfa inbakicept) (Lafyatis et al, 2020; Mascarenhas et al, 2020; Yap et al, 2020), TGFβRII-Fc fusion 
(AVID200) (Lafyatis et al, 2020; Mascarenhas et al, 2020; Yap et al, 2020), TGFβRII-anti-PD-L1 IgG1 fusion (M7824, 
bintrafusp alfa) (Tan et al, 2021; Khasraw et al, 2021; Kang et al, 2020; Strauss et al, 2020), and anti-TGF-β antibody 
(fresolimumab) (Lacouture et al, 2015; Morris et al, 2014).  
All Adverse Events listed in the Table below are defined as "Expected" for the purpose of Expedited Reporting. These AEs 
should be reported according to Section 10. 
CTCAE v5.0 System Organ Class 
(SOC)  
CTCAE Term 
Reported in Subject Receiving: 
IL-2 
IL-15 
TGF-β antagonist 
Blood and lymphatic system disorders 
Anemia  
X 
X 
X 
Disseminated intravascular coagulation 
X 
 
 
Eosinophilia 
X 
 
 
Febrile neutropenia 
X 
 
 
Leukocytosis 
X 
 
 
Cardiac Disorders 
Atrial fibrillation  
X 
 
 
Atrial flutter 
X 
 
 
Cardiac arrest  
X 
 
 
Chest pain - cardiac  
X 
X 
 
Conduction disorder  
X 
 
 
Mobitz type I  
X 
 
 
Mobitz (type) II atrioventricular block  
X 
 
 
Myocardial infarction  
X 
 
 
Myocarditis  
X 
 
 
Palpitations  
 
 
X 
Pericardial effusion  
X 
 
 
Pericardial tamponade  
X 
 
 
Pericarditis  
X 
 
 
Restrictive cardiomyopathy  
X 
 
 
Supraventricular tachycardia  
X 
X 
 
Sinus bradycardia  
X 
 
 
Ventricular arrhythmia  
X 
 
 
Ventricular tachycardia  
X 
X 
 
Endocrine disorders Eye disorders 
Hypothyroidism  
X 
 
 
Blurred vision  
 
X 
 
Extraocular muscle paresis  
 
 
X 
Optic nerve disorder  
X 
 
 
Other, mydriasis  
X 
 
 
Other, pupillary disorder  
X 
 
 
Papilledema  
 
X 
 
Uveitis 
 
X 
 
 
 
 
 
 
Gastrointestinal disorders 
Abdominal distension 
X 
 
 

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CTCAE v5.0 System Organ Class 
(SOC)  
CTCAE Term 
Reported in Subject Receiving: 
IL-2 
IL-15 
TGF-β antagonist 
Abdominal pain  
X 
X 
X 
Colitis 
X 
 
 
Colonic perforation  
X 
 
 
Constipation  
 
 
X 
Diarrhea  
X 
X 
X 
Duodenal hemorrhage  
X 
 
 
Duodenal ulcer  
X 
X 
 
Esophageal fistula  
X 
 
 
Gastritis  
X 
X 
 
Lower gastrointestinal hemorrhage  
X 
 
 
Nausea  
X 
X 
X 
Mucositis oral  
X 
X 
 
Obstruction gastric  
X 
 
 
Oral hemorrhage 
 
 
X 
Pancreatitis  
X 
X 
 
Rectal perforation  
X 
 
 
Retroperitoneal hemorrhage  
X 
 
 
Small intestinal perforation  
X 
 
 
Intra-abdominal hemorrhage  
X 
 
 
Upper gastrointestinal hemorrhage  
X 
 
 
Visceral arterial ischemia  
X 
X 
 
Vomiting 
X 
X 
X 
General disorders and administration 
site conditions 
Chills  
X 
X 
 
Edema limbs  
X 
X 
 
Fatigue  
X 
X 
X 
Fever  
X 
X 
X 
Flu like symptoms  
X 
X 
X 
Hypothermia  
X 
 
 
Localized edema  
X 
 
 
Malaise  
X 
 
 
Multi-organ failure  
X 
 
 
Injection site reaction 
X 
X 
X 
Pain 
X 
X 
 
Hepatobiliary disorders 
Cholecystitis  
X 
 
 
Hepatic failure  
X 
 
 
Immune system disorders 
Allergic reaction  
X 
 
 
Anaphylaxis  
X 
 
 
Cytokine release syndrome 
X 
X 
 
Infections and infestations 
Bacteremia  
X 
X 
 
Endocarditis infective  
X 
 
 
Hepatic infection  
X 
 
 
Lung infection  
X 
X 
 
Meningitis  
X 
 
 
Shingles  
 
 
X 
Skin infection  
X 
 
 
Sepsis 
X 
X 
 

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CTCAE v5.0 System Organ Class 
(SOC)  
CTCAE Term 
Reported in Subject Receiving: 
IL-2 
IL-15 
TGF-β antagonist 
Investigations 
Alanine aminotransferase increased  
X 
X 
 
Alkaline phosphatase increased  
X 
X 
 
Aspartate aminotransferase increased  
X 
X 
 
Blood bilirubin increased  
X 
X 
 
Cardiac troponin I increased  
 
X 
 
CPK increased  
 
 
X 
Creatinine increased 
X 
X 
 
Lymphocyte count decreased  
 
X 
 
Neutrophil count decreased  
X 
X 
 
Platelet count decreased  
X 
X 
X 
Urine output decreased  
X 
X 
 
Weight gain  
X 
 
 
White blood cell decreased 
X 
X 
 
Metabolism and 
nutrition disorders 
Acidosis  
X 
 
 
Anorexia  
X 
X 
 
Hyperglycemia  
X 
 
 
Hyperuricemia  
X 
 
X 
Hypoalbuminemia   
 
X 
 
Hypocalcemia  
X 
X 
 
Hypomagnesemia  
X 
 
 
Hypophosphatemia 
 
X 
 
Musculoskeletal and connective tissue 
disorders 
Arthralgia  
 
X 
 
Arthritis  
X 
 
 
Myositis  
X 
 
 
Rhabdomyolysis 
X 
 
 
Neoplasms benign, malignant  
Tumor hemorrhage 
 
 
X 
Nervous system disorders 
Cognitive disturbance  
X 
 
 
Dizziness  
X 
 
X 
Edema cerebral  
X 
 
 
Encephalopathy  
X 
 
 
Headache  
 
X 
X 
Intracranial hemorrhage  
X 
 
X 
Neuralgia  
X 
 
 
Peripheral motor neuropathy  
X 
 
 
Seizure  
X 
 
 
Stroke  
X 
 
 
Syncope 
X 
 
 
Transient ischemic attacks 
X 
 
 
Psychiatric disorders 
Agitation  
X 
 
 
Anxiety  
X 
 
 
Confusion  
X 
X 
 
Delirium  
X 
 
 
Depressed level of consciousness 
X 
 
 
Depression  
X 
 
 
Insomnia  
X 
 
 
Psychosis  
X 
 
 

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CTCAE v5.0 System Organ Class 
(SOC)  
CTCAE Term 
Reported in Subject Receiving: 
IL-2 
IL-15 
TGF-β antagonist 
Suicidal ideation 
X 
 
 
Renal and urinary 
disorders 
Acute kidney injury  
X 
 
 
Chronic kidney disease 
X 
 
 
Respiratory, thoracic 
and mediastinal 
disorders 
Adult respiratory distress syndrome 
X 
 
 
Allergic rhinitis  
X 
X 
 
Apnea  
X 
 
 
Cough  
X 
 
 
Dyspnea  
X 
X 
 
Epistaxis  
 
 
X 
Laryngeal hemorrhage  
X 
 
X 
Pleural effusion  
 
X 
 
Pneumothorax  
X 
 
 
Pulmonary edema  
X 
 
 
Respiratory failure  
X 
 
 
Pharyngeal mucositis  
X 
 
 
Tracheal fistula 
X 
 
 
Skin and subcutaneous 
tissue disorders 
Dry skin  
 
X 
 
Erythroderma 
X 
 
 
Hyperkeratosis  
 
 
X 
Pruritus  
X 
X 
X 
Other, actinic keratosis  
 
 
X 
Other, basal cell carcinoma  
 
 
X 
Other, keratoacanthoma  
 
 
X 
Other, lichenoid keratosis  
 
 
X 
Other, squamous cell carcinoma 
 
 
X 
Rash acneiform  
X 
 
 
Rash maculo-papular  
X 
X 
X 
Stevens-Johnson syndrome  
X 
 
 
Urticaria 
X 
 
 
Vascular Disorders 
Arterial thromboembolism  
X 
 
 
Capillary leak syndrome 
X 
 
 
Hypertension  
 
X 
 
Hypotension 
X 
X 
 
Other, mucosal bleeding 
 
X 
X 
Phlebitis  
X 
 
 
Thromboembolic event  
X 
 
 
Vasculitis 
X 
 
 
 
 
 
 

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Appendix III – Response Evaluation Criteria in Solid Tumors (RECIST) Quick 
Reference (CTEP) 
Eligibility 
 
Only patients with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint.  
Measurable disease - the presence of at least one measurable lesion. If the measurable disease is restricted to 
a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
Measurable lesions - lesions that can be accurately measured in at least one dimension with longest diameter 
≥20 mm using conventional techniques or ≥10 mm with spiral CT scan. 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm with conventional 
techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses 
that are not confirmed and followed by imaging techniques; and. 
 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 
weeks before the beginning of the treatment.  
 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up.  
 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable 
lymph nodes). For the case of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
Methods of Measurement –  
 
CT and MRI are the best currently available and reproducible methods to measure target lesions selected for 
response assessment. Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm.  This 
applies to tumors of the chest, abdomen and pelvis. Head and neck tumors and those of extremities usually 
require specific protocols. 
 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and surrounded by 
aerated lung. However, CT is preferable.  
 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should not be used to 
measure tumor lesions. It is, however, a possible alternative to clinical measurements of superficial palpable 
lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been fully and widely 
validated. Their uses in this specific context require sophisticated equipment and a high level of expertise that 
may only be available in some centers. Therefore, the utilization of such techniques for objective tumor response 
should be restricted to validation purposes in specialized centers. However, such techniques can be useful in 
confirming complete pathological response when biopsies are obtained. 
 
Tumor markers alone cannot be used to assess response.  If markers are initially above the upper normal limit, 
they must normalize for a patient to be considered in complete clinical response when all lesions have 
disappeared. 
 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after treatment to 
differentiate between residual benign lesions and residual malignant lesions in tumor types such as germ cell 
tumors). 
 
 

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Baseline documentation of “Target” and “Non-Target” lesions 
 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative of all 
involved organs should be identified as target lesions and recorded and measured at baseline.  
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability 
for accurate repeated measurements (either by imaging techniques or clinically).  
 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. 
The baseline sum LD will be used as reference by which to characterize the objective tumor. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence or absence of each should be noted 
throughout follow-up.  
 
Response Criteria 
Evaluation of target lesions 
* Complete Response 
(CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD 
* Progressive Disease 
(PD): 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started 
 
Evaluation of non-target lesions 
* Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of tumor marker 
level 
* Incomplete Response/    
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance of tumor 
marker level above the normal limits 
* Progressive Disease 
(PD): 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions (1)  
(1) Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the opinion of the 
treating physician should prevail and the progression status should be confirmed later on by the review panel (or study 
chair). 
 
 

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Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In 
general, the patient's best response assignment will depend on the achievement of both measurement and confirmation 
criteria  
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be classified as having “symptomatic deterioration”. Every 
effort should be made to document the objective progression even after discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the evaluation 
of complete response depends on this determination, it is recommended that the residual lesion be investigated 
(fine needle aspirate/biopsy) to confirm the complete response status. 
Confirmation 
 
The main goal of confirmation of objective response is to avoid overestimating the response rate observed.  In 
cases where confirmation of response is not feasible, it should be made clear when reporting the outcome of such 
studies that the responses are not confirmed. 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first met. Longer 
intervals as determined by the study protocol may also be appropriate.  
 
In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general, not less than 6-8 weeks) that is defined in the study protocol  
Duration of overall response 
 
The duration of overall response is measured from the time measurement criteria are met for CR or PR 
(whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as 
reference for PD the smallest measurements recorded since the treatment started. 
Duration of stable disease 
 
SD is measured from the start of the treatment until the criteria for disease progression are met, taking as 
reference the smallest measurements recorded since the treatment started.  
 
The clinical relevance of the duration of SD varies for different tumor types and grades. Therefore, it is highly 
recommended that the protocol specify the minimal time interval required between two measurements for 
determination of SD. This time interval should take into account the expected clinical benefit that such a status 
may bring to the population under study.  
Response review 

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 
For trials where the response rate is the primary endpoint it is strongly recommended that all responses be 
reviewed by an expert(s) independent of the study at the study’s completion.  Simultaneous review of the patients’ 
files and radiological images is the best approach.  
Reporting of results 
 
All patients included in the study must be assessed for response to treatment, even if there are major protocol 
treatment deviations or if they are ineligible.  Each patient will be assigned one of the following categories: 1) 
complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). 
 
All of the patients who met the eligibility criteria should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered as failing to respond to treatment (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate.  Precise definitions for categories 4-9 will be protocol specific. 
 
All conclusions should be based on all eligible patients. 
 
Sub-analyses may then be performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, early discontinuation of treatment, 
major protocol violations, etc.).  However, these sub-analyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.   
 
The 95% confidence intervals should be provided. 
 
 

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Appendix IV – Targeted Toxicity Worksheet 
See Section 10.2 for time points 
 
 
 
 
 
 
based on CTCAE v5 
 Patient Initials or ID:  _______ Date of Assessment:  _________     Assessment Time Point:  _________  
ADL = activities of daily living     
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Injection site 
reaction 
None 
Tenderness with or 
without associated 
symptoms (e.g., warmth, 
erythema, itching) 
Pain; lipodystrophy; edema; 
phlebitis 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Flu-like symptoms* 
None  
 
Mild flu-like symptoms 
present 
Moderate symptoms; limiting 
instrumental ADL 
Severe symptoms; limiting 
instrumental ADL 
……………………… 
*includes fever, chills, body aches, malaise, loss of appetite and dry cough 
Fatigue 
None 
Fatigue relieved by rest 
Fatigue not relieved by rest; 
limiting instrumental ADL 
Fatigue not relieved by rest, 
limiting self care ADL 
……………………… 
Fever 
None 
38.0 - 39.0◦ C (100.4 -
102.2◦ F) 
> 39.0 - 40.0◦C (102.3 - 104.0◦F) 
> 40.0 ◦ C (>104.0◦ F) for ≤ 24 hrs 
> 40.0 ◦ C (>104.0◦ F) for > 24 
hrs 
Headache 
None 
Mild pain 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self care 
ADL 
……………………… 
Palpitations 
None 
Mild symptoms; intervention 
not indicated 
Intervention indicated 
……………………… 
……………………… 
Nausea 
None 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased without 
significant weight loss, 
dehydration or malnutrition 
Inadequate oral caloric or 
fluid intake; tube feeding, 
TPN, or hospitalization 
indicated 
……………………… 
Vomiting 
None 
Intervention not indicated 
Outpatient IV hydration; 
medical intervention indicated 
Tube feeding, TPN, or 
hospitalization indicated 
Life-threatening consequences; 
urgent intervention indicated 
Diarrhea 
None 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 - 6 stools per day 
over baseline; moderate increase 
in ostomy output compared to 
baseline; limiting instrumental ADL 
Increase of >=7 stools per day 
over baseline; hospitalization 
indicated; severe increase in 
ostomy output compared to 
baseline; limiting self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
Constipation 
None 
Occasional or intermittent 
symptoms; occasional use 
of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with regular 
use of laxatives or enemas; limiting 
instrumental ADL 
Obstipation with manual 
evacuation indicated; limiting 
self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
Other Skin/ 
Subcutaneous – 
Specify 
_____________  
None 
Per CTCAE v5 criteria 
Per CTCAE v5 criteria 
Per CTCAE v5 criteria 
Per CTCAE v5 criteria 
 
Person Completing Form:   
 
 
 
 
 
 
Signature of Person Completing This Form:   
 
 
 
 
 
 

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Appendix V – FACT-G Quality of Life Questionnaire 
 
 
 

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Appendix VI – Skin Condition Questionnaire 
 
The below is the content of the questionnaire – the actual questionnaire will be administered through REDCap. 
 
Patients may have changes in the condition of their skin following treatment with the study 
medication.  
Please indicate the extent to which you have experienced these changes during the past 4 weeks. 
Please describe any changes you have experienced. 
During the past 4 weeks: 
1. Have you experienced any changes in the condition of your skin at the site of study medication 
injection?      Yes☐   No☐ 
If Yes, please describe the changes: 
 
2. Aside from the injection site, have you experienced any new changes in the condition of your skin 
following treatment with the study medication?   Yes☐   No☐ 
If Yes, please describe the changes: 
 
3. Have you experienced any changes in pre-existing skin conditions following treatment with the 
study medication?   Yes☐   No☐ 
If Yes, please describe the changes: