Clinical trial NCT03829501
Conditions: Squamous Cell Carcinoma of Head and Neck Non-small Cell Lung Cancer Hepatocellular Carcinoma Esophageal Cancer Gastric Cancer Melanoma Renal Cell Carcinoma Pancreatic Cancer Cervical Cancer Triple Negative Breast Cancer Advanced Cancer Metastatic Cancer
Sponsor: Kymab Limited
Start date: 2019-01-28; Completion date: 2024-10-03
Enrollment: 222 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A Phase 1/2, open label, multi-center study to evaluate the safety, efficacy and tolerability of alomfilimab as single agent and in combination with anti-PD-L1 (atezolizumab) in adult patients with selected advanced malignancies, who are ineligible for or there are no available therapies known to confer a clinical benefit for their disease, or they have exhausted all such available options in each indication and therefore will be patients for whom a clinical trial is appropriate.

Detailed description:

Arms: arm 1: Participants will receive alomfilimab 0.8 to 240 mg as a single agent via intravenous (IV) infusion every 3 weeks (Q3W). arm 2: Participants will receive alomfilimab 2.4 to 80 mg in combination with atezolizumab 1200 mg via IV infusion Q3W. arm 3: Anti-PD-(L)1 naïve participants with pancreatic cancer, triple negative breast cancer (BC) or head and neck squamous cell carcinoma (HNSCC) will receive alomfilimab 2.4 to 24 mg in combination with atezolizumab 1200 mg via IV infusion Q3W. arm 4: Pre-treated participants with pancreatic cancer, triple negative BC or HNSCC will receive alomfilimab 2.4 to 24 mg in combination with atezolizumab 1200 mg via IV infusion Q3W.
Interventions: intervention 1: Alomfilimab intervention 2: Atezolizumab
Intervention descriptions: intervention 1: A human anti-ICOS monoclonal antibody intervention 2: An anti-PD-L1 monoclonal antibody

Protocol documents:
Prot_000.pdf: 
Protocol Number: KY1044-CT01 
Official Title: A Phase 1/2, Open-Label, Multi-Center Study of the Safety and Efficacy of KY1044 As 
Single Agent and in Combination with Anti-PD-L1 (Atezolizumab) in Adult Patients with Selected 
Advanced Malignancies 
NCT Number: NCT03829501 
Document Date: 10 November 2021 


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AMENDED CLINICAL TRIAL PROTOCOL 07 
Protocol title: 
A Phase 1/2, Open-label, Multi-center Study of the 
Safety and Efficacy of KY1044 as Single Agent and in 
Combination with Anti-PD-L1 (Atezolizumab) in Adult 
Patients with Selected Advanced Malignancies 
Protocol number: 
KY1044-CT01/ TCD17370 
Amendment number: 
06 
Compound number 
(INN/Trademark): 
KY1044/SAR445256 (alomfilimab) 
Brief title: 
KY1044 Phase 1/2 study as single agent and in 
combination with atezolizumab 
Study Phase: 
1/2 
Sponsor name: 
Kymab Ltd 
Legal registered 
address: 
The Bennet Building (B930) 
Babraham Research Campus 
Cambridge, CB22 3AT 
United Kingdom 
Tel: 
 
Monitoring team’s 
representative name 
and contact 
information: 
Regulatory agency 
identifier number(s): 
IND: 
139250 
EudraCT: 
2018-003172-12 
NCT: 
Not applicable 
WHO: 
Not applicable 
EUDAMED: 
Not applicable 
Other 
Not applicable 
Date: 10-Nov-2021 
Total number of pages: 
217 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 07 
All 
10 November 2021, 
version 1 (electronic 1.0) 
Clinical Study Protocol Version 6.0 
All 
07 May 2021 
Clinical Study Protocol Version 5.0 
All 
28 July 2020 
Clinical Study Protocol Version 4.0 
All 
08 May 2019 
Clinical Study Protocol Version 3.0 
All 
24 January 2019 
Clinical Study Protocol Version 2.0 
All 
14 November 2018 
Clinical Study Protocol Version 1.0 
(original) 
All 
24 August 2018 
Note: The name and numbering of the protocol is based on a new numbering system followed by the Sponsor.  
Amended Clinical Trial Protocol 07 (10 November 2021) 
This amended clinical trial protocol 07 (Amendment 6) is considered to be substantial based 
on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament 
and the Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reasons for this amendment to Protocol KY1044-CT01 are to define Triple 
Negative Breast Cancer (TNBC) and Head and Neck Squamous Cell Carcinoma (HNSCC) as 
selected indications of interest for Phase 2 and to clarify and add safety language. 
 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Whole document 
New logo has been added and an 
update to the amendment number 
version, date has been made 
To be compliant with company 
conventions 
Cover page and 
reviewers/approvers 
Update of cover page has been made 
To reflect the changes resulting 
from the acquisition and to 
comply with the SOP applicable 
to the protocol template utilized 
Section Protocol Synopsis 
- Statistical analysis
and Section 9.4.2.1
80% has been added in the reference 
to confidence intervals 
To maintain consistency in the 
CIs stated in the protocol 
Section protocol synopsis 
- Planned study dates
- Duration of study
and Section 3.4
Q3 2023/ Q1 2024 has been added 
To reflect new timelines and to 
provide clarity to the vendors 
Approximately 70 cycles have been 
specified 
Section protocol synopsis 
- Indication: Phase 2
- Study Population
Abbreviation
Section 3.1 ; 3.1.2 and 3.1.4 
Adding TNBC to list of indications 
To specify the indications 
selected for Phase 2 expansion. 
TNBC and HNSCC selected as 
indications of interest for Phase 2 
Section protocol synopsis: 
- Secondary objective
And Section 2.1.2
A secondary objective has been 
added: “- To assess PK of 
atezolizumab in combination with 
KY1044” 
To complete the secondary 
objectives  
Section Protocol Synopsis 
- Secondary endpoints: PK
measures
And Section 2.2.2
The definition of PK measures: 
“KY1044 PK measures (eg, 
maximum concentration [Cmax], 
half-life); Serum concentration vs. 
time profiles  has been replaced by: 
“Serum concentrations and PK 
parameters (eg, Cmax, t1/2) of 
KY1044 and of atezolizumab if in 
combination.” 
To clarify the definition of  PK 
measures  
Section Protocol Synopsis 
- Study Design
Figure 3.2 Section
Section 3.1; 3.4; 5.3 and
Table 6-1; Table 6-2 and
Table 6-8
The mode of administration of 
KY1044 description has been 
modify: “for up to 48 months or until 
the patient discontinues the study.” 
Has been removed and replaced by 
“Study treatment will be 
administered for up to 48 months or 
until the patient discontinues the 
study treatment” 
To clarify the language on 
duration of treatment 
Flexibility in language has been 
added to up to 48 months treatment 
duration: will replaced by may  be up 
to 48 months; maximum delated in 
max period up to 48 months 
To introduce flexibility in 
maximum treatment duration 
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Section # and Name 
Description of Change 
Brief Rationale 
Section Protocol Synopsis  
- Key inclusion criteria 
and Section 4.2 
 
Inclusion criteria has been defined 
for the HNSCC and NSCLC 
indications    
For clarification and better 
understanding of HNSCC and 
NSCLC indications inclusion 
criteria  
Section Protocol Synopsis 
- Pharmacokinetic variables 
Absorption has beenreplaced by 
distribution in the definition of PK 
variables 
For language accuracy  
Section Protocol Synopsis 
- Duration of the study 
Section 3.1; Figure 3-1; 
Section 3.6 and Section 5.3 
Will has been replaced by may in 
“provisions will be made”  
To be compliant with Section 3.4 
Study duration. 
Section 3.1.4 
 
n for selected indications has been 
updated 
 
Statistical calculations for new 
cohorts 
 
Figure 3-1 
Figure of study design has been 
updated in view of new patient 
number for selected indications and 
Phase 2 choosed design 
To be compliant with defined 
study design 
Section 3.4 
Sentence: “up to 2 years (or as long 
as the treatment continues if it lasts 
more than 2 years)” has been added 
to “All patients will be followed up 
for survival …” 
For follow up duration precision  
Section 9.2  
Sample size  
determination Phase 2 
 
The cohort expansion number has 
been updated to up to 40 per 
subgroup. The corresponding section 
pertaining to CIs has also been 
updated. 
 
Statistical calculations for new 
cohorts 
 
Section 
protocol 
synopsis 
and 4.3 
 
Fridericia's formula (QTcF) specified 
for calculations 
 
Protocol deviations  required this 
clarification to be included 
 
Table 6-1 and Table 6-2 
 
Timeline for confirmatory scan 
clarified to include the language”4 to 
8 weeks. 
 
To comply with the precise 
language in the iRECIST 
guidelines and ensure consistent 
reporting of tumor assessments  
 
And a sentence: “A window of 
±3 days is permissible to complete 
the assessments” has been added to 
footnote of both tables 
To add flexibility in time to 
complete assessments 
Table 6-4 
A footnote has been added #c to 
Biomarker Sample Collection Plan 
(Tumor/Blood Samples) for 
Phase 1 and 2 Table 6-4 
For clarification on biopsy and 
tumor samples 
Section 7.1, Section 7.1.2 and 
Section 7.1.5 
 
Clarification of language relating to 
AE and SAE reporting 
 
To ensure better  data collection 
and reporting  
Section 7.1.6 
 
Infusion related reactions, overdose 
and pregnacy  have now been 
designated as the AESI for both 
IMPs 
Consensus reached at the SMT 
after analysis of the AEs deemed 
as IRRS by the PIs 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1.7 
 
Language pertaining to reporting of 
deaths has been updated 
To ensure better data collection 
and reporting 
Section 7.2.2 
Definition of symptomatic overdose 
for IMPs has been included in 
guidance for overdose section 
For precision 
Section 8 
One reason for treatment 
discontinuation: “48 months of 
treatment” has been added 
And sentence “Patients will be 
automatically discontinued in case of 
death.” Has been removed 
For treatment discontinuation 
clarity and accuracy 
Section 8.1 
Clarification on patients follow up 
has been made: “(all reasons 1 to 
6 listed above)” 
For clarification 
Section 8.2.3 
End of Study for Individual Patients 
definition has been completed by 
adding: “is defined as the date […] 
last participant in the trial globally.” 
For clarification of overall end of 
study definition 
Section 9.4.3 
Section safety analysis has been 
completed by adding a chapter: 
“Actual and change from baseline 
[…]range value will be displayed.” 
For clarification 
Section 9.4.4 
The additional pharmacokinetic 
section has been rephrase. Text “The 
estimation of area […] summarized 
in order to linearity of 
pharmacokinetics.” Has been 
removed. And section for 
Exploratory and PK population 
analysis have been added. 
Clarification of PK analysis 
section 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
corrections) were implemented throughout the protocol. 
 
 
 
 
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COMPLIANCE STATEMENT  
The study will be conducted in compliance with the protocol, informed consent regulations, 
the general principles of the Declaration of Helsinki and the ICH E6(R2) guidelines related to 
GCP. In addition, the study will adhere to all applicable state, regional and national regulatory 
requirements. 
The electronic data capture systems and other applicable electronic systems used in the conduct 
of the study will comply with ICH E6(R2), Section 5.5.3 guidance on use of electronic trial 
data handling and/or remote electronic trial data systems and the Food and Drug Administration 
(FDA), 21 CFR Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance for 
Industry: Computerized Systems Used in Clinical Trials. 
Central safety, Pharmacokinetic (PK) and pharmacodynamic (PD) analyses will be performed 
in laboratories qualified in accordance with the procedures of the Sponsor or the Sponsor’s 
contracted CRO. Local safety analysis will be performed in accordance with institutional 
standards applicable at the relevant Investigator site.  
All episodes of non-compliance will be documented and addressed. Significant 
non-compliance (with potential to impact on patient safety or the integrity of data) will be 
notified to Sponsor promptly. Noncompliance with the protocol, SOPs, ICH GCP, and/or 
applicable regulatory requirement(s) will lead to prompt action by the Sponsor to secure 
compliance. If serious and/or persistent non-compliance is identified on the part of an 
investigator/institution, Sponsor will terminate the investigator's/institution’s participation in 
the trial in accordance with ICH GCP. 
The Sponsor will ensure there is appropriate oversight of any trial-related duties and functions 
carried out on its behalf by contracted vendors, and where applicable ensure the Sponsor’s 
contracted CRO(s) have appropriate systems processes to provide oversight of duties 
subcontracted to another party by them. 
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PROTOCOL SYNOPSIS  
Protocol identifier: 
KY1044-CT01 
Study title: 
A Phase 1/2, open-label, multi-center study of the safety and efficacy of KY1044 
as single agent and in combination with anti-PD-L1 (atezolizumab) in adult 
patients with selected advanced malignancies 
Sponsor: 
Kymab Ltd 
Phase: 
1/2 
Study type: 
Interventional 
Indication: 
Phase 1:  
Advanced/metastatic malignancies, and preferred indications: head and neck 
squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), 
hepatocellular carcinoma (HCC), gastric/esophageal cancer, melanoma, renal cell 
cancer, pancreatic cancer, cervical cancer, and triple negative breast cancer (BC) 
Phase 2: 
• 
Anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed cell 
death-ligand 1 (anti-PD-L1) treatment naïve: HNSCC, NSCLC, triple 
negative breast cancer (TNBC), gastric/esophageal and cervical cancer 
• 
Anti-PD-(L)1 pre-treated: HNSCC, NSCLC, TNBC, gastric/esophageal and 
cervical cancer 
• 
Indications in which anti-tumor activity has been observed in Phase 1 
Purpose and rationale: 
The purpose of this “first-in-human” study of KY1044 is to characterize the 
safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and 
anti-tumor activity of KY1044 administered intravenously (IV) as single agent 
and in combination with atezolizumab in adult patients with advanced/metastatic 
malignancies 
Primary objectives 
• 
Phase 1: to characterize the safety and tolerability of KY1044 as single agent 
and in combination with atezolizumab and to identify recommended doses 
for future studies 
• 
Phase 2: to estimate the anti-tumor efficacy of KY1044 as single agent and 
in combination with atezolizumab 
Secondary objectives 
• 
To evaluate the preliminary anti-tumor activity of KY1044 as single agent 
and in combination with atezolizumab (Phase 1 only)  
• 
To characterize the safety and tolerability of KY1044 as single agent and in 
combination with atezolizumab (Phase 2 only)  
• 
To characterize the PK profile of KY1044 as single agent and in combination 
with atezolizumab  
• 
To assess PK of atezolizumab in combination with KY1044 
• 
To assess emergence of anti-KY1044 and anti-atezolizumab antibodies 
following one or more IV infusions of KY1044 as single agent and/or in 
combination with atezolizumab, respectively 
• 
To assess changes in biomarkers from baseline in tumor tissue as potential 
predictors of efficacy of KY1044 as single agent and in combination with 
atezolizumab 
• 
To describe the survival rate at 12 and 24 months of patients treated with 
KY1044 as single agent and in combination with atezolizumab for each 
disease group 
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Exploratory objectives 
• 
To assess the pharmacodynamic effect of KY1044 as single agent and in 
combination with atezolizumab in tumor tissue  
• 
To assess the pharmacodynamic effect of KY1044 as single agent and in 
combination with atezolizumab in peripheral blood  
• 
To determine the level of target occupancy in response to KY1044 as single 
agent (Phase 1)  
Study design: 
This study is a first in human, open-label, Phase 1/2, multi-center study consisting 
of a Phase 1 dose escalation component with KY1044 as single agent and a dose 
escalation of KY1044 in combination with atezolizumab that will start after at 
least two cohorts of KY1044 as single agent have been considered to be safe and 
tolerable.  
KY1044 will be administered IV every 3 weeks (Q3W) and Atezolizumab will be 
administered according to dosing instructions given in the approved label for 
marketing (1200 mg IV Q3W). Study treatment will be administered for up to 
48 months or until the patient discontinues the study treatment.  
Patients should not discontinue treatment based on progressive disease per 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) unless clinical 
deterioration or increase in tumor markers is observed. 
Phase 1 dose escalation: 
The Phase 1 dose escalation part of the study will enroll cohorts of minimum 
three patients.  To assess the safety profile of KY1044 it will be required that each 
cohort satisfies the following requirements: 
• 
At least two patients are anti-PD-(L)1 naïve  
• 
Only one patient has a non-preferred tumor type  
• 
All inclusion/exclusion criteria are met. 
Phase 1: Enrichment cohorts (optional) 
An optional enrichment part may include the testing of additional patients at one 
or more dose levels to better understand the safety, tolerability, biomarkers, PK, 
preliminary anti-tumor efficacy and /or PK/PD relationships of KY1044 as single 
agent and/or in combination with atezolizumab.  
The enrichment part of the study will only use doses that have already been 
explored in the Phase 1 dose escalation part of the study, and have been 
determined to be safe.  
Phase 2:  
In the absence of identifying a maximal tolerated dose (MTD) or single 
efficacious dose in Phase 1, an initial Phase 2 dose assessment part in one or more 
specific indication(s) will be opened to compare the efficacy and biomarker 
readouts of two biologically relevant dose levels of KY1044 (as single agent or in 
combination with atezolizumab) in a more homogeneous population.  Together 
with safety, efficacy and biomarker data from Phase 1, data from this part will 
assist with the selection of the recommended Phase 2 dose (RP2D). 
Once the MTD and/or RP2D for KY1044 as single agent or in combination with 
atezolizumab has been defined, a Phase 2 expansion component to assess 
preliminary anti-tumor efficacy in additional selected indications may commence. 
Patients who are either anti-PD-(L)1 treatment naïve or who have had prior 
treatment with anti-PD-(L)1 will be considered as separate groups. 
In anti-PD-(L)1 naive patients: 
In Phase 2 approximately 15 patients will be enrolled in the anti-PD-(L)1 naïve 
subgroup per each indication, in the single agent and the combination group.  
In anti-PD-(L)1 pre-treated patients: 
In the anti-PD-(L)1 pre-treated subgroup a minimum of five patients will be 
recruited in each indication. These patients will have already progressed on 
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previous immunotherapy; hence any individual response would indicate a proof 
of mechanism in these patient groups.  If signs of efficacy have been observed in 
any of these anti-PD-(L)1 pre-treated indications a further expansion to 
15 patients will be considered. 
Sample size: 
In Phase 1, each of the dose escalations (single agent and combination therapy) 
will include a maximum of 36 patients, unless no dose levels are determined to be 
safe or the safety review committee (SRC) decides to stop the dose escalation part.  
If fewer than 36 patients are required to dose escalate, the remainder may be 
included in the enrichment part.  The Phase 1 part of the study (dose escalation 
and enrichment cohorts) may contain approximately 150 patients.  The actual 
number of patients recruited in the Phase 2 part of the study will depend on the 
number of tumor indications investigated and on the number of expansions; 
however the total number in Phase 2 is not anticipated to exceed 262 patients. 
Study population: 
• 
The Phase 1 dose escalation and enrichment parts of the study will be 
conducted in adult patients with advanced/metastatic malignancies and 
selected indications: NSCLC, HNSCC, HCC, gastric/esophageal cancer, 
melanoma, renal, cervical cancer, TNBC and pancreatic cancer.  
• 
An initial Phase 2 dose assessment part will be opened in one or more specific 
indication(s), in which efficacy has been observed in Phase 1 to support 
definition of the RP2D for future indications. 
• 
A Phase 2 KY1044 single agent part will be opened should signs of 
anti-tumor activity (defined as either complete response (CR), partial 
response (PR) or durable stable disease (SD) with tumor shrinkage that does 
not qualify for PR) be seen in the Phase 1 dose escalation/enrichment.  
• 
A Phase 2 KY1044 combination with atezolizumab part will enroll patients 
in 
selected indications (NSCLC, HNSCC, TNBC, cervical and 
gastric/esophageal cancer and any indication where KY1044 in combination 
with atezolizumab has shown signs of anti-tumor activity in the Phase 1 dose 
escalation)  
Key inclusion criteria: 
1. Histologically documented advanced/metastatic malignancies 
2. Phase 1 and Phase 2 patients with advanced/metastatic malignancies who have 
measurable  disease (non-measurable disease is allowed only in Phase 1) as 
determined by RECIST 1.1 will be eligible if, according to the NCCN 
guidelines,  there are no available therapies known to confer a clinical benefit 
for their disease, or they have exhausted all such available options. 
Additionally, the following specific tumor indications will be enrolled:  
a. Phase 1 (including enrichment part): 
Patients 
with 
advanced/metastatic 
malignancies, 
and 
preferred 
indications 
(NSCLC, 
HNSCC, 
HCC, 
melanoma, 
cervical, 
gastric/esophageal, renal, pancreatic, and triple negative BC) 
b. Phase 2 KY1044 single agent: 
Patients with advanced/metastatic malignancies in indications in which 
signs of anti-tumor activity (CR, PR or durable SD with tumor shrinkage 
that does not qualify for PR) were seen during the dose 
escalation/enrichment of KY1044 as single agent. 
c. 
Phase 2 KY1044 in combination with atezolizumab: 
Patients with advanced/metastatic malignancies in the selected 
indications below, and/or indications which have shown promising 
activity in Phase 1: 
• 
NSCLC (anti-PD-(L)1 therapy naïve and pre-treated between 1 and 
2 prior lines of systemic therapy for advanced disease) 
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• 
Recurrent and/or metastatic HNSCC (anti-PD-(L)1 therapy naïve 
and pre-treated between 1 and 2 prior lines of systemic therapy for 
advanced disease)  
• 
Gastric/ Esophageal cancer (anti-PD-(L)1 therapy naïve and 
pre-treated) 
• 
Cervical cancer (anti-PD-(L)1 therapy naïve and pre-treated) 
• 
Indications, in which signs of anti-tumor activity has been observed 
in Phase 1 with KY1044 in combination with atezolizumab 
3. Prior therapy with anti-PD-(L)1 inhibitors is allowed provided any toxicity 
attributed to prior anti-PD-(L)1-directed therapy did not lead to 
discontinuation of therapy. 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 
5. Life expectancy longer than 12 weeks. 
6. Must have a site of disease amendable to biopsy, and be candidate for tumor 
biopsy, according to the treating institution’s guidelines. Patients must be 
willing to undergo a new tumor biopsy at screening and during therapy on the 
study. 
7. Women of childbearing potential and men must agree to use adequate 
contraception prior to study entry, for the duration of study participation and 
for at least 5 months after discontinuing study treatment, or longer if the 
half-life of KY1044 is observed to exceed that of atezolizumab. 
Key exclusion criteria: 
1. Presence of symptomatic central nervous system (CNS) metastases unless 
neurologically stable (for 4 weeks) and off steroids for at least 2 weeks before 
the first dose of study treatment. 
2. History of severe hypersensitivity reactions to other monoclonal antibodies 
(mAbs) and/or their excipients. 
3. Known presence of neutralizing anti-atezolizumab antibodies. 
4. Patients previously exposed to anti-PD-(L)1 treatment who are not adequately 
treated for skin rash or have no replacement therapy for endocrinopathies.  
5. Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV) 
or active hepatitis C virus (HCV) infection.  Patients with HCC, whose HBV 
or HCV infection is controlled by antiviral therapy, should not be excluded  
Patients with any severe infection within 4 weeks prior to initiation of study 
treatment, including, but not limited to, hospitalization for complications of 
infection.  
6. Active autoimmune disease or a documented history of autoimmune disease, 
including ulcerative colitis and Crohn’s disease or any condition that requires 
systemic steroids. 
7. Malignant disease, other than that being treated in this study. Exceptions to 
this exclusion criterion include malignancies that were treated curatively and 
have not recurred within 2 years prior to the first dose of study treatment; 
completely resected basal cell and squamous cell skin cancers; and completely 
resected carcinoma in situ of any type. 
8. Systemic steroid therapy or any immunosuppressive therapy (≥10 mg/day 
prednisone or equivalent). 
9. Anti-CTLA4, anti-PD-(L)1 treatment within 4 weeks of the first dose of study 
treatment 
10. Pretreatment with anti-CTLA4 antibodies in combination with other 
antibodies or drugs, specifically targeting T-cell stimulation or checkpoint 
pathways.  
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11. Systemic anti-cancer therapy (tyrosine kinase inhibitor (TKI) and/or 
chemotherapy) within 2 weeks of the first dose of study treatment. For 
cytotoxic agents that have major delayed toxicity, eg, mitomycin C and 
nitrosourea, 4 weeks is indicated as washout period. 
12. Use of live or live attenuated vaccines against infectious diseases (examples 
include, but are not limited to, intranasal influenza, measles, mumps, rubella, 
oral polio, Bacillus Calmette-Guérin vaccine, rotavirus, varicella, yellow 
fever, TY21a typhoid vaccines etc) within 4 weeks of the first dose of study 
treatment and it should not be planned to administer such a vaccine during the 
course of the study.  SARS-CoV-2 vaccines authorized for use by the 
competent local regulatory health authorities for active immunization to 
prevent COVID-19 are allowed (unless the vaccine is live or live attenuated) 
and must be given in accordance with the prevailing immunization guidelines. 
SARS-CoV-2 vaccination may be given at least 7 days prior to the planned 
first dose of study treatment.  
13. Participation in an interventional, investigational study within 4 weeks of the 
first dose of study treatment. 
14. Impaired cardiac function or clinically significant cardiac disease, including 
any of the following: 
a. Clinically significant and/or uncontrolled heart disease such as 
congestive heart failure requiring treatment (New York Heart 
Association (NYHA) Grade ≥2), uncontrolled hypertension or clinically 
significant arrhythmia 
b. QTcF >470 msec on screening electrocardiogram (ECG) using 
Fridericia's formula (QTcF) or congenital long QT syndrome 
c. Acute myocardial infarction or unstable angina pectoris <3 months prior 
to first dose of study treatment 
15. Presence of Common Terminology Criteria for Adverse Events Version 5 
(CTCAE v5) ≥Grade 2 toxicity (except alopecia, peripheral neuropathy and 
ototoxicity, which are excluded if CTCAE v5 ≥Grade 3) due to prior cancer 
therapy. 
16. Radiotherapy within 2 weeks of the first dose of study treatment, except for 
palliative radiotherapy to a limited field, such as for the treatment of bone pain 
or a focally painful tumor mass. To allow evaluation for response to treatment, 
patients enrolled in the Phase 2 part must have remaining measurable disease 
that has not been irradiated. 
Investigational 
medicinal product: 
KY1044 and atezolizumab (TECENTRIQ®) 
Route of 
administration: 
IV 
Treatment regimen(s): 
IV infusion of KY1044 Q3W. Atezolizumab is administered IV Q3W. 
Efficacy assessments: 
Tumor assessment as per RECIST 1.1. and immune-related  (i)RECIST 
Safety assessments: 
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events 
(SAEs), including changes in laboratory values, vital signs and ECGs. 
Other assessments: 
PK measures (see below), Receptor Occupancy, Immunogenicity (anti-drug 
antibody (ADA)). 
Pharmacodynamic assessment on pre- and post- treatment, newly obtained tumor 
samples, plasma and peripheral blood mononuclear cells (PBMCs). 
Pharmacogenomics.  
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Pharmacokinetic 
variables: 
Measures for distribution and elimination for KY1044 as single agent and in 
combination with atezolizumab and for atezolizumab. 
Primary endpoint: 
Phase 1: 
• 
Safety: Incidence and severity of AEs and SAEs, including changes in 
laboratory parameters, vital signs and ECGs 
• 
Tolerability: Dose interruptions, reductions and dose intensity 
• 
The incidence of Dose Limiting Toxicities (DLTs) with KY1044 as single 
agent during the first 21 days of treatment  
• 
The incidence of DLTs with KY1044 in combination with atezolizumab 
during the first 21 days of treatment  
Phase 2: 
• 
Overall response rate (ORR) per RECIST 1.1  
Secondary endpoint: 
Efficacy measures 
• 
Best Overall Response (BOR), Progression Free Survival (PFS) and Duration 
of Response (DOR) per RECIST 1.1 
• 
ORR and PFS per iRECIST (Phase 1 and Phase 2) 
• 
ORR per RECIST 1.1 (Phase 1 only)  
• 
Survival rate at 12 and 24 months 
Safety:  
• 
Incidence and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and ECGs (Phase 2) 
• 
Tolerability: Dose interruptions, reductions and dose intensity (Phase 2) 
PK measures:  
• Serum concentrations and PK parameters (eg, Cmax, t1/2) of KY1044 and of 
atezolizumab if in combination. 
ADAs 
• 
Presence and/or concentration of anti-KY1044 and anti-atezolizumab 
antibodies 
Biomarkers: 
Presence of tumor-infiltrating lymphocytes (TILs) as determined by expression 
of  inducible T cell costimulator (ICOS), Forkhead box P3 (FOXP3) and CD8 
cells (immunohistochemistry) 
Exploratory endpoints: 
Tumor tissue: 
• 
Expression of immune- and response related markers such as (but not limited 
to) PD-L1, CD163, CD68 by immunohistochemistry (IHC) 
• 
messenger ribonucleic acid (mRNA) gene signature (transcriptomics/ 
Nanostring) with special interest in interferon (IFN) gene signature 
(PanInflammatory panel and/or IO360 panel) 
Peripheral blood: 
• 
Peripheral, soluble ligands and cytokine levels (eg, interferon gamma (IFNγ), 
tumor 
necrosis 
factor 
alpha 
(TNF-α), 
granulocyte-macrophage 
colony-stimulating factor (GM-CSF) contingent on availability of assay (ie, 
Single Molecule Array SIMOA) 
• 
Phenotype and markers of immune cells (ICs) activation in peripheral blood 
(eg, CD3, CD8, CD4, regulatory T cells (TRegs), CD4 memory cells, CD25, 
FOXP3, CD45RA, ICOS, CD14, CD45, CD56, CD19 and inducible T-cell 
Costimulator Ligand (ICOSLG) fluorescence-activated cell sorting (FACS) 
or ChipCytometry) 
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• 
PBMCs gene signature (RNA) (transcriptomics/Nanostring)  
• 
ICOS Receptor Occupancy (RO) in PBMCs (KY1044 as single agent in 
Phase 1 only) 
Statistical analysis: 
Primary endpoints: Phase 1 
Treatment-related AEs/SAEs coded by primary System Organ Class (SOC) and 
Preferred Term (PT) will be summarized in those receiving at least one infusion 
of KY1044. Additional summaries by severity of AEs/SAEs will also be 
produced. 
Actual and change from baseline data for vital signs, ECG parameters and clinical 
laboratory values will be reported using summary statistics.  
The number of dose interruption, reductions and incidence of DLTs will be 
summarized. 
Primary endpoint: Phase 2 
ORR per RECIST 1.1 will be presented for each indication along with exact 80% 
and 95% confidence intervals  
Phase 1 will be reported by dose group(s) within KY1044 single agent and 
KY1044 combination groups. 
Phase 2 of the study will be reported by indication and dose group(s) within 
KY1044 single agent and KY1044 combination groups, split by anti-PD-(L)1 
naïve and pre-treated groups. 
Wherever possible, patients with the same tumor type who have received the 
recommended dose(s)/schedule(s) of KY1044 as single agent or in combination 
will be pooled for analysis. 
No formal statistical testing will be performed during Phase 2. Instead confidence 
intervals will be constructed around the objective response rate observed in each 
cohort, and this will enable decisions to be made around the likely success of 
future studies. A Go‑no‑go decision grid for Phase 2 cohort expansion will be 
developed for each indication.-- 
Final data analysis will be performed at the end of the study. 
Planned study dates: 
Start of clinical phase 
End of clinical phase 
Q1 2019 
Q3 2023 / Q1 2024 
Duration of the study: 
The duration of the study for each patient will consist of up to 28 days of 
screening, up to 48 months of treatment (approximately 70 cycles) and 90 days of 
safety follow-up.  
The completion of the study is defined as the last visit for end of safety follow-up 
for the last patient on treatment.  Survival data will be reported and censored at 
the completion of the study for all patients. Additional provisions may be made 
for patients who are ongoing on treatment and having clinical benefit at 48 months 
for continuation of treatment.   
Key words: 
Phase 1/2, KY1044, atezolizumab, immunotherapy, cancer 
 
 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 07 .................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES .................................................... 2 
DOCUMENT HISTORY........................................................................................................... 2 
STUDY PERSONNEL .............................................................................................................. 6 
COMPLIANCE STATEMENT ................................................................................................. 8 
PROTOCOL SYNOPSIS .......................................................................................................... 9 
TABLE OF CONTENTS ......................................................................................................... 16 
LIST OF TABLES ................................................................................................................... 21 
LIST OF FIGURES ................................................................................................................. 21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................... 22 
1 
BACKGROUND INFORMATION ................................................................................. 28 
1.1 
Introduction ...................................................................................................... 28 
1.2 
An Introduction to ICOS and its Biology ......................................................... 28 
1.2.1 
Expression of ICOS in Cancer ......................................................... 29 
1.3 
Overview of Disease and Current Trends in Treatment ................................... 30 
1.4 
Investigational Medicinal Product(s) ............................................................... 31 
1.4.1 
Identity of IMPs ............................................................................... 31 
1.4.2 
Overview of KY1044 ...................................................................... 31 
1.4.3 
Overview of Atezolizumab .............................................................. 35 
1.4.4 
Overview of the Combination of KY1044 with Anti-PD-(L)1 
Inhibitors .......................................................................................... 37 
1.5 
Rationale ........................................................................................................... 37 
1.5.1 
Study Rationale and Purpose ........................................................... 37 
1.5.2 
Rationale for Study Design .............................................................. 38 
 
 
1.6 
Summary of Known and Potential Risks and Benefits .................................... 41 
1.6.1 
Unmet Need in the Selected Indications .......................................... 41 
1.6.2 
Possible Immune-related Toxicities Identified with Other ICIs ...... 41 
1.6.3 
Potential Risks of KY1044 Therapy as Single Agent and in 
Combination with Atezolizumab ..................................................... 41 
1.6.4 
Key Risks of Atezolizumab ............................................................. 42 
1.6.5 
Benefit/Risk of KY1044 as Single Agent and in Combination with 
Atezolizumab Regarding Potential Infections with Severe Acute 
Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) .................... 44 
2 
OBJECTIVES AND ENDPOINTS .................................................................................. 44 
2.1 
Objectives ......................................................................................................... 44 
2.1.1 
Primary Objective ............................................................................ 44 
2.1.2 
Secondary Objectives ...................................................................... 45 
2.1.3 
Exploratory Objectives .................................................................... 45 
2.2 
Endpoints .......................................................................................................... 45 
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2.2.1 
Primary Endpoints ........................................................................... 45 
2.2.2 
Secondary Endpoints ....................................................................... 46 
2.2.3 
Exploratory Endpoints ..................................................................... 46 
3 
STUDY DESIGN ............................................................................................................. 47 
3.1 
Overall Study Design and Plan ........................................................................ 47 
3.1.1 
Definitions of Study Cohorts and Groups: ...................................... 47 
3.1.2 
Tumor Indications in Phase 1 and Phase 2 ...................................... 47 
3.1.3 
Phase 1 ............................................................................................. 48 
3.1.4 
Phase 2 ............................................................................................. 48 
3.2 
Study Flow ....................................................................................................... 51 
3.3 
Study Safety Review Committee (SRC) .......................................................... 51 
3.4 
Study Duration ................................................................................................. 52 
3.5 
Timing of Interim Analysis and Design Adaptations....................................... 52 
3.6 
Definition of End of Study (EOS) .................................................................... 53 
3.7 
Early Study Termination .................................................................................. 53 
3.8 
Blinding ............................................................................................................ 53 
4 
STUDY POPULATION ................................................................................................... 53 
4.1 
Number of Patients ........................................................................................... 53 
4.1.1 
Number of Patients for Dose Escalation and Cohort Composition . 53 
4.2 
Inclusion Criteria .............................................................................................. 54 
4.3 
Exclusion Criteria ............................................................................................. 55 
5 
TREATMENT OF PATIENTS ........................................................................................ 57 
5.1 
Presentation of Study Treatments .................................................................... 57 
5.1.1 
KY1044 ............................................................................................ 57 
5.1.2 
Atezolizumab (TECENTRIQ®) ....................................................... 58 
5.2 
Study Treatment Administration ...................................................................... 58 
5.2.1 
Dosing Regimen .............................................................................. 58 
5.2.2 
Infusion of IMPs .............................................................................. 58 
5.2.3 
Precautions for IMP Administration (KY1044 and Atezolizumab) 59 
5.2.4 
Monitoring of IMP Administration (KY1044 and Atezolizumab) .. 59 
5.2.5 
Ancillary Treatments ....................................................................... 60 
5.3 
Treatment Duration .......................................................................................... 60 
5.4 
Dose Escalation Guidelines .............................................................................. 61 
5.4.1 
Starting Dose Rationale ................................................................... 61 
5.4.2 
Provisional Dose Levels .................................................................. 61 
5.4.3 
Cohort Modification ........................................................................ 63 
5.4.4 
Dose Escalation Procedures ............................................................. 63 
5.4.5 
Dose Escalation Decisions ............................................................... 64 
5.4.6 
Maximum Tolerated Dose ............................................................... 64 
5.4.7 
Recommended Dose for Further Development ............................... 65 
5.4.8 
Intra-patient Dose Escalation ........................................................... 65 
5.5 
Dose Limiting Toxicities .................................................................................. 65 
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5.6 
Dose Modifications and Management of Toxicities ........................................ 66 
5.6.1 
Dose Modifications and Dose Delays .............................................. 66 
5.6.2 
Follow-up for Toxicities .................................................................. 67 
5.6.3 
Atezolizumab Specific Recommendations: ..................................... 87 
5.7 
Concomitant Medication and Dietary Supplements ......................................... 87 
5.8 
Lifestyle Restrictions ........................................................................................ 89 
5.9 
Patient Numbering and Treatment Assignment ............................................... 90 
5.10 
Supply, Packaging, Labelling and Storage ....................................................... 90 
5.11 
IMP Accountability Records ............................................................................ 91 
5.12 
Procedures for Monitoring Patient Compliance ............................................... 91 
6 
STUDY ASSESSMENTS ................................................................................................ 91 
6.1 
Screening Assessments .................................................................................. 101 
6.1.1 
Written Informed Consent ............................................................. 101 
6.1.2 
Screening and Enrollment into the Study ...................................... 101 
6.1.3 
Screen Failures ............................................................................... 101 
6.1.4 
Demographic Information ............................................................. 102 
6.1.5 
Medical History ............................................................................. 102 
6.2 
Assessment of Efficacy .................................................................................. 102 
6.2.1 
Tumor Assessments ....................................................................... 102 
6.3 
Assessment of Pharmacodynamics ................................................................ 105 
6.3.1 
Biomarkers ..................................................................................... 105 
6.3.2 
Tumor Samples .............................................................................. 107 
6.3.3 
Blood Samples ............................................................................... 108 
6.3.4 
Storage, Re-use and Destruction of Biological Samples ............... 109 
6.4 
Pharmacokinetic and Anti-drug Antibody Procedures ................................... 109 
6.4.1 
Pharmacokinetic Procedures .......................................................... 109 
6.4.2 
Pharmacokinetic and Anti-drug Antibody Sampling Schedule ..... 109 
6.4.3 
Pharmacokinetic and Anti-drug Antibody Sample Preparation and 
Shipment ........................................................................................ 112 
6.5 
Assessment of Safety and Tolerability ........................................................... 113 
6.5.1 
Physical Examination .................................................................... 113 
6.5.2 
Abbreviated Physical Examination ................................................ 113 
6.5.3 
ECOG Performance Status ............................................................ 113 
6.5.4 
Body Weight and Height ............................................................... 114 
6.5.5 
Adverse Events .............................................................................. 114 
6.5.6 
Safety Laboratory Tests ................................................................. 114 
6.5.7 
Vital Signs ..................................................................................... 117 
6.5.8 
12-lead ECG .................................................................................. 118 
6.5.9 
Virology Tests ............................................................................... 119 
6.5.10 
Monitoring for Drug Induced Liver Damage ................................ 119 
6.5.11 
Oxygen Saturation ......................................................................... 119 
6.5.12 
Imaging for Interstitial Lung Disease (Pneumonitis) .................... 119 
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6.6 
Total Blood Volume ....................................................................................... 120 
7 
SAFETY MONITORING AND REPORTING ............................................................. 120 
7.1 
Definition of an Adverse Event ...................................................................... 120 
7.1.1 
Toxicity Management Algorithms (According to SITC) .............. 120 
7.1.2 
Severity of Adverse Events ........................................................... 120 
7.1.3 
Causality of Adverse Events .......................................................... 121 
7.1.4 
Follow-up of Adverse Events ........................................................ 121 
7.1.5 
Serious Adverse Event Assessment and Reporting to the 
Sponsor .......................................................................................... 121 
7.1.6 
Adverse Events of Special Interest ................................................ 123 
7.1.7 
Deaths ............................................................................................ 123 
7.1.8 
Reporting to Competent Authorities, IECs/IRBs and Other 
Investigators ................................................................................... 124 
7.2 
Important Medical Procedures to be Followed .............................................. 124 
7.2.1 
Medical Emergencies and Sponsor Contacts ................................. 124 
7.2.2 
Guidance for Overdose .................................................................. 124 
7.2.3 
Protocol Deviations ....................................................................... 124 
7.2.4 
Pregnancy ...................................................................................... 125 
8 
WITHDRAWAL OF PATIENTS FROM TREATMENT AND/OR THE STUDY ..... 125 
8.1 
Follow-up of Patients Off Treatment ............................................................. 126 
8.1.1 
Withdrawal of Informed Consent .................................................. 126 
8.1.2 
Lost to Follow-up .......................................................................... 127 
8.2 
End of Treatment and End of Study Procedures ............................................ 127 
8.2.1 
Safety Follow-up Visit ................................................................... 127 
8.2.2 
Follow-up Period ........................................................................... 127 
8.2.3 
End of Study for Individual Patients ............................................. 128 
8.3 
Replacement Policy ........................................................................................ 128 
8.3.1 
Phase 1 Dose Escalation Parts: ...................................................... 128 
8.3.2 
Phase 2 Part: .................................................................................. 128 
9 
STATISTICAL CONSIDERATIONS ........................................................................... 128 
9.1 
Modified Toxicity Probability Interval (mTPI-2) Design .............................. 128 
9.1.1 
Rationale for mTPI-2 Design ......................................................... 128 
9.1.2 
Simulation Results ......................................................................... 129 
9.2 
Sample Size Determination ............................................................................ 131 
9.3 
Analysis Set .................................................................................................... 132 
9.3.1 
Full Analysis Set ............................................................................ 132 
9.3.2 
Safety Set ....................................................................................... 132 
9.4 
Statistical Analyses ........................................................................................ 132 
9.4.1 
Demographic and Baseline Characteristics ................................... 133 
9.4.2 
Efficacy Analysis ........................................................................... 133 
9.4.3 
Safety Analysis .............................................................................. 134 
9.4.4 
Pharmacokinetic Analysis ............................................................. 135 
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9.4.5 
Handling of Withdrawals and Missing Data ................................. 136 
9.4.6 
Protocol Deviations ....................................................................... 136 
10 QUALITY CONTROL AND QUALITY ASSURANCE.............................................. 136 
10.1 
Monitoring ...................................................................................................... 136 
10.2 
Audits and Inspections ................................................................................... 136 
10.3 
Data Quality Assurance .................................................................................. 137 
11 REGULATORY AND ETHICAL CONSIDERATIONS .............................................. 137 
11.1 
IEC/IEB Approval .......................................................................................... 137 
11.2 
Regulatory Approval ...................................................................................... 137 
11.3 
Patient Confidentiality .................................................................................... 138 
11.4 
Protocol Amendments .................................................................................... 138 
11.5 
Principal Investigator Responsibilities ........................................................... 138 
12 DATA HANDLING AND RECORD KEEPING .......................................................... 139 
12.1 
Data Capture ................................................................................................... 139 
12.2 
Data Management .......................................................................................... 139 
12.3 
Record Archiving and Retention .................................................................... 139 
13 FINANCING AND INSURANCE ................................................................................. 140 
14 PUBLICATION POLICY .............................................................................................. 140 
15 REFERENCES ............................................................................................................... 141 
16 APPENDICES ................................................................................................................ 146 
16.1 
Appendix 1 - RECIST 1.1 (Eisenhauer et al., 2009) and Update 2016 (Schwarz 
et al., 2016) ..................................................................................................... 147 
16.2 
Appendix 2 - iRECIST ................................................................................... 179 
16.3 
Appendix 3 - Adverse Events of Special Interest .......................................... 202 
16.4 
Appendix 4 - Modified Toxicity Probability Interval Design No 2 (mTPI2) 
Design and Simulations .................................................................................. 203 
16.5 
Appendix 5 - Protocol Amendments .............................................................. 209 
17 ADDENDA ..................................................................................................................... 213 
17.1 
Addendum 1 ................................................................................................... 213 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Definition 
Abs 
Antibodies 
ADA 
Anti-drug Antibody 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
ADCP 
Antibody-Dependent Cellular Phagocytosis 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APAC 
Asia Pacific 
APCs 
Antigen Presenting Cells 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUC 
Area under the concentration time curve 
AUCinf 
Area under the concentration time curve to infinity 
BMI 
Body Mass Index 
BOR 
Best Objective Response 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CD 
Cluster of Differentiation 
CEA 
Carcinoembryonic Antigen 
CFR 
Code of Federal Regulations 
C-G 
Cockroft-Gault 
CK 
Creatine Kinase 
CK-MB 
Creatine Kinase-Muscle/Brain 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum Concentration 
Cmin 
Trough Concentration 
CNA 
Copy Number Alterations 
CNS 
Central Nervous System  
COVID-19  
Coronavirus disease 2019  
CR 
Complete Response 
CRO 
Contract Research Organization 
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Abbreviation 
Definition 
CT 
Computed Tomography  
CTCAE v5 
Common Terminology Criteria for Adverse Events version 5 
CTFG 
Clinical Trial Facilitation Group 
CTLA-4 
Cytotoxic T lymphocyte Antigen-4 
DLT 
Dose Limiting Toxicity  
dMMR 
Mismatch-repair deficiency 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form  
EDTA 
Ethylenediaminetetraacetic acid 
EEA 
European Economic Area 
EOS 
End of Study  
EOT 
End of Treatment 
eTMF 
Electronic Trial Master File 
EU 
European Union 
FACS 
Fluorescence-Activated Cell Sorting 
FAS 
Full Analysis Set 
FCγ 
Fragment crystallizable gamma 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin Embedded 
FIH 
First In Human  
FOXP3 
Forkhead box P3 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GGT 
GammaGlutamyl Transferase 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
hCG 
Human Chorionic Gonadotropin 
Hct 
Hematocrit 
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Abbreviation 
Definition 
HCV 
Hepatitis C virus 
HDL 
High Density Lipoprotein 
HED 
Human Equivalent Dose 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
IB 
Investigator’s Brochure 
IC 
Immune cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICI 
Immune Checkpoint Inhibitors 
ICOS 
Inducible T cell Costimulator 
ICOSLG 
Inducible T-cell Costimulator Ligand 
IEC 
Independent Ethics Committee 
IFN 
Interferon Gamma 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IMP 
Investigational Medical Product 
IND 
Investigational New Drug 
irAE 
Immune-related Adverse Events 
IRB 
Independent Review Board 
iRECIST 
Immune-Related Response Evaluation Criteria in Solid Tumors 
irPD 
Immune-Related Progressive Disease  
ISF 
Investigator Site File 
IV 
Intravenous 
IXRS 
Interactive X=Voice/Web Response System 
KD 
Equilibrium dissociation constant 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoprotein 
LFT 
Liver Function Test 
LPS 
Lipopolysaccharide 
mAbs 
Monoclonal Antibodies 
Max 
Maximum 
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Abbreviation 
Definition 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
Mean Fluorescence Intensity 
Min 
Minimum 
Mins 
Minutes 
MMR 
Measles, Mumps, Rubella 
MoA 
Mechanism of Action 
mPFS 
Median Progression Free Survival 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
MRSD 
Maximum Recommended Starting Dose 
MSI 
Microsatellite Instability 
MTD 
Maximal tolerated dose 
mTPI2 
Modified Toxicity Probability Interval Design No 2 
N, No., n 
Number 
NCA 
Noncompartmental Analysis 
NL  
New Lesion 
NOAEL 
No Observed Adverse Effect Level 
NSCLC 
Non-Small Cell Lung Cancer 
NTLs 
Non-Target Lesions 
NYHA 
New York Heart Association 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Pharmacodynamic 
PD-1 
Programmed Cell Death Protein-1 
PD-L1 
Programmed Cell Death-Ligand 1 
PFS 
Progression Free Survival 
PI 
Principal Investigator  
PK 
Pharmacokinetic 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
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Abbreviation 
Definition 
PT 
Preferred Term  
Q3W 
Every 3 weeks 
RBCC 
Red Blood Cell Count 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RNA 
Ribonucleic Acid 
RO 
Receptor Occupancy 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-Cov-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SD 
Stable Disease 
SDV 
Source Document Verification 
SIMOA 
Single Molecule Array 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee 
StD 
Standard Deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
t½ 
Half-life 
T4 
Thyroxine 
tmax 
Time to maximum observed serum concentration 
TC  
Tumor cells 
TCGA 
The Cancer Genome Atlas 
TCR 
T Cell Receptor 
TEff 
T-effector cells 
TGF-  
Transforming Growth Factor Beta 
TILs 
Tumor-Infiltrating Lymphocytes 
TK 
Toxicokinetics 
TKI 
Tyrosine Kinase Inhibitor 
TMB 
Tumor Mutational Burden 
TME 
Tumor Microenvironment 
TNBC  
Triple Negative Breast Cancer 
TNFα 
Tumor Necrosis Factor alpha 
TPS 
Tumor Proportion Score 
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Abbreviation 
Definition 
TRegs 
Regulatory T cells 
UCC 
Urothelial Cell Carcinoma   
ULN 
Upper Limit of Normal 
USA 
United States of America 
UTI 
Urinary Tract Infection 
 
 
 
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1 
BACKGROUND INFORMATION  
1.1 
Introduction  
In recent years there has been a significant paradigm shift in cancer therapies with the approval 
of antibodies targeting immune checkpoints (eg, ipilimumab for cytotoxic T lymphocyte 
antigen-4 [CTLA-4], nivolumab and pembrolizumab for programmed cell death protein-1 
[PD-1] and atezolizumab, durvalumab and avelumab for programmed cell death-ligand 1 
[PD-L1]) (1).  These immune checkpoint inhibitors (ICI) are associated with a strong and 
long-lasting response in patients suffering from several malignancies, including but not limited 
to metastatic melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell 
carcinoma (HNSCC), Hodgkin lymphoma, renal and bladder cancer (1).  A high proportion of 
patients, however, show intrinsic or acquired resistance to ICI monotherapies (2).  These 
patients represent a population with high unmet medical needs that might benefit from 
alternative approaches, such as combination therapies, whereby different immune modulators, 
by affecting the signaling of distinct pathways, may provide enhanced activity in combination.  
There is accumulating evidence that the immunosuppressive tumor microenvironment (TME) 
is one of the major challenges in cancer immunotherapy as it is one of the major causes of ICI 
failure.  It is therefore important to understand and tackle the tissue-protective cellular elements 
of the TME to improve the response rate to ICI.  Analysis of human cancers and mouse models 
has demonstrated that non-responsiveness to ICI can often be caused by suppressive 
mechanisms in the TME. Amongst these, regulatory T cells (TRegs), which express high levels 
of inducible T cell costimulator (ICOS), play a vital immunosuppressive role (3). 
ICOS, a third member of the cluster of differentiation (CD)28/CTLA-4 family, is expressed on 
activated T cells and is a marker for highly suppressive antigen-specific TRegs (4, 5).  ICOS 
signaling controls forkhead box P3 (FOXP3)+ TRegs expansion, survival, and 
interleukin-10 (IL-10) production. High levels of ICOS+ TRegs have been described in several 
indications, including HNSCC, NSCLC, esophageal, hepatocellular carcinoma (HCC) and 
cervical cancer (The Cancer Genome Atlas [TCGA] data analysis and [6]), and represent an 
unfavorable prognostic indicator in advanced cancer (3, 6, 7).  Finally, the preferential high 
expression of ICOS on intratumoral TRegs makes this protein a strong candidate for a depleting 
antibody strategy. 
By immunizing Kymouse™ in which endogenous Icos gene has been knocked out, the Sponsor 
identified a novel fully human immunoglobulin (Ig)G1 monoclonal antibody, KY1044, which 
binds to ICOS and depletes ICOShigh expressing cells by virtue of fragment crystallizable 
gamma (Fc) receptor interactions, while stimulating ICOSlow expressing T-effector cells 
(TEff).  The depletion of ICOS+ TRegs with KY1044, or the combined effect of KY1044 and 
PD-L1 blockade in the clinic may have significant antitumor efficacy and the potential to 
rescue patients that are proven to be refractory or resistant to PD-(L)1 inhibitors as single 
agents. 
1.2 
An Introduction to ICOS and its Biology  
ICOS is a member of the CD28/CTLA-4 family, and is expressed upon activation on T cells 
(5).  At steady state, ICOS is also expressed on memory T cells (CD45RO+or CD44high) as well 
as on the majority of FOXP3+ regulatory CD4+ T cells.  Importantly, available data demonstrate 
that TRegs express significantly higher levels of ICOS than TEff (Figure 1-1) (8).  ICOS has only 
one known ligand, called ICOSLG/B7-H2 (5), which is constitutively expressed on antigen 
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presenting cells (APCs) such as B cells and dendritic cells, but has also been shown to be 
up-regulated in response to tumor necrosis factor alpha (TNFα) and lipopolysaccharide (LPS) 
(9, 10).  Activation of ICOS prevents cell death, modifies T cells' cytoskeleton and upregulates 
cellular metabolism (5).  In response to ICOS signaling, IL-10 production is specifically 
observed in ICOShigh TRegs (11).  ICOS-mediated costimulation of T cells also leads to the 
production of effector cytokines such as IL-4, interferon gamma (IFNγ), and (TNFα) from 
ICOS+ CD8 and CD4 T cells (12).  Since its discovery two decades ago, ICOS has been shown 
to play a key role in immune cell signaling, and the overall immune response towards 
pathogens and immunogenic tumors (13, 14), and is necessary for the establishment and 
maintenance of antigen specific TEff and TRegs (11, 15, 16).  
ICOS knockout mice are viable and fertile (4, 17, 18).  Extended phenotyping analyses 
confirmed that the mice demonstrate immune-related defects including reduced humoral 
immunity, as shown by impaired Ig class-switching and a reduction in the size and number of 
germinal centers.  Mice fully lacking ICOS signaling also demonstrate reduced T cell 
activation, proliferation and survival.  Finally, ablation of ICOS in mice is also associated with 
a lower number of memory and TRegs (11).  
ICOS is expressed on different CD4 T cell subsets.  Although blockage of CTLA-4 with 
ipilimumab has been shown to induce ICOS expression on Th1 CD4 T cells which is associated 
with a higher response rate in treated patients (15), it was previously reported that ICOS is 
expressed more on the surface of Th2 cells (which are IL-4 and IL-10 producing cells) rather 
than on Th1 cells (which produce IFN) (12).  Similarly, murine ICOS+ CD4 TRegs are 
characterized by superior survival and highly suppressive properties compared with 
ICOS- TRegs (8).  Altogether, these data demonstrate that ICOS is preferentially expressed on 
the surface of pro-tumorigenic T cells.  
1.2.1 Expression of ICOS in Cancer  
In 
humans, 
ICI 
have 
shown 
to 
be 
particularly 
active 
in 
the 
so-called 
immunological/inflammatory and/or highly mutated tumors. These include melanoma, 
NSCLC, HNSCC, gastric cancer, Hodgkin lymphomas, microsatellite instability (MSI) 
positive tumors, renal and urothelial cell carcinoma (UCC) (19).  Although ICI show good 
efficacy and have been approved in these indications, there are still high numbers of patients 
not responding to these therapeutic antibodies. One of the resistance mechanism associated 
with lack of response to ICI is the presence of immune suppressive mechanisms such as 
presence of TRegs in the TME (19).  In addition, recent publications have shown that poor 
prognosis in ovarian, gastric and liver cancers is associated with a high number of ICOS+ TRegs 
(3, 6, 7). In HCC, it has been demonstrated that around 45% of the TRegs are ICOS+ and are 
highly immunosuppressive as they are expressing both IL-10 and transforming growth factor 
beta (TGF-) (6). Similarly, it was reported that ICOS+ TRegs isolated in melanoma samples are 
the most prominent suppressive cells in the TME (20).  
In order to assess ICOS expression in other indications, TCGA datasets were interrogated for 
the relative levels of ICOS messenger ribonucleic acid (mRNA) expression in different cancers. 
From this exercise, indications that exhibit high levels of ICOS transcript were identified. 
These include tumors originating from the esophagus, head and neck, stomach, cervix, testis, 
skin and the lung. However, differences were also observed within the immune cell types (CD8 
and TRegs) expressing ICOS in these indications, which could be associated with a different 
level of sensitivity to anti-ICOS therapy. 
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Finally, a link between viral etiology or the presence of certain bacteria with T cell exhaustion 
and high TRegs content has been previously highlighted (21). Since ICOS expression on TRegs 
has been reported during chronic infection disease (22), it is hypothesized that an anti-ICOS 
antibody with cell killing (antibody-dependent cellular cytotoxicity [ADCC] and 
antibody-dependent cellular phagocytosis [ADCP]) properties may also be beneficial to treat 
squamous cell cancers associated with chronic viral infections (eg, human papillomavirus in 
esophageal and cervical cancer or Epstein-Barr virus-associated nasopharyngeal cancer) and 
gastric cancer with Helicobacter pylori infections (3, 21, 22). 
1.3 
Overview of Disease and Current Trends in Treatment  
This study will be conducted in patients whose tumors are most likely to benefit from inhibition 
of ICOS as single agent or in combination with anti-PD-L1.  
Patients recruited in the study will have either exhausted, or will be ineligible for current 
options of standard of care. In several of these indications, check point inhibitors have either 
been approved in the first-, second- and later line setting, or are currently under investigation 
with preliminary encouraging data. This study will address an urgent medical need also for 
patients who have progressed with either primary or secondary resistance to previous 
immunotherapy. 
In this study, patients with advanced/metastatic malignancies will be enrolled in the Phase 1 
dose escalation part, with preference for HNSCC, gastric/esophageal cancer, HCC, NSCLC, 
melanoma, cervical, renal, pancreatic and triple negative BC, as high expression of ICOS and 
FOXP3 have been described as prognostic factors in these cancer indications. Some of these 
tumors are amongst the most frequent tumor types worldwide (23). 
Advances in recent years and the use of targeted therapies and ICI have resulted in 
improvements in patient outcomes compared to chemotherapy. Selection of molecularly 
defined subtypes of cancer patients and a better understanding of the TME, in particular basic 
mechanisms of tumor biology and immunology, has revolutionized results eg, in patients with 
melanoma treated with ipililumab or BRAF inhibitors. Subsequently treatment with 
anti-PD-(L)1 checkpoint inhibitors has produced extremely encouraging results in several 
cancer indications. These results led to the marketing approval of pembrolizumab, nivolumab, 
atezolizumab, durvalumab and avelumab across multiple tumor indications. 
Anticancer immunotherapy has surpassed outcomes in subgroups of patients treated with 
molecular targeted agents in terms of durable response and overall survival (OS) and offers a 
change in future perspectives for these patients.  Despite these encouraging results, the 
proportion of patients who do not respond to immunotherapy (innate resistance) or who 
progress (develop secondary resistance mechanisms) is still high and there is room for further 
improvement and unmet clinical need.  Furthermore, analysis of biomarkers such as 
PD-L1 positivity by immunohistochemistry (IHC) has shown initial promising results for 
patients with high expression of PD-L1 (Tumor Proportion Score [TPS] >50%) and has led to 
the approval of pembrolizumab in first line metastatic NSCLC.  However, the predictive value 
of PD-L1 expression in other malignancies remains inconsistent.  Frequently PD-L1 undefined 
or patients with low expression of PD-L1 can respond well, depending on the indication 
(nivolumab in gastric cancer [CheckMate-032] [24]) and in second-line metastatic NSCLC 
(25).  Similarly it was reported that the tumor mutation burden is also a useful predictive 
biomarker for treatment response to ICI. An increased number of non-synonymous point 
mutations is associated with improved objective response and a durable clinical benefit (26). 
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1.4.3 Overview of Atezolizumab  
For non-clinical toxicology, clinical pharmacology, pharmacokinetics, please refer to the 
atezolizumab IB. 
1.4.3.1 Clinical Data Summary of Atezolizumab Safety and Efficacy  
As of the end of 2018, atezolizumab is approved for patients with locally advanced or 
metastatic UCC who are cisplatin ineligible or whose tumors have progressed following prior 
platinum-containing chemotherapy. It is also approved for patients with metastatic NSCLC 
after platinum containing chemotherapy.  Approvals in these indications have been granted in 
a number of countries including the United States of America (USA), Taiwan and the EU. Data 
presented in this Section are those reported by Shah et al, 2018 (42) post approval of 
atezolizumab in the USA and EU. 
Safety: 
The recommended dose for atezolizumab is 1200 mg every 3 weeks given via intravenous 
infusion (42).  
In a Phase 1 study of 277 patients with advanced cancer, atezolizumab was well tolerated as a 
single agent with an incidence rate of 12.6% for Grade 3 to 4 treatment related adverse events 
(AEs). Immune-related Grade 3 to 4 treatment-related AEs had a low incidence rate of 1%. 
Notably, there were 3 cases of Grade 3 to 4 aspartate aminotransferase (AST) increase and 
3 cases of Grade 3 to 4 alanine aminotransferase (ALT) increase. No Grade 3 to 5 cases of 
pneumonitis were reported. 
Safety in urothelial cell carcinoma: 
A Phase 1 study of atezolizumab was performed with a cohort of 68 patients with previously 
treated urothelial bladder cancer. Atezolizumab was well tolerated with a median duration of 
treatment of 65 days. Treatment-related AEs were reported in 57% of patients, however, only 
4% were Grade 3 in severity. These comprised one case each of asthenia, thrombocytopenia 
and hypophosphatemia. The most common immune-mediated AEs (decreased appetite and 
fatigue) were Grade 1 to 2 in severity. 
A Phase 2 study (IMvigor 210) was subsequently performed with 2 cohorts; Cohort 1 included 
119 treatment naïve patients with advanced urothelial cancer ineligible for cisplatin therapy, 
whilst Cohort 2 included 310 patients previously treated with platinum-based chemotherapy. 
Both cohorts received atezolizumab 1200 mg every 3 weeks until progression. In Cohort 1, the 
most common treatment-related AEs included fatigue, diarrhea and pruritus. Grade 3 to 4 
treatment-related AEs were reported in 16% of patients and included fatigue (3%), ALT 
increase (3%) and AST increase (3%). There was a single Grade 5 treatment-related event 
which was a case of sepsis. In Cohort 2, 69% of patients reported treatment-related AEs. There 
were no treatment-related deaths and only 16% of AEs were Grade 3 to 4. The most common 
Grade 3 to 4 treatment-related AE was fatigue (2%). Immune-mediated AEs were present in 
7% of patients and included two cases each of pneumonitis, ALT increase, AST increase, rash 
and dyspnea.  
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Safety in NSCLC: 
Several Phase 2/3 studies have investigated the use atezolizumab in patients with NSCLC, 
including BIRCH (NCT02031458), FIR (NCT01846416), POPLAR (NCT01903993) and 
OAK (NCT2008227). Patients were given atezolizumab 1200 mg every 3 weeks by 
intravenous infusion. 
The Phase 2 POPLAR study compared atezolizumab to docetaxel (75 mg/m2 every 3 weeks) 
in patients previously treated for NSCLC. Atezolizumab had a favorable toxicity profile 
compared to docetaxel with fewer Grade 3 to 4 AEs (40% vs 53%), fewer treatment related 
Grade 3 to 4 AEs (11% vs 39%), fewer treatment-related AEs causing dose modification or 
interruption (11% vs 24%) and fewer discontinuations (1% vs 18%). There was a single 
Grade 5 treatment-related AE of cardiac failure in the atezolizumab arm whilst the docetaxel 
arm had three Grade 5 treatment-related AEs. Immune-related AEs were also reported in the 
atezolizumab arm and included AST increase (4% of patients), ALT increase (4%), 
pneumonitis (3%) and colitis (1%).  
In the Phase 3 OAK study, atezolizumab and docetaxel (75 mg/m2 every 3 weeks) were 
compared and atezolizumab demonstrated a superior safety profile. The most common 
treatment-related AEs in the atezolizumab arm were fatigue (14%), nausea (9%), decreased 
appetite (9%) and asthenia (8%). Immune-related AEs including pneumonitis, hepatitis and 
colitis had a low incidence rate (≤1%). There were fewer Grade 3 to 4 treatment related AEs 
with atezolizumab compared to docetaxel (15% vs 43%) and fewer AEs leading to 
discontinuation (8% vs 19%). 
For immune-related AEs please refer to Section 1.6. 
Further information on the current atezolizumab safety data can be found in the latest 
atezolizumab Investigator Brochure. 
Efficacy data 
Phase 1 monotherapy  
A response rate of 18% and median progression free survival (mPFS) of 18 weeks was reported 
in 175 evaluable patients with activity seen in multiple tumor types. 
Atezolizumab monotherapy efficacy data from the OAK and POPLAR studies in advanced, 
metastatic second line NSCLC versus docetaxel (850 and 287 patients respectively) and the 
IMvigor 210 study in locally advanced, metastatic UCC, either in patients who were cisplatin 
ineligible (Cohort 1, 119 patients) or in cisplatin-resistant patients (Cohort 2, 310 patients) are 
summarized below (for further details please refer to the atezolizumab label [43]) and 
Weinstock et al., 2017 (44). 
Efficacy in urothelial cell carcinoma: 
PD-L1 status:  
Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay 
and subgroups were defined by PD-L1 expression on tumor cells (TC) and immune cells (IC). 
In immune cells, Grade IC0 corresponded to <1% PD-L1 expression, Grades IC1, IC2 and IC3 
corresponded to 1% to 4%, 5% to 9% and ≥10%, respectively. In TCs, TC0 corresponded to 
<1% PD-L1 expression, grades TC1, TC2 and TC3 corresponded to 1% to 4%, 5% to 49% and 
≥50%, respectively. 
Study IMvigor210 (Cohort 1): The ORR was 23% (n=119) in all patients.  
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Study IMvigor210 (Cohort 2): The ORR was 15% in all patients (n=310), 26% in the IC2/3 
group and 18% in the IC1/2/3 group.  
Efficacy in NSCLC: 
PD-L1 status: In both studies, eligible patients were stratified by PD-L1 expression status in 
tumor-infiltrating IC, by the number of prior chemotherapy regimens, and by histology. 
Overall, 16% of patients in both studies were classified as having high PD-L1 expression, 
defined as having PD-L1 expression on ≥50% of TC or ≥10% of IC.  
Study OAK: OS was 13.8 months for atezolizumab versus 9.6 months for docetaxel. ORR 
was 14% for atezolizumab and 13% for docetaxel, however, in the atezolizumab group the 
DOR was 16.3 months versus 6.2 months in the docetaxel group. At IC-TC 3, OS was 
20.5 months for atezolizumab versus 8.9 months for docetaxel; ORR was 31% for 
atezolizumab and 11% for docetaxel. 
Study POPLAR: Atezolizumab showed an improvement in median OS of 12.6 months, versus 
9.7 months for docetaxel. ORR was 15% for both drugs, atezolizumab and docetaxel, however, 
in the atezolizumab group the DOR was 14.3 months versus 7.2 months in the docetaxel group. 
At IC-TC 3, OS was 15.5 months for atezolizumab versus 11.1 months for docetaxel; ORR 
was 38% for atezolizumab and 13% for docetaxel. 
1.4.4 Overview of the Combination of KY1044 with Anti-PD-(L)1 Inhibitors  
1.4.4.1 Non-clinical Data  
Pre-clinical tumor efficacy studies have been conducted in the CT26.WT syngeneic model with 
KY1044 in combination with anti-PD-L1 mIgG2a or anti-PD-1 antibodies.  These experiments 
demonstrated that in this syngeneic model, KY1044 was associated with a better anti-tumor 
response when combined with anti-PD-L1 than with anti-PD-1 (See Section 1.4.2.2) and refer 
to Figure 1-2 and to the KY1044 IB (37). 
1.4.4.2 Clinical Data  
This is a first in man study therefore clinical data of the combination of KY1044 with 
atezolizumab are not available. 
1.5 
Rationale  
1.5.1 Study Rationale and Purpose  
KY1044 is a new investigational medicinal product intended for the treatment of patients with 
advanced/metastatic malignancies to overcome specific tumor escape mechanisms and activate 
anti-tumor effector cells. Pre-clinical studies of KY1044 as single agent and in combination 
with anti-PD-L1 have demonstrated efficacy with the synergistic activity of the combination 
capable of improving survival and preventing recurrence of the same tumor.  Pre-clinical 
studies have not demonstrated any toxicities in rodents and/or non-human primates.  Taken 
together, these data suggest that killing of the ICOShigh TRegs combined with a stimulation of 
TEff using KY1044 may lead to significant anti-tumor efficacy in patients with 
advanced/metastatic malignancies. 
PD-(L)1 blockade has proven clinical efficacy in various disease settings; a great proportion of 
patients, however, do not respond or progress on anti-PD-(L)1 therapies as single agent. One 
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of the indicated reasons for lack of response or progression is the non-permissive 
immunosuppressive TME, often rich in TRegs.  These patients are thus ideally placed to test 
KY1044 as single agent or in combination with atezolizumab.  
1.5.2 Rationale for Study Design  
This is a first in human (FIH), open-label, Phase 1/2 study of parallel cohorts with KY1044 as 
single agent and in combination with atezolizumab. The purpose of the study is to evaluate the 
safety and tolerability, determine the maximal tolerated dose (MTD) or recommended Phase 2 
dose (RP2D) and to assess preliminary efficacy of KY1044 as single agent or in combination 
with atezolizumab in a range of indications. 
The study consists of the following parts:  
Phase 1:  
• A Phase 1 dose escalation part with KY1044 as single agent in patients with 
advanced/metastatic malignancies (all comers) and selected indications.  
• A Phase 1 dose escalation part with KY1044 in combination with atezolizumab in all 
comers and selected advanced/metastatic malignancies. This part of the study will start 
after at least two cohorts of KY1044 as single agent have been considered to be safe 
and tolerable.  
These parts of the study will allow determination of the MTD/RP2D of KY1044 (as single 
agent and in combination with atezolizumab) from the collective experience in the clinic 
considering the safety data, PK data, pharmacodynamic data and any early anti-tumor activity 
observed. 
Enrichment part (optional): 
To further explore safety, PK, pharmacodynamic markers and preliminary anti-tumor activity 
at different dose levels, additional patients may be recruited in cohorts of KY1044 as single 
agent or in combination with atezolizumab already considered to be safe.  The overall number 
of patients included across all cohorts in the Phase 1 dose escalation and enrichment parts will 
be approximately 150. 
Phase 2: 
In the absence of identifying an MTD or single efficacious dose in Phase 1, an initial Phase 2 
dose assessment part will be opened to compare the efficacy and biomarker readouts of two 
biologically relevant dose levels of KY1044 as a single agent or in combination with 
atezolizumab, in one or more specific indication(s) to support further definition of the RP2D 
for future indications.  Once the MTD/RP2D has been established, a Phase 2 expansion 
component will open to evaluate clinical efficacy of KY1044 as single agent and in 
combination with atezolizumab in selected indications which should benefit from the KY1044 
MoA.  
Because ICOS plays a more subtle role in modulating T cell function than either PD-L1 or 
PD-1, it is not expected that KY1044 would have major anti-tumor activity as single agent in 
the clinic. Therefore, patients will be treated with KY1044 as single agent in Phase 2 only if 
evidence of anti-tumor activity is detected in the dose escalation/enrichment Phase 1 parts. 
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1.6 
Summary of Known and Potential Risks and Benefits  
1.6.1 Unmet Need in the Selected Indications  
Patients recruited into the study will be ineligible for or will have exhausted current standard 
of care options in each indication and therefore will be patients for whom a clinical trial is 
appropriate.  
The study will be conducted in patients with advanced/metastatic malignancies which, 
according to published data, are rich in TRegs and therefore most likely would benefit from the 
dual MoA of KY1044. This dual MoA is also anticipated to improve the TEff to TReg ratio and 
overcome resistance mechanism against anti-PD-(L)1 inhibitors, which are mediated via TRegs, 
and therefore patients who have progressed or who did not respond to previous checkpoint 
inhibitor treatment are also included in this study. 
1.6.2 Possible Immune-related Toxicities Identified with Other ICIs  
The manipulation of the immune response via checkpoint inhibition is associated with a unique 
spectrum of side effects termed immune-related adverse events (irAEs) or, occasionally, 
adverse events of special interest (AESI). IrAEs include dermatologic, gastrointestinal (GI), 
hepatic, endocrine, and other less common inflammatory events. IrAEs are believed to arise 
from general immunologic enhancement, and temporary immunosuppression with 
corticosteroids, TNFα antagonists, hormone replacement or other agents can be an effective 
treatment in most cases. These irAEs might also be expected after treatment with KY1044. 
In general, treatment of moderate or severe irAEs requires interruption of the checkpoint 
inhibitor and the use of corticosteroid immunosuppression. Treatment is based upon the 
severity of the observed toxicity:  
• For patients with Grade 2 (moderate) immune-related toxicities, treatment with the 
checkpoint inhibitor should be withheld and should not be resumed until symptoms or 
toxicity is Grade 1 or less. Corticosteroids (prednisone 0.5 mg/kg/day or equivalent) 
should be started immediately if applicable. 
• For patients experiencing Grade 3 or 4 (severe or life-threatening) immune-related 
toxicities, treatment with the checkpoint inhibitor should be permanently discontinued. 
High doses of corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) should be 
given. When symptoms subside to Grade 1 or less, steroids can be gradually tapered 
over at least 1 month. 
Serologic, immunologic and histologic (biopsy) data should be used to support an irAE 
diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin, or other etiologic causes of the irAE. 
1.6.3 Potential Risks of KY1044 Therapy as Single Agent and in Combination with 
Atezolizumab  
Due to the MoA of KY1044, there is a potential risk of shifting the balance of immune tolerance 
towards a more immune activated state, by depleting ICOShigh TRegs cells and stimulating TEff, 
thereby promoting irAEs.  
The 
MoA 
of 
KY1044 
requires 
TCR 
dependent 
engagement 
to 
act 
as 
an 
agonistic/co-stimulatory antibody. This excludes the risk of a cytokine release syndrome as 
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observed by superagonistic antibodies that do not require TCR engagement (see 
Section 1.4.2.3). 
KY1044 will preferentially deplete ICOShigh expressing cells by ADCC (especially in the 
TME), and should have minimal depleting effects on ICOSmedium/low TEff in the tumor and 
lymphoid tissues. The level of ICOS expression on TRegs varies depending on the tissue 
analyzed.  Pre-clinical experiments in tumor-bearing mice have shown that intratumoral TRegs 
expressed nearly 10-fold more ICOS (as quantified by mean fluorescent intensity) than 
peripheral lymphoid organs.  Altogether this differential expression would make the 
intratumoral TRegs more sensitive to depletion than TRegs in peripheral organs.  
Single and repeated administration of KY1044 to cynomolgus monkeys led to reductions in 
total CD4+ memory T cells in peripheral blood. There was no clear evidence of reversibility 
after administration of single doses at 0.1, 1 and 10 mg/kg over the 28 day post-dose 
observation period and absolute counts at 28 days post-dose were +18%, -20%, -56% and -63% 
of mean pre-treatment values at dose levels of 0, 0.1, 1 and 10 mg/kg, respectively. Reductions 
in total CD4+ memory T cells of up to 80% were observed at dose levels of 30 and 100 mg/kg 
after repeated weekly administration of KY1044 for 4 weeks.  As outlined in Section 1.5.3 in 
more detail, this limited depletion of circulating memory cells per se is not considered to 
present a significant risk of loss of immunologic memory to previous pathogenic antigen 
exposure or vaccinations due to the different effects of KY1044 observed in peripheral blood 
and lymphoid tissue and the lack of effects on naïve CD4 cells. Intact memory T cell response 
with effective tumor cell rejection was also observed in mice, after treatment with KY1044 
(see Section 1.4.2.2). 
KY1044-related changes in rats and monkeys consisted of reductions in lymphoid 
follicles/germinal centers in spleen and lymph nodes and these are consistent with the expected 
pharmacology (see above). After repeat dosing, the germinal centers/follicles in lymphoid 
tissue were reduced (ranging from minimal to marked in severity) but were not fully ablated, 
even at doses as high as 150 mg/kg. In addition, the number of B cells in monkeys was not 
diminished and there was no indication of higher susceptibility to infections in rats or monkeys, 
therefore these changes are not considered to pose an increased risk for infections.  
Taken together there is a potential for aggravating immune related AEs however, considering 
the heterogeneity of TRegs and the fact that KY1044 will preferentially deplete ICOShigh 
expressing cells, the risk seems to be justified considering the disease state of the patients 
enrolled in this study and the potential benefit of enhancing an anti-tumor immune response.  
For more detail on non-clinical safety, please refer to Section 1.4.2. 
1.6.4 Key Risks of Atezolizumab  
Key risks are presented below. For more details, please refer to the atezolizumab IB and 
Section 1.4.3. 
Overall the safety profile of atezolizumab seems to be very similar to that reported with other 
Anti-PD-(L)1 inhibitors recently analyzed in a large meta-analysis across 48 trials, including 
6938 patients (46),  
When combining ICI, for example ipilimumab plus nivolumab in melanoma, an increase of 
CTCAE v5 ≥Gr3 irAE by up to 20% (when compared to ipilimumab monotherapy) and up to 
40% (when compared to nivolumab monotherapy), has been observed together with significant 
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gains in efficacy (improvement of ORR and mPFS of 11.5 months versus 2.9 months for 
ipilimumab monotherapy or 6.9 months for nivolumab monotherapy). 
As outlined above, there is also a potential risk for aggravating immune related AEs, when 
combining KY1044 with atezolizumab.  The incidence of irAEs for atezolizumab as 
monotherapy is summarized below: 
Incidence of irAEs across all clinical trials: 
Across all clinical trials (n=2616 patients) the incidences of immune-related events were as 
follows: Infections (42%), colitis/diarrhea (20%), immune related hepatitis (9.0%) 
hypothyroidism (4.6%), pneumonitis (2.6%), hyperthyroidism (1.6%), infusion reactions 
(1.3%), adrenal insufficiency (0.4%), type I diabetes mellitus (<0.1%) and hypophysitis 
(<0.1%), (atezolizumab label [43]).  
Other clinically significant immune-related adverse reactions were reported in ≤1.0% of 
patients:  
Cardiac: myocarditis. 
Dermatologic: bullous dermatitis, pemphigoid, erythema multiforme, Stevens Johnson 
Syndrome (SJS)/toxic epidermal necrolysis (TEN).  
Gastrointestinal: pancreatitis, including increases in serum amylase or lipase levels. 
General: systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis. 
Hematological: autoimmune hemolytic anemia, immune thrombocytopenic purpura. 
Musculoskeletal: myositis, rhabdomyolysis. Neurological: Guillain-Barre syndrome, 
myasthenia syndrome/myasthenia gravis, demyelination, immune-related 
meningoencephalitis, aseptic meningitis, encephalitis, facial and abducens nerve paresis, 
polymyalgia rheumatica, autoimmune neuropathy, and Vogt-Koyanagi-Harada syndrome.  
Ophthalmological: uveitis, iritis.  
Renal: nephrotic syndrome, nephritis.  
Vascular: vasculitis. 
Overall the incidence of AEs leading to discontinuations was small and was reported for 
pneumonitis and hepatitis in 0.4% of patients, and for diarrhea and colitis in 0.2% of patients.  
Summary Benefit: Risk Statement 
Although potential benefits of KY1044 as single agent or in combination with atezolizumab in 
advanced/metastatic malignancies are unknown at this time, the study design aims to minimize 
potential risks for patients and will try to maximize clinical benefit. In all late stage tumor 
indications, and in the preferred tumor indications, there is a high unmet medical need for novel 
therapeutic agents and improvement of efficacy over currently approved treatments.  
There are precedents for an antibody against ICOS with dual MoA (for example, JTX-2011). 
Although patient numbers are limited, the reported Phase 1/2 data investigating JTX-2011 as 
single agent and in combination with nivolumab seem to have been well tolerated (47, 48).  
Based on the pre-clinical data and the MoA, KY1044 as single agent and in combination with 
atezolizumab offers the option of a potentially well tolerated immune checkpoint combination 
without further aggravation of toxicities, by selectively targeting ICOShigh TRegs, and 
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stimulating TEff and overall improving the CD8: TRegs ratio leading to an enhanced anti-tumor 
response.  
The starting dose for the Phase 1 dose escalation with KY1044 as single agent were selected 
on the basis of PK/PD modelling of pre-clinical data, target engagement in tumor tissue, 
efficacy in pre-clinical pharmacology studies and characterization of the safety profile of 
KY1044 in cynomolgus monkeys and rats.  
KY1044 is not considered to be a high-risk biologic based on the MoA and antibody 
characteristics, the nature of the target, and the relevance of the animal species. No 
KY1044-related adverse effects have been identified to date in GLP and non-GLP dose range 
finding studies in cynomolgus monkeys up to 100 mg/kg and rats up to dose levels of 
150 mg/kg.  
Atezolizumab is approved for treatment of locally advanced or metastatic UCC and metastatic 
NSCLC after platinum containing chemotherapy and is currently being tested as monotherapy 
and in combination in clinical trials in several other indications, as discussed in the 
atezolizumab IB.  
No additional risks compared to other checkpoint inhibitor trials have been identified that 
would preclude investigation in combination with KY1044. 
The available data suggest that the benefit/risk of evaluating KY1044 as single agent and in 
combination with atezolizumab in this Phase 1/2 study appears acceptable based on the lack of 
effective alternative treatments, the limited life expectancy due to advanced disease, and the 
strength of the scientific hypothesis under evaluation. Furthermore, the study design (see 
Section 3.1) aims to minimize potential risks, and safety monitoring for each of the indication 
enrolled is in place for those risks deemed to be most likely or serious (see Section 5.4 
and Section 5.6).  
1.6.5 Benefit/Risk of KY1044 as Single Agent and in Combination with Atezolizumab 
Regarding Potential Infections with Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-Cov-2)  
There is no change in the overall benefit/risk of treating cancer patients with KY1044 as single 
agent or in combination with atezolizumab in regard to the coronavirus disease 2019 
(COVID-19) pandemic.  In case of the implementation of restrictions due to COVID-19, the 
advice provided in Addendum 1 should be followed. 
2 
OBJECTIVES AND ENDPOINTS  
2.1 
Objectives  
2.1.1 Primary Objective  
Phase 1: 
To characterize the safety and tolerability of KY1044 as single agent and in combination with 
atezolizumab and to identify recommended doses for future studies. 
Phase 2: 
To estimate the anti-tumor efficacy of KY1044 as single agent and in combination with 
atezolizumab. 
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2.1.2 Secondary Objectives  
• To evaluate the preliminary anti-tumor activity of KY1044 as single agent and in 
combination with atezolizumab (Phase 1 only) 
• To characterize the safety and tolerability of KY1044 as single agent and in 
combination with atezolizumab (Phase 2 only)  
• To characterize the PK profile of KY1044 as single agent and in combination with 
atezolizumab  
• To assess PK of atezolizumab in combination with KY1044 
• To assess emergence of anti-KY1044 and anti-atezolizumab antibodies following one 
or more IV infusions of KY1044 single agent and/or in combination with atezolizumab  
• To assess changes in biomarkers from baseline in tumor tissue as potential predictors 
of efficacy of KY1044 as single agent and in combination with atezolizumab  
• To describe the survival rate at 12 and 24 months of patients treated with KY1044 as 
single agent and in combination with atezolizumab for each disease group 
2.1.3 Exploratory Objectives  
• To assess the PD effect of KY1044 as single agent and in combination with 
atezolizumab in tumor tissue  
• To assess the PD effect of KY1044 as single agent and in combination with 
atezolizumab in peripheral blood  
• To determine the level of target occupancy in response to KY1044 as single agent 
(Phase 1 only) 
2.2 
Endpoints  
2.2.1 Primary Endpoints  
Phase 1 
• Safety: Incidence and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and electrocardiograms (ECGs) 
• Tolerability: Dose interruptions, reductions and dose intensity 
• The incidence of DLTs with KY1044 as single agent during the first 21 days of 
treatment  
• The incidence of DLTs with KY1044 in combination with atezolizumab during the first 
21 days of treatment 
Phase 2 
• ORR per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)  
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2.2.2 Secondary Endpoints  
Efficacy measures: 
• Best Overall Response (BOR), PFS and DOR per RECIST 1.1 
• ORR and PFS per immune-related (i)RECIST (Phase 1 and Phase 2) 
• ORR per RECIST 1.1 (Phase 1 only)  
• Survival rate at 12 and 24 months  
Safety: 
• Safety: Incidence and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and ECGs (Phase 2) 
• Tolerability: Dose interruptions, reductions and dose intensity (Phase 2) 
PK measures: 
• Serum concentrations and PK parameters (eg, Cmax, t1/2) of KY1044 and of 
atezolizumab if in combination  
Anti-drug antibodies: 
• Presence and/or concentration of anti-KY1044 and -anti atezolizumab antibodies  
Biomarkers: 
• Presence of tumor-infiltrating lymphocytes (TILs) as determined by expression of 
ICOS, FOXP3 and CD8 cells (IHC)  
2.2.3 Exploratory Endpoints  
Tumor tissue: 
• Expression of immune- and response related markers such as (but not limited to) 
PD-L1, CD163, CD68 by IHC 
• mRNA gene signature (transcriptomics/ Nanostring) with special interest in IFN gene 
signature (PanInflammatory panel and/or IO360 panel) 
Peripheral blood: 
• Peripheral, 
soluble 
ligands 
and 
cytokine 
levels 
(eg, 
IFNγ 
TNFα, 
granulocyte-macrophage colony-stimulating factor (GM-CSF)) contingent on 
availability of assay (ie, SIMOA) 
• Phenotype and markers of IC activation in peripheral blood (eg, CD3, CD8, CD4, TRegs, 
CD4 memory cells, CD25, FOXP3, CD45RA, ICOS, CD14, CD45, CD56, CD19 and 
ICOSLG) (fluorescence-activated cell sorting (FACS) or ChipCytometry) 
• PBMCs gene signature (ribonucleic acid, RNA) (transcriptomics/Nanostring)  
• ICOS Receptor Occupancy (RO) in PBMCs (KY1044 as single agent in Phase 1 only) 
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3 
STUDY DESIGN  
3.1 
Overall Study Design and Plan  
This study is a first in human, open--label, Phase 1/2, multi-center study consisting of a Phase 1 
dose escalation component with KY1044 as single agent and a dose escalation of KY1044 in 
combination with atezolizumab that will start after at least two cohorts have been treated with 
KY1044 as single agent and the treatment is considered to be safe and tolerable.  
An initial Phase 2 dose assessment part will open in one or more specific indication(s) to 
compare the efficacy and biomarker readouts of two biologically relevant dose levels of 
KY1044 (as single agent or in combination with atezolizumab) that have been determined to 
be safe in Phase 1.  These data in combination with safety, efficacy and biomarker data from 
Phase 1 will support definition of the RP2D.   
Once the MTD and/or RP2D for KY1044 as single agent or in combination with atezolizumab 
has been defined, the Phase 2 component may be extended to assess preliminary anti-tumor 
efficacy in additional selected indications. TNBC and HNSCC are selected as indications of 
interest for Phase 2. KY1044 and atezolizumab will be administered IV Q3W until a patient 
experiences unacceptable toxicity, progressive disease as per RECIST 1.1/iRECIST and/or 
withdraws consent. Patients should not discontinue treatment based on progressive disease per 
RECIST 1.1 unless clinical deterioration or increase in tumor markers is observed. iRECIST 
should always be considered. The maximum treatment period for each patient may be up to 
48 months. Provisions may be made to continue treatment after this timepoint for patients who 
show clinical benefit. 
The overall study design is presented in Figure 3-1. 
3.1.1 Definitions of Study Cohorts and Groups:  
Phase 1 cohorts:  
All cohorts in Phase 1 will be defined by dose level. 
Phase 2 groups: 
Groups will be defined based on previous anti-PD-(L)1 treatment per tumor indication. 
3.1.2 Tumor Indications in Phase 1 and Phase 2  
Phase 1: 
In Phase 1, patients with advanced/metastatic malignancies (all comers) and with preferred 
indications will be enrolled. Preferred indications are: HNSCC, gastric/esophageal cancer, 
HCC, NSCLC, melanoma, cervical cancer, renal cell cancer, pancreatic cancer and triple 
negative BC (TNBC). 
Phase 2: 
In Phase 2, patients will be enrolled  
• In one or more specific indication(s), in which efficacy has been observed in Phase 1 
to support definition of the RP2D for future indications and 
• In tumor indications, where signs of anti-tumor activities were detected during Phase 1 
(indications, where complete response (CR), partial response (PR) or durable stable 
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disease (SD) with tumor shrinkage that does not qualify for PR have been observed) 
and  
• In selected indications, HNSCC, NSCLC, gastric/esophageal cancer, cervical cancer, 
TNBC. 
3.1.3 Phase 1  
Dose escalation part - KY1044 single agent 
In the Phase 1 part of the study, cohorts of patients with advanced/metastatic malignancies, 
preferentially those with indications which are expected to be ICOS+, will be treated with 
KY1044 as single agent Q3W until the MTD is reached or a lower RP2D is established. It is 
expected that a RP2D based on safety, PK, and PD data may be established before the MTD is 
reached, as this has been the case with other checkpoint inhibitors. 
The dose escalation will be guided by the Modified Toxicity Probability Interval Design 
(mTPI-2 design, Guo et al 2017 [49]), which is an adaptive dose-finding method that allows 
dose escalation and de-escalation according to the precalculated decision table in Section 9. 
The maximum sample size for dose escalation in each Phase 1 component (single agent and 
combination therapy) will be 36 patients, using cohorts of a minimum of three patients (for 
further details see Section 4.1.1).  
Dose escalation part - KY1044 in combination with atezolizumab 
The combination part of the study will commence after at least two cohorts of KY1044 as 
single agent have been considered to be safe and tolerable and the data suggest that it is 
reasonable to begin treatment in combination. The combination dose escalation will follow a 
Q3W dosing schedule. Treatment in combination will escalate until the MTD is reached or a 
lower RP2D is established based on safety, PK and available PD data. The dose escalation will 
be guided by the mTPI-2 design (49), which is an adaptive dose-finding method that allows 
dose escalation and de-escalation according to the precalculated decision table. The maximum 
sample size for dose escalation will be 36 patients using cohorts of a minimum of three patients. 
(for further details see Section 4.1.1).  
Optional Phase 1 enrichment part 
An optional enrichment part may include the testing of additional patients at one or more dose 
levels to better understand the safety, tolerability, PK, preliminary anti-tumor efficacy and/or 
PK/PD relationships of KY1044 as single agent and/or in combination with atezolizumab.  
The enrichment part of the study will only use doses that have already been explored in the 
Phase 1 dose escalation parts of the study, and have been determined to be safe.  
Total number of patients in Phase 1 
The total number of patients included across all cohorts in the Phase 1 dose escalation and 
enrichment parts will be approximately 150. 
3.1.4 Phase 2  
In the absence of identifying an MTD or single efficacious dose in Phase 1, an initial Phase 2 
dose assessment part in one or more specific indication(s) will be opened to compare the 
efficacy and biomarker readouts of two biologically relevant dose levels of KY1044 (as single 
agent or in combination with atezolizumab) in a more homogeneous population.  Up to 
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20 patients (ie, 15 anti-PD-(L)1 naïve patients and where feasible five anti-PD-(L)1 pre-treated 
patients) will be included at each dose level and indication.  Together with safety, efficacy and 
biomarker data from Phase 1, data from this part will assist with the selection of the RP2D.  
Once the MTD and/or RP2D has been identified, Phase 2 may be extended to explore efficacy 
at the RP2D in additional selected indications as described below.  
KY1044 single agent 
A Phase 2 part may be opened should signs of anti-tumor activity (defined as CR, PR or durable 
SD with tumor shrinkage that does not qualify for PR) be seen in at least one patient in the 
Phase 1 dose escalation/enrichment in any indication (in either anti-PD-(L)1 naïve or 
pre-treated patients).  Initially up to 15 anti-PD-(L)1 naïve patients will be enrolled and 
depending on early efficacy additionally up to 30 patients will be enrolled per each indication.  
In the anti-PD-(L)1 pre-treated group of patients, initially five patients will be enrolled per 
indication and depending on early efficacy in these patients, additionally up to 15 patients will 
be enrolled in certain indications. 
KY1044 in combination with atezolizumab 
Patients will be enrolled in the Phase 2 part in selected indications (HNSCC, NSCLC, 
gastric/esophageal and cervical cancers and any indication showing activity in the Phase 1 dose 
escalation of the combination) in order to assess preliminary anti-tumor efficacy. These patient 
will also either be 
• Anti-PD-(L)1 treatment naïve or  
• Pre-treated with anti-PD-(L)1 
In the anti-PD-(L)1 treatment naïve group, initially approximately 15 patients will be enrolled, 
certain indications (TNBC and HNSCC) may be further expanded to up to approximately 
40 patients. 
In the anti-PD-(L)1 pre-treated group, initially a minimum of 10 patients will be enrolled in 
each of the defined indications ( HNSCC) which may be further expanded to up to 40 patients, 
depending on emerging efficacy data.  
Should enrolment for any of these disease indications not be feasible, or if the early response 
assessment (see below) suggests that there is only limited benefit in one or more of these 
indications, then enrolment to that group may be closed before the target is met. 
Early response assessment in Phase 2: 
The early assessment of ORR will compare observed response rates to historical controls, to 
define a minimum number of objective responses (CR, PR or durable SD with tumor shrinkage 
that does not qualify for PR) per RECIST 1.1 per each indication in the initial Phase 2 phase, 
in order to decide if enrolment should be further extended up to 40 patients.  
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Figure 3-1: 
Study Design  
 
BC=breast cancer; CR=complete response; HCC=hepatocellular carcinoma; HNSCC=head and neck squamous cell carcinoma; min=minimum; NSCLC=non-small cell lung cancer; 
PD-L1=programmed cell death ligand 1; PR=partial response; RP2D=recommended Phase 2 dose; SD=stable disease. 
* 
This part will only be opened in relevant indications if signs of anti-tumor activity (defined as at least one confirmed CR, PR or durable SD with tumor shrinkage that does not qualify for 
PR) are observed in the Phase 1 dose escalation/enrichment part with KY1044 as single agent. 
** 
Enrichment part: Should more data about safety, biomarkers or PK be required more patients may be tested at different doses levels with KY1044 as single agent or in combination with 
atezolizumab. 
*** 
In the initial Phase 2 dose assessment part, two dose levels (for KY1044 as single agent or in combination) will be explored in one or more indication(s) which has shown efficacy during 
Phase 1, to identify the RP2D. 
**** 
For selected tumor types, the number of patients enrolled per group could be reduced, depending on enrolment feasibility in the ongoing study. 
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3.2 
Study Flow  
Patients will undergo assessments during a (maximum) 28-day screening period, pre-dose and 
periodically during treatment, as outlined in Section 6. For both regimens of 
KY1044 administration as single agent and in combination with atezolizumab, treatment will 
continue until a patient experiences unacceptable toxicity, progressive disease as per iRECIST 
and/or withdrawal of consent.  
Safety follow-up will be performed 90 days after the end of treatment.  
Patients who do not have progressive disease (as per RECIST 1.1/iRECIST) at the time of 
discontinuing treatment will receive tumor assessments for evaluation of PFS until disease 
progression, or starting alternative treatment or the overall end of study (EOS) if earlier (see 
Section 8.2.1).  
All patients who do not withdraw consent for the study will be followed up for survival unless 
they are lost to follow-up, or overall EOS has been declared (see Section 3.6). 
Figure 3-2: 
Study Flow per Patient  
 
* Note: Additional provisions may be made for patients who are ongoing on treatment and are 
still receiving clinical benefit at 48 months for continuation of treatment.  
3.3 
Study Safety Review Committee (SRC)  
A safety review committee (SRC), will be responsible for review of all safety data arising from 
the study on an ongoing basis and for dose escalation decisions after each cohort in the Phase 1 
parts, as described in Section 5.4.  
During Phase 1, regular meetings will be held to review and monitor safety and tolerability of 
KY1044. Dose escalation will be considered at a meeting after the minimum DLT period of 
21 days for each cohort. Safety, tolerability and PK data will be reviewed to confirm the safety 
of the current dose level and agree the next step for dose escalation until identification of the 
MTD and/or RP2D, completion of all defined dose levels, or a decision that further increase of 
dose is not warranted. Safety data reviewed will be cumulative, including later occurring Aes 
(after Cycle 1), which will be considered at subsequent SRC meetings and dose decisions may 
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be amended depending on emerging data. The dose escalation decisions will be formally 
minuted and the minutes distributed to all members.  
The SRC may decide to stop one or more cohorts, or the entire study, if it judges that patients 
are placed at undue risk because of clinically significant findings.  Enrolment to the study will 
be paused in the event of any Grade 4 or 5 (death) toxicities which are not clearly explained by 
the underlying disease or extraneous causes. In case of a decision to stop further enrolment or 
stop patient’s treatment the sites and the Clinical Research Associates will be notified 
immediately via email about the decision, its reason and expectations regarding further actions. 
Additionally, appropriate measures will be taken in the Interactive X=Voice/Web Response 
System (IXRS; blocking dispensing of IMP, blocking screening and enrolment as appropriate). 
Additional actions may include requesting sites to contact patients and requesting ad hoc visits 
to provide relevant information and evaluate safety as needed. The event will be notified to 
relevant Ethics Committees, Independent Review Boards and Regulatory Authorities as 
required by local regulations, including local law and institutional requirements. Only 
following a comprehensive investigation on the cause of these events, which rules out the role 
of the investigational drug, and after fulfillment of relevant regional or national regulatory 
requirements, can enrolment be restarted in agreement with the SRC. 
The SRC will comprise as a minimum the Principal Investigator’s (Pis) (or medically qualified 
designee) and the Sponsor’s physicians.  Further internal or external experts may be consulted 
by the SRC as necessary. A complete list of members of the SRC will be included into the 
cohort management plan. 
The SRC will remain in place for Phase 2, and meeting frequencies will be decided dependent 
on emerging data.  
There will be no formal independent data monitoring board for this study. 
3.4 
Study Duration  
The study duration for an individual patient will include the screening period of up to 28 days, 
a study period of up to 48 months of treatment (approximately 70 cycles), and 90 days of safety 
follow-up after the last dose of study treatment.  Provision may be made for patients who are 
still on treatment and receiving documented clinical benefit at 48 months.  In this instance, 
Investigators should consult with the Sponsor prior to continuing treatment beyond 48 months.  
All patients will be followed up for survival up to 2 years (or as long as the treatment continues 
if it lasts more than 2 years) after the start of treatment unless they withdraw consent, are lost 
to follow-up or the overall end of the study is declared by the Sponsor. 
3.5 
Timing of Interim Analysis and Design Adaptations  
Preliminary analysis: 
A preliminary analysis of the study data will be performed and reported based on all patients’ 
data up to the time when all patients from the Phase 1 part have completed at least six cycles 
of treatment or discontinued the study and the initial patients from the Phase 2 part have had at 
least one tumor assessment after six months of treatment or discontinued the study. 
Final data analysis: 
A final data analysis will be performed at the end of the study. 
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3.6 
Definition of End of Study (EOS)  
The completion of the study is defined as the last visit for the last patient on treatment (for 
patients, who stopped treatment earlier follow-up will be ended at this point).  Additional 
provisions for treatment continuation may be made for patients who are ongoing on treatment 
and having clinical benefit at 48 months.  
3.7 
Early Study Termination  
The study can be terminated at anytime for any reason by the Sponsor (including failure to 
enroll, futility, SRC decision etc.). Should this be necessary, ongoing patients should be seen 
as soon as possible for the End of Treatment (EOT) visit and the assessments for EOT and 
safety follow-up visit, should be performed as described in Section 8.  
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.  The Sponsor will ensure that the Investigators/institutions/ 
Institutional Review Boards (IRBs) and/or independent ethics committees (IECs) and the 
regulatory authority(ies) are promptly informed of the termination or suspension of the study 
and of the reason(s) for the termination or suspension. 
Early termination for individual patients is addressed in Section 8. 
3.8 
Blinding  
Not applicable. This is an open-label study. 
4 
STUDY POPULATION  
Adult patients with advanced/metastatic malignancies and selected tumor indications, who are 
either anti-PD-(L)1 therapy naïve or pre-treated will be recruited into the study.  Details of 
indications selected for each part of the study are specified in the inclusion criteria 
(Section 4.2). 
4.1 
Number of Patients  
Each of the Phase 1 dose escalations (single agent and combination therapy) will include a 
maximum of 36 patients, unless no dose levels are determined to be safe or the SRC decides to 
stop the dose escalation part.  If fewer than 36 patients are required to dose escalate, the 
remainder may be included in the enrichment part.  The total number of patients included across 
all cohorts in the Phase 1 dose escalation and enrichment parts will be approximately 150. 
The actual number of patients recruited in the Phase 2 component will depend on the number 
of tumor indications investigated and on the number of expansions; however the total number 
of patients in Phase 2 is not anticipated to exceed 262 patients. 
4.1.1 Number of Patients for Dose Escalation and Cohort Composition  
The Phase 1 dose escalation parts of the study will be based on cohorts of 3 patients. More 
patients may be enrolled into each cohort to assure at least 3 evaluable patients for dose 
escalation decisions. To assess the safety profile of KY1044 it will be required that each cohort 
satisfies the following requirements:  
• At least two patients are anti-PD-(L)1 naïve.  
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• Only one patient has a non-preferred tumor type (See Section 3.1.2).  
• All inclusion/exclusion criteria are met.  
4.2 
Inclusion Criteria  
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent must be obtained prior to any procedures 
2. Age ≥18 years (≥20 years in Taiwan) 
3. Histologically documented advanced/metastatic malignancies 
4. Phase 1 and Phase 2 patients with advanced/metastatic malignancies who have measurable 
disease (non-measurable disease is allowed only in Phase 1) as determined by RECIST 1.1 
(refer to Appendix 1) will be eligible if, according to the NCCN guidelines, there are no 
available therapies known to confer a clinical benefit for their disease, or they have 
exhausted all such available options. Additionally, the following specific tumor indications 
will be enrolled:  
a. Phase 1 (including enrichment part): 
Patients with advanced/metastatic malignancies, and preferred indications as identified 
in Section 3.1 (NSCLC, HNSCC, HCC, melanoma, cervical, gastric/esophageal, renal, 
pancreatic, and triple negative BC) 
b. Phase 2 KY1044 single agent: 
Patients with advanced/metastatic malignancies in indications in which signs of 
anti-tumor activity (CR, PR or durable SD with tumor shrinkage that does not qualify 
for PR) were seen during the dose escalation/enrichment of KY1044 as single agent. 
c. Phase 2 KY1044 in combination with atezolizumab: 
Patients with advanced/metastatic malignancies in the selected indications below, 
and/or indications which have shown promising activity in Phase 1: 
• 
NSCLC (anti-PD-(L)1 therapy naïve and pre-treated between 1 and 2 prior lines 
of systemic therapy for advanced disease) 
• 
Gastric/Esophageal (anti-PD-(L)1 therapy naïve and pre-treated) 
• 
Recurrent and/or metastatic HNSCC (anti PD (L)1 therapy naïve and pre treated 
between 1 and 2 prior lines of systemic therapy for advanced disease) 
• 
Cervical (anti-PD-(L)1 therapy naïve and pre-treated) 
• 
Indications, in which signs of anti-tumor activity has been observed in Phase 1 
with KY1044 in combination with atezolizumab 
5. Prior therapy with anti-PD-(L)1 inhibitors is allowed provided any toxicity attributed to 
prior anti-PD-(L)1-directed therapy did not lead to discontinuation of therapy 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 
7. Life expectancy longer than 12 weeks. 
8. Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy 
according to the treating institution’s guidelines.  Patient must be willing to undergo a new 
tumor biopsy at screening, and during therapy on the study 
9. Females of childbearing potential must be using two highly effective contraceptive 
measures for the duration of study participation and for at least 5 months after discontinuing 
study treatment, or longer if the half-life of KY1044 is observed to exceed that of 
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atezolizumab (see Section 5.8).  Females must not be breast feeding and must have a 
negative pregnancy test prior to start of dosing or must have evidence of non-childbearing 
potential by fulfilling one of the following criteria at screening: 
• Post-menopausal defined as aged ≥50 years and amenorrhoeic for at least 12 months 
following cessation of all exogenous hormonal treatments 
• Women less than 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for at least 12 months following the cessation of exogenous hormonal 
treatments, and have serum follicle-stimulating hormone and luteinizing hormone 
levels in the postmenopausal range for the institution 
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation 
10. For the duration of study participation and for at least 5 months after discontinuing study 
treatment, or longer if the half-life of KY1044 is observed to exceed that of atezolizumab, 
sexually active males must use barrier contraception (ie, condoms). See Section 5.8. 
4.3 
Exclusion Criteria  
Patients eligible for this study must not meet any of the following criteria: 
1. Presence of symptomatic CNS metastases, or CNS metastases that require local 
CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of 
corticosteroids within the prior 2 weeks of first dose of study treatment.  Patients with 
treated brain metastasis, unless neurologically stable (for 4 weeks post-treatment and prior 
to study enrolment) and off of steroids for at least 2 weeks before the first dose of study 
treatment 
2. History of severe hypersensitivity reactions to other mAbs and/or their excipients 
3. Known presence of neutralizing anti-atezolizumab antibodies (for patients previously 
treated with atezolizumab) 
4. Having out of range laboratory values defined as: 
• Creatinine clearance or glomerular filtration rate ≤30 mL/min estimated by the 
Cockroft-Gault (C-G) or other medically acceptable formulas such as MDRD 
(Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease 
Epidemiology Collaboration) 
• Total bilirubin >1.5 x Upper Limit of Normal (ULN), except for patients with Gilbert’s 
syndrome who are excluded if total bilirubin >3.0 x ULN or direct bilirubin >1.5 x ULN 
• ALT >3 x ULN, except for patients that have tumor involvement of the liver, who are 
excluded if ALT >5 x ULN 
• AST >3 x ULN, except for patients that have tumor involvement of the liver, who are 
excluded if AST >5 x ULN 
• Absolute neutrophil count (ANC) <1.0 x 109/L 
• Platelet count <75 x 109/L 
• Hemoglobin <9 g/dL 
5. Impaired cardiac function or clinically significant cardiac disease, including any of the 
following: 
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• Clinically significant and/or uncontrolled heart disease such as congestive heart failure 
requiring treatment (New York Heart Association (NYHA) Grade ≥2), uncontrolled 
hypertension or clinically significant arrhythmia 
• QTcF >470 msec on screening ECG using Fridericia’s formula (QTcF) or congenital 
long QT syndrome 
• Acute myocardial infarction or unstable angina pectoris <3 months prior to first dose 
of study treatment 
6. Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or active 
hepatitis C virus (HCV) infection.  Active HBV infection is defined as HBV viral load 
≥2000 IU/mL (104 copies/mL).  Active HCV infection is defined as anti-HCV positive or 
detectable HCV RNA.  HBV or HCV positive patients with HCC who started anti-viral 
therapy before initiation of IMP and have HBV viral load <2000 IU/mL (104 copies/mL) 
and no detectable HCV RNA titers are eligible.  The anti-viral therapy should continue 
throughout the treatment period.  
Patients with any severe infection within 4 weeks prior to initiation of study treatment 
including, but not limited to, hospitalization for complications of infection. 
7. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
criterion include the following: malignancies that were treated curatively and have not 
recurred within 2 years prior to the first dose of study treatment; completely resected basal 
cell and squamous cell skin cancers; and completely resected carcinoma in situ of any type 
8. Any medical condition that would, in the Investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures or interpretation of study results 
9. Active autoimmune disease or a documented history of autoimmune disease, including 
ulcerative colitis and Crohn’s disease or any condition that requires systemic steroids, 
except vitiligo or resolved asthma/atopy that is treated with broncho-dilators (eg, albuterol) 
10. Patients previously exposed to anti-PD-(L)1 treatment who are not adequately treated for 
skin rash or had no replacement therapy for endocrinopathies should be excluded 
11. Patients with a history of drug-induced pneumonitis or current pneumonitis 
12. Systemic steroid therapy or any immunosuppressive therapy (≥10 mg/day prednisone or 
equivalent). Topical, inhaled, nasal, and ophthalmic steroids are not prohibited 
13. Herbal preparations/medications (including, but not limited to: St. John’s Wort, kava, 
ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and 
ginseng) are prohibited from the time that patients enter the screening period (at least 7 days 
prior to first dose of study treatment) until the last dose of study treatment (3 weeks for 
St John’s Wort) 
14. Warfarin and other types of long acting anticoagulants (such as phenprocumon and or 
anti-Xa inhibitors with a half-life of >12 hours) is prohibited within 4 weeks of the first 
dose of study treatment and patients requiring anticoagulant treatment should switch to low 
molecular weight heparin or anti-Xa inhibitors with a half-life of ≤12 hours 
15. Use of live or live attenuated vaccines against infectious diseases (examples include, but 
are not limited to, intranasal influenza, measles, mumps, rubella, oral polio, Bacillus 
Calmette-Guérin vaccine, rotavirus, varicella, yellow fever, TY21a typhoid vaccines etc) 
within 4 weeks of the first dose of study treatment and it should not be planned to 
administer such a vaccine during the course of the study.  SARS-CoV-2 vaccines 
authorized for use by the competent local regulatory health authorities for active 
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immunization to prevent COVID-19 are allowed (unless the vaccine is live or live 
attenuated) and must be given in accordance with the prevailing immunization guidelines. 
SARS-CoV-2 vaccination may be given at least 7 days prior to the planned first dose of 
study treatment.  Refer to Table 5-6 for more instruction with regard to SARS-CoV-2 
vaccination. 
16. Systemic anti-cancer therapy (TKI and/or chemotherapy) within 2 weeks of the first dose 
of study treatment. For cytotoxic agents that have major delayed toxicity, eg, mitomycin C 
and nitrosoureas, 4 weeks is indicated as washout period 
17. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, 
insertion of a central venous access device, and insertion of a feeding tube are not 
considered major surgery) 
18. Anti-CTLA4, anti-PD-(L)1 treatment within 4 weeks of the first dose of study treatment 
19. Pre-treatment with anti-CTLA4 antibodies in combination with any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathway 
20. Participation in an interventional, investigational study within 4 weeks of the first dose of 
study treatment 
21. Presence of CTCAE v5 ≥Grade 2 toxicity (except alopecia, peripheral neuropathy and 
ototoxicity, which are excluded if CTCAE v5 ≥Grade 3) due to prior cancer therapy 
22. Use of hematopoietic colony-stimulating growth factors (eg, granulocyte-colony 
stimulating factor (G-CSF), GM-CSF, M-CSF) ≤2 weeks prior to start of study treatment. 
An erythroid stimulating agent is allowed if it was initiated at least 2 weeks prior to the first 
dose of study treatment and the patient is on a stable dose 
23. Radiotherapy within 2 weeks of the first dose of study treatment, except for palliative 
radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful 
tumor mass. To allow evaluation for response to treatment, patients enrolled in the Phase 2 
part must have remaining measurable disease that has not been irradiated. 
24. Pregnant or lactating women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human chorionic 
gonadotropin (hCG) laboratory test. In rare cases of an endocrine-secreting tumor, hCG 
levels may be above normal limits, but without existing pregnancy. In these cases, there 
should be a repeat serum beta-hCG test (with a non-rising result) and a vaginal/pelvic 
ultrasound to rule out pregnancy. Upon confirmation of results and discussion with the 
Medical Monitor, these patients may enter the study.  
5 
TREATMENT OF PATIENTS  
5.1 
Presentation of Study Treatments  
5.1.1 KY1044  
KY1044 is presented as a clear to opalescent sterile solution that is colorless to slightly yellow, 
brown or brown-yellow, and is filled to a nominal 1 mL volume in a single-dose 2 mL clear 
glass vial. KY1044 is formulated at a nominal concentration of 50 mg/mL in 25 mM 
L-histidine/histidine 
hydrochloride, 
240 mM 
sucrose 
and 
0.02% 
(weight/volume) 
polysorbate 80 at pH 5.5.  KY1044 will be diluted in 0.9% NaCl solution prior to 
administration via IV infusion. 
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5.1.2 Atezolizumab (TECENTRIQ®)  
Atezolizumab is presented as a colorless to slightly yellow sterile solution, filled to a nominal 
20 mL volume in a single-dose vial.  Atezolizumab is formulated at a nominal concentration 
of 60 mg/mL in glacial acetic acid (16.5 mg), L-histidine (62 mg), sucrose (821.6 mg) and 
polysorbate 20 (8 mg) at a pH of 5.8.  Atezolizumab will be added to an IV infusion bag 
containing 0.9% NaCl solution prior to administration. 
5.2 
Study Treatment Administration  
The study treatment is defined as KY1044 as single agent or in combination with atezolizumab.  
All dosages prescribed and dispensed to patients and all dose changes during the study must be 
recorded in the patient’s hospital files and on the electronic case report form (eCRF).  
5.2.1 Dosing Regimen  
Table 5-1: 
Dose and Treatment Schedule  
Study 
treatments 
Pharmaceutical 
form 
Route of 
administration 
Dose 
Frequency 
and/or 
Regimen 
 
 
 
Phase 1 
Phase 2 
dose 
assessment 
Phase 2 
 
KY1044 
Solution 
IV infusion 
Escalating 
doses  
starting at 
0.8 mg  
One of two 
biologically 
relevant 
doses 
RP2D 
Q3W 
(±3 days) 
Atezolizumab 
Solution 
IV infusion 
1200 mg  
1200 mg 
1200 mg 
Q3W 
(±3 days) 
Q3W=every three weeks 
Patients are to receive KY1044 doses (either as single agent or in combination with 
atezolizumab) within a 3 days visit window.  However, the next dose (as single agent or in 
combination) may be delayed by up to 7 days to recover from previous Aes.  
If doses are not received within this time frame, the dose should be missed and patients should 
receive the next planned dose according to the schedule on Day 1 of the next cycle.  If the 
patient experiences a related toxicity, the management guidelines provided in Section 5.6 
should be followed. 
5.2.2 Infusion of IMPs  
KY1044 will be administered via IV infusion over 30 to 60 minutes.  If well tolerated at the 
first infusion, subsequent infusions may be given over 30 minutes. 
Atezolizumab will be administered via IV infusion over 60 minutes. If well tolerated at the first 
infusion, subsequent infusions may be given over 30 minutes. 
When given in combination, both IMPs are to be administered within 24 hours, however 
separate infusion sets must be used for each investigational product.  KY1044 is to be 
administered first and promptly followed by a saline solution flush to empty the line as 
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described in the pharmacy manual. Slow saline infusion will continue for approximately 1 hour 
before starting the atezolizumab infusion in the same infusion site.  There should be a period 
of at least 1 hour after the infusion(s) are complete whereby the patient requires close 
observation.  
After receiving the first infusion in Phase 1, patients will be either hospitalized or remain in 
the clinic for at least 6 to 8 hours until the last assessments. They will be provided with 
instructions for after hour care per institutional standard and will return to the clinic on C1D2. 
At all other infusion visits the observation period after the infusion should be at least 3 hours 
before patients are discharged. In Phase 2, the observation period after infusion of IMP should 
initially be at least 3 hours before patients are discharged. This time window maybe further 
reduced during later cycles and when more safety data for each patient are available. 
Neither KY1044 or atezolizumab should be co-administered with other drugs through the same 
IV line.  The date, start time, completion time and time and length of any interruptions must be 
recorded in the eCRF. 
Further instructions for the preparation and administration of KY1044 and atezolizumab are 
described in the Pharmacy Manuals. 
5.2.3 Precautions for IMP Administration (KY1044 and Atezolizumab)  
A physician must be present at the site or immediately available to respond to emergencies 
during all administrations of KY1044 alone or with atezolizumab.  Fully functional 
resuscitation facilities should be available.  KY1044 or atezolizumab must not be administered 
via IV push or bolus. 
In each cohort of the dose escalation of KY1044 as a single agent, dosing will be staggered 
such that administration of the first patient in each cohort is separated by at least 48 hours from 
dosing the next patient. Subsequent patients will be treated at least 24 hours apart during the 
Phase 1 dose escalation part of the study.  
In the combination cohorts, dosing will be staggered, such that administration of the first 
patient in the first cohort is separated by at least 72 hours from dosing the next patient, with 
subsequent patients being treated at least 24 hours apart in this cohort. In subsequent cohorts 
the first patient in each cohort will always be dosed 48 hours apart from the next patient. 
Subsequent patients will be treated at least 24 hours apart during the dose escalation part of the 
study. 
5.2.4 Monitoring of IMP Administration (KY1044 and Atezolizumab)  
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in Section 6.5.7. 
In the event of an infusion-related reaction ≤Grade 2, the infusion rate of KY1044 or 
atezolizumab must be decreased by 50% or interrupted until resolution of the event (up to 
4 hours) and re-initiated at 50% of the initial rate until completion of the infusion. If the 
infusion reaction is caused by KY1044, the atezolizumab infusion may be delayed until the 
next day and/or until recovery from the event.  For these patients, subsequent infusions may be 
administered at 50% of the initial rate and premedication should be considered.  In the event 
of more severe infusion reactions (CTCAE v5 >Grade 2), IMP should be permanently 
discontinued. 
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5.2.5 Ancillary Treatments  
Patients should not receive premedication to prevent infusion reaction before the first infusion 
of KY1044, in order to determine if premedication is necessary.  If a patient experiences an 
infusion reaction, he/she may receive premedication on subsequent dosing days.  The 
premedication should be chosen per institutional standard of care, at the discretion of the 
treating physician.  
Acute allergic reactions should be treated as needed per institutional standard of care.  In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status. If a patient experiences a Grade 3 anaphylactic/anaphylactoid 
reaction, the patient will be discontinued from the study. 
Guidelines on management of KY1044 and atezolizumab infusion reactions are provided 
in Table 5-5. 
The CTCAE v5 category of “Infusion related reaction” should be used to describe KY1044 and 
atezolizumab infusion reactions, unless the Investigator considers another category, such as 
“Allergic reaction,” “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a 
specific situation. 
5.3 
Treatment Duration  
All patients treated with either KY1044 as single agent or in combination with atezolizumab 
will begin study treatment on Cycle 1 Day 1.  Each cycle will consist of 21 days (±3 days). The 
next scheduled dose (as single agent or in combination) may be delayed by up to 7 days to 
recover from previous Aes.  If the next dose (as single agent or in combination) cannot be 
administered within the above mentioned 7-day delay, then the dose should be skipped.  Dosing 
will resume at the scheduled dose or the next lower dose.  Dose modifications should follow 
Section 5.6. 
If more than one consecutive dose of KY1044 as single agent or in combination with 
atezolizumab has to be skipped due to study treatment-related toxicities, then the default 
position is that IMPs should be permanently discontinued.  However, if a patient who misses 
more than one consecutive dose due to a study treatment-related toxicity experiences clinical 
benefit, and in the opinion of the Investigator it is in the patient’s best interest to remain on 
study, then the patient may continue treatment after discussion with the Medical Monitor. 
A patient may continue treatment with KY1044 as single agent or in combination with 
atezolizumab within this clinical study, as long as they are continuing to derive benefit from 
treatment, until the patient experiences unacceptable toxicity or confirmed disease progression 
per iRECIST. Patients will not be withdrawn from the study due to progressive disease per 
RECIST 1.1, unless clinically indicated.  
Criteria for treatment cessation or patient withdrawal from the study are outlined in Section 8, 
and management of toxicities is outlined in Section 5.6. 
Patients with SD, PR, unconfirmed CR, and unconfirmed progressive disease will continue 
treatment in additional cycles.  
Patients who meet the following criteria will NOT continue treatment in additional cycles: 
• Patients who experience unacceptable toxicity. 
• Patients with confirmed progressive disease. These patients will enter the Safety 
follow-up period unless the Investigator considers it to be in the patient’s best interest 
to remain on the study, and after discussion with the Medical Monitor.  
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• Patients with an unconfirmed progressive disease who show signs of clinical 
deterioration or toxicity. These patients will enter the Safety follow-up period, and will 
continue to be followed-up until confirmed progressive disease or initiation of a new 
treatment.  
Accumulating evidence indicates that objective responses to immunotherapy follows delayed 
kinetics of weeks or months and can be preceded by initial apparent radiological progression 
or appearance of new lesions (NLs) or some enlarging lesions, while other target lesions are 
regressing (“mixed response”) (50). It is therefore reasonable to allow for these possibilities 
and continue to treat the patient until progression is confirmed and found to be advancing at 
the next imaging assessment as per iRECIST. These considerations should be balanced by 
clinical judgment as to whether the patient is clinically deteriorating and unlikely to receive 
any benefit from continued treatment. 
Such deterioration will be assessed to have occurred after a clinical event that, in the 
Investigator’s opinion, is attributable to disease progression, is unlikely to reverse with 
continued study treatment and therefore indicates that the patient is not benefiting from study 
treatment and cannot be managed by the addition of supportive care.  
The decision to continue or stop treatment should be discussed with the Medical Monitor and 
will be documented in the study files. 
The maximum duration of the treatment period for each patient within this study may be up to 
48 months. Provisions may be made for patients who are still on treatment and receiving benefit 
at this timepoint. 
5.4 
Dose Escalation Guidelines  
5.4.1 Starting Dose Rationale  
Doses for the Phase 1 dose escalation part with KY1044 as single agent were selected based 
on PK/PD modelling of pre-clinical data, target engagement in tumor tissue, efficacy in 
pre-clinical pharmacology studies and characterization of the safety profile of KY1044 in 
cynomolgus monkeys and rats. The starting dose of KY1044 for the first cohort as single agent 
will be a single infusion of 0.8 mg KY1044. The proposed dose range for the Phase 1 dose 
escalation with KY1044 as single agent is 0.8 to 240 mg (and potentially above) with dose 
level increases between 300% to 333% for the next higher dose.  Intermediate dose levels may 
also be explored, depending on emerging safety and PK/PD data.  This dose range was selected 
to ensure a safe starting dose, to facilitate assessment of safety, tolerability and anti-tumor 
activity over a pharmacologically relevant dose range and to provide adequate exposure to 
support future clinical investigation of KY1044.  Provisionally, the starting dose for KY1044 
in combination with atezolizumab is expected also to be 0.8 mg, unless emerging safety data 
and the SRC recommend to start at a lower dose level. For more detail please refer to 
Section 5.4.2.  
5.4.2 Provisional Dose Levels  
Table 5-2 and Table 5-3 describe the starting dose for the Phase 1 parts, and the dose levels 
that may be evaluated during this trial. 
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Table 5-2: 
Provisional Dose Levels (Phase 1 KY1044 Single Agent)  
Dose level 
KY1044 proposed 
dosea 
Increment from 
previous dose 
Concentration after 
dilution 
Type of infusion 
material 
-1b 
0.24 mg 
 -70% 
0.048 mg/mL 
10 mL syringe (PP) 
1 
(starting 
dose) 
0.8 mg 
Starting dose 
0.08 mg/mL 
10 mL syringe (PP) 
2 
2.4 mg 
300% 
0.12 mg/mL 
20 mL syringe (PP) 
3 
8 mg 
333% 
0.4 mg/mL 
20 mL syringe (PP) 
4 
24 mg 
300% 
0.24 mg/mLd 
100 mL bag (PE or 
PVC) 
5 
80 mg 
333% 
0.8 mg/mLd 
100 mL bag (PE or 
PVC) 
6 
240 mg c 
300% 
2.4 mg/mLd 
100 mL bag (PE or 
PVC) 
MTD=maximal tolerated dose; PD=pharmacodynamics; PE=polyethylene; PK=pharmacokinetic; PP=polypropylene; 
PVC=polyvinyl chloride. 
a 
It is possible for additional and/or intermediate dose levels to be added during the study.  Cohorts may be added at any 
dose level below the MTD to better understand safety, PK or PD. Multiple dose levels below the MTD may be 
evaluated simultaneously in order to obtain PK and PD data across a range of doses. 
b 
Dose level -1 represents treatment doses for patients requiring a dose reduction from the starting dose level. No dose 
reduction below dose level -1 is permitted for this study 
c 
Dose levels above 240 mg may be explored depending on emerging data 
d 
Concentrations are approximate as there may be slight variation in the fill volume of commercially available saline IV 
bags. The whole contents of the bag will be delivered to ensure that the entire dose is delivered to the patient. 
Table 5-3: 
Provisional Dose Levels (Phase 1 KY1044 in Combination with Atezolizumab)  
Dose level 
KY1044 proposed dosea 
Atezolizumab proposed dose 
-1b 
0.24 mg 
1200 mg 
1 (starting dose) 
0.8 mg 
1200 mg 
2 
2.4 mg 
1200 mg 
3 
8 mg 
1200 mg 
4 
24 mg 
1200 mg 
5 
80 mg 
1200 mg 
6 
240 mg c 
1200 mg 
MTD=maximal tolerated dose; PD=pharmacodynamic; PK=pharmacokinetic. 
a 
It is possible for additional and/or intermediate dose levels to be added during the study.  Cohorts may be added at any 
dose level below the MTD in order to better understand safety, PK or PD. Multiple dose levels below the MTD may be 
evaluated simultaneously in order to obtain PK and PD data across a range of doses. 
b 
Dose level -1 represents treatment doses for patients requiring a dose reduction from the starting dose level. No dose 
reduction below dose level -1 is permitted for this study. 
c 
Dose levels above 240 mg maybe explored depending on emerging data 
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5.4.3 Cohort Modification  
For the purposes of dose escalation decisions (Phase 1 of KY1044 as single agent or in 
combination with atezolizumab), each cohort will consist of three newly enrolled patients who 
will be treated at the specified dose level and will meet the criteria in Section 4.1.1.  Should 
only two of these patients in the first cohort recruited to the study be considered evaluable (ie, 
meet the criteria described below for a patient to be considered evaluable [Section 5.4.5.1]) and 
neither patient has experienced a treatment-related toxicity CTCAE v5 >Grade 1, then a dose 
escalation decision may be made following a dose escalation meeting.  If, one or both patients 
experience a treatment-related toxicity CTCAE v5 >Grade 1, or if the SRC decide additional 
information is required before making a dose escalation decision, then additional patients will 
be enrolled to this cohort to reach the minimum of three evaluable patients.  Subsequent cohorts 
will have at least three evaluable patients.  
5.4.4 Dose Escalation Procedures  
The first cohort enrolled in the study will be treated with single agent KY1044 at the starting 
dose as specified in Table 5-2.  Once this cohort has completed the DLT follow-up period 
(21 days) and the dose escalation decision has been determined by the SRC to escalate, the 
second cohort for the single agent will open for dosing.  After the first two cohorts have been 
declared safe and tolerable, combination dosing will begin at the planned starting dose in 
parallel to proceeding with dose escalation of the single agent. 
The combination dose escalation will proceed provided that the starting dose of the 
combination does not exceed the MTD of the single agent.  Provisionally, the first cohort 
enrolled in the study will be treated with the starting dose for KY1044 at a flat dose of 0.8 mg 
in combination with atezolizumab (a lower dose of KY1044 may be considered for starting the 
combination if emerging data support this, but will not be higher than 0.8 mg for KY1044 and 
1200 mg for atezolizumab).  
The assessment of DLT data will be made after the third patient in a given cohort has completed 
the minimum DLT follow-up period (21 days) or is otherwise evaluable (see Section 5.4.5.1).  
The SRC will meet for the dose escalation meeting, once required data have been entered into 
the eCRF, cleaned and laboratory analyses have been performed.  
After the dose escalation meeting, the new dose will be officially confirmed and the new cohort 
will be opened for dosing patients.  Drug administration at the next dose level may not proceed 
until the Investigator receives written confirmation, indicating that the results of the previous 
dose level were evaluated and that it is permissible to proceed to a higher dose level. The 
number of cohorts explored will be dependent on the tolerability of the compound. 
Dose escalation will continue until identification of the MTD and/or the RP2D, completion of 
all defined dose levels, or a decision that further increase of dose is not warranted. 
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5.4.5 Dose Escalation Decisions  
5.4.5.1 Evaluable Patients  
For dose escalation decisions, patients in either single agent or combination cohorts can be 
considered evaluable after having met the following criteria:  
• Have completed a minimum of one cycle of treatment with the minimum safety 
evaluation (Cycle 1, 21 days) or have had a DLT within the first cycle of treatment (first 
21 days) 
• Have adequate drug exposure (ie, full infusion of planned doses of KY1044 and 
atezolizumab if appropriate) 
Dose escalation decisions will occur when the cohort of at least three patients has met these 
criteria.  If only two patients in a cohort are evaluable and neither patient has experienced a 
treatment-related toxicity CTCAE v5>Grade 1, dose escalation decisions may be considered 
(see Section 5.4.3). 
5.4.5.2 Data for Dose Escalation Decisions  
Decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing study, including safety information (all CTC grade Aes, ECGs and 
laboratory values, DLTs, all CTCAE v5>Grade 1 toxicity data) and available PK data from 
evaluable patients. 
The SRC must reach a consensus on whether to declare the MTD, escalate the dose any further, 
or whether to de-escalate and/or recruit additional numbers of patients at the current dose level.  
The mTPI-2 decision table will be used by the SRC in addition to other data mentioned in this 
section to aid in the recommended escalation and de-escalation decisions (see Section 9).  
Patient safety will be monitored on an ongoing basis by the SRC and the dose levels and 
continuation of dosing at a certain dose level will potentially be amended, depending on 
emerging data from earlier cohorts.  
5.4.6 Maximum Tolerated Dose  
5.4.6.1 MTD Definition  
The MTD will be defined as follows in each of the Phase 1 parts: 
• KY1044 single agent: the MTD is defined as the highest drug dosage not expected to 
cause DLT in 30% or more of the treated patients in the DLT follow-up period, 
corresponding to the first 21 days of KY1044 treatment during the escalation part of 
the study.  
• KY1044 combination with atezolizumab: the MTD is defined as the highest drug 
dosage not expected to cause DLT in 30% or more of the treated patients in the DLT 
follow-up period, corresponding to the first 21 days of combined treatment during the 
escalation part of the study.  
• The SRC will use all data previously mentioned as well as the mTPI-2 decision table in 
determining the MTD.  The MTD is determined based on the isotonic regression 
specified in Guo et al. 2017 (49).  The determined MTD is the dose for which the 
isotonic estimate of the toxicity rate is the closest to the target toxicity rate of 30% and 
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less than 35%.  The parameters of mTPI-2 design and operating characteristics are 
described in Section 9.  
5.4.7 Recommended Dose for Further Development  
The RP2D will be declared when the MTD and/or the optimal biological dose(s) is established 
in the Phase 1 dose escalation and/or enrichment component and/or the initial Phase 2 dose 
assessment part of the study.  This will be a composite of safety, drug exposure, target 
occupancy, PK/PD association and signs of anti-tumor activity. 
5.4.8 Intra-patient Dose Escalation  
Depending on emerging data and in the case that KY1044 as single agent or the combination 
with atezolizumab is well tolerated, intra-patient dose escalation of KY1044 dose may be 
permitted to RP2D once defined to avoid suboptimal dosing for patients treated in cohorts at 
lowest dose levels. 
5.5 
Dose Limiting Toxicities  
A DLT is defined as a clinically relevant AE or abnormal laboratory value of CTCAE 
≥Grade 3 assessed as unrelated to disease, disease progression, inter-current illness or 
concomitant medications, which occurs within the first cycle (21 days) of treatment with 
KY1044 as single agent or in combination with atezolizumab during the dose escalation part 
of the study, with the exceptions described in Table 5-4. 
National Cancer Institute CTCAE Version 5.0 will be used for all grading.  For dose-escalation 
decisions, DLTs will be considered by the SRC.  Aes meeting the criteria of DLT (please refer 
to Table 5-4) will be also collected in Cycle 2 and later cycles and will be considered by the 
SRC for ongoing safety decision. 
The Investigator must notify the Sponsor immediately of any unexpected CTCAE v5 
≥Grade 3 Aes or laboratory abnormalities.  Prior to enrolling patients into a higher dose level, 
all CTCAE v5 ≥Grade 2 will be reviewed for all patients at the current dose level and will also 
be considered for further dose escalation. 
Table 5-4: 
Criteria for Defining Dose Limiting Toxicities  
For dose escalation and cohort expansion, DLT will be adjudicated as follows: 
Any Grade 4 Aes will be adjudicated DLTs with the exception of: 
 
Neutropenia lasting <72 hours that is not associated with fever or other clinical symptoms. 
 
Lymphopenia 
 
Electrolyte abnormalities that are not associated with clinical sequelae and are corrected with 
appropriate management or supplementation within 72 hours of the onset. 
Any Grade 3 Aes will be adjudicated as DLTs except for: 
 
Nausea and vomiting persisting for <2 days after optimal anti-emetic therapy. 
 
Thrombocytopenia without significant bleeding (including platelet transfusions). 
 
Diarrhea persisting for <2 days after optimal anti-diarrhea treatment. 
 
Hypertension persisting <7 days after treatment.  
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Infection or fever in the absence of neutropenia persisting <5 days.  
 
Rash or photosensitivity persisting <7 days after treatment. 
 
Fatigue lasting <7 days. 
 
LFT elevations (AST/ALT) persisting <7 days after treatment with corticosteroids. 
 
Immune-related adverse events persisting <7 days after treatment with corticosteroids. 
The following Grade 2 Aes will be adjudicated as DLTs: 
 
Total bilirubin CTCAE v5 ≥Grade 2 with ALT/AST CTCAE v5 ≥Grade 2.  
 
Pneumonitis persisting >7 days despite treatment with corticosteroids.  
 
Eye pain or reduction of visual acuity that does not respond to topical therapy and does not improve 
to Grade 1 severity within 2 weeks of the initiation of topical therapy OR requires systemic treatment.  
 
Other clinically significant toxicities (cardiotoxicity, neurotoxicity) including a single event or 
multiple occurrences of the same event that lead to a dosing delay of >7 days in Cycle 1. 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE v5=Common Terminology 
Criteria for Adverse Events Version 5; DLT=dose limiting toxicity; LFT=liver function test. 
5.6 
Dose Modifications and Management of Toxicities  
5.6.1 Dose Modifications and Dose Delays  
For patients who do not tolerate the protocol -specified dosing schedule, dose adjustments are 
permitted to allow the patient to continue the study treatment. The following guidelines must 
be followed: 
• If a patient experiences an AE meeting the criteria for a DLT as outlined in Section 5.5 
(including events occurring after Cycle 1), treatment should be withheld.  Dose 
modifications for toxicities related to the study medication are summarized in 
Table 5-5. Following resolution of the toxicity to Grade 1 or to the patient’s baseline 
value (as outlined in the safety management guidelines in Table 5-5), the patient may 
resume study treatment at the same or the next lower dose level (Table 5-2, Table 5-3) 
assessed to be safe (on the same dosing schedule [administration every 21 days]), if 
there is no evidence of disease progression as per iRECIST.  
• For patients in the dose escalation part of the study receiving KY1044 in combination 
with atezolizumab, the KY1044 dose level will be lowered to the next lower dose level.  
Dose reductions of atezolizumab are not allowed.  
• The decision to resume treatment with KY1044 as single agent or in combination with 
atezolizumab following the occurrence of a DLT is at the discretion of the Investigator.  
If the Investigator considers it to be in the patient’s best interest to resume therapy 
before the toxicity has resolved to Grade 1, or to resume without dose reduction, this 
may be permitted on a case by case basis, following discussion with the Medical 
Monitor. 
• Dose reductions for KY1044 to below 0.24 mg (less than starting dose -1) are not 
permitted. 
• If a patient who misses more than one consecutive dose due to study treatment -related 
toxicity experiences clinical benefit, and in the opinion of the Investigator it is in the 
patient’s best interest to remain on study, then the patient may continue treatment after 
discussion with the Medical Monitor. 
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• Patients who discontinue study treatment for a study related AE or a study -related 
abnormal laboratory value must complete their EOT visit and safety followup 
procedures as described in Section 5.6.2 below and be followed up for PFS and survival 
(please refer to Section 8.2.2). 
• Active SARS-Cov-2 infections in patients enrolled into the study should be treated as 
Aes.  This also applies to any other concurrent illnesses, which might occur during the 
study.  Treatment interruption of KY1044 as single agent and in combination with 
atezolizumab should be considered on an individual patient basis after discussion with 
the Medical Monitor. 
• All interruptions or change to study drug administration must be recorded in the 
patient’s hospital files and eCRF. 
5.6.2 Follow-up for Toxicities  
• The emergence of irAEs may be anticipated based on overall experience in clinical 
studies with similar immunomodulators. 
• An irAE is a clinically important AE of unknown etiology associated with the study 
drug exposure.  IrAEs are typically low grade and self-limited, often occurring after 
multiple doses, and most frequently involving the GI tract (diarrhea/colitis), skin 
(rashes), liver (hepatitis), and endocrine systems (a variety of endocrinopathies) and 
lung (pneumonitis).  Serologic, histologic (tumor sample) and immunological 
assessments should be performed as deemed appropriate by the Investigator, to verify 
the immune related nature of the AE, and exclude the neoplastic, infectious or metabolic 
origin of the AE.  Management Algorithms (Table 5-5) have been developed to assist 
Investigators in assessing and managing the following groups of Aes: Infusion 
reactions, 
Hematological, 
Cardiological, 
GI, 
Renal, 
Pulmonary, 
Hepatic, 
Endocrinopathy, 
Dermatological, 
Neurological, 
Ophthalmological, 
and 
Rheumatological Aes. 
• Patients whose treatment is interrupted or permanently discontinued due to an irAE, 
AE or clinically significant laboratory value, must be followed-up at least once a week 
(or more frequently if required by institutional practices, or if clinically indicated) for 
4 weeks, and subsequently at approximately 4-week intervals, until resolution or 
stabilization of the event, whichever comes first.  Appropriate clinical experts should 
be consulted as deemed necessary.  
• In case of a suspected irAE, the relevant immunological assessments (eg, rheumatoid 
factor, anti-deoxyribonucleic acid (DNA) Ab, etc.) should be performed and guidelines 
as outlined in Table 5-5 (and laboratory assessments Section 6.5.6) should be followed.  
All patients must be followed up for irAEs, Aes and SAEs for 90 days following the last dose 
of KY1044 as single agent or in combination with atezolizumab. 
Table 5-5 outlines the follow-up evaluation recommended for selected toxicities. For any 
irAEs/Aes Grade 1 and/or Grade 2, treatment with KY1044 and atezolizumab (if applicable) 
should be maintained at the determined dose and schedule, unless otherwise specified 
in Table 5-5. 
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Table 5-5: 
Management of Toxicities Defined as Study Treatment-related Only  
Infusion Reaction and Cytokine Release Syndrome (CRS) 
Grade 
CTCAE description 
Management 
Specialist referral 
1 
Mild 
transient 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention 
not 
indicated 
• 
Drug infusion rate may be decreased, or infusion temporarily interrupted, until resolution of the 
event 
• 
Consider reducing the rate of infusion upon re-initiation or subsequent infusions 
• 
NSAIDs (eg, acetaminophen), antihistamines, opioids, and corticosteroids may be used per 
Investigator/ institutional guidelines 
• 
Consider premedication for subsequent infusions per Investigator/ institutional guidelines 
• 
If CRS is suspected (very high fever and precipitous drops in blood pressure, myalgia, change in 
mental status) treat with corticosteroids according to local standards (and/or with tocilizumab)1 
• 
Take blood for cytokine measurements immediately after the occurrence of the AE and during 
treatment   
 
2 
Therapy 
or 
infusion 
interruption 
indicated 
but 
responds 
promptly 
to 
symptomatic 
treatment 
(eg, 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic 
medications 
indicated for ≤24 hours 
3 
Prolonged (eg, not rapidly 
responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following initial improvement; 
hospitalization indicated for 
clinical sequelae 
• 
Permanently discontinue ICI 
• 
For severe/life-threatening reactions, manage the patient as clinically appropriate (eg, 
antihistamines, 
oxygen, 
fluids, 
opioids, 
corticosteroids, 
bronchodilators, 
etc.) 
per 
Investigator/institutional guidelines 
• 
Provide supplemental oxygen, fluids, and other resuscitative measures and/or measures for 
symptomatic relief (see under Grade 2, above) as needed. Monitor vital signs (eg, BP, HR, 
respiration, and temperature) every 15 ±5 minutes until resolution 
✓ 
Refer to allergist to 
prevent 
future 
reactions 
4 
Life-threatening consequences; 
urgent intervention indicated 
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HAEMATOLOGICAL 
Grade 
CTCAE description 
Management 
Specialist referral 
Anemia 
1 
Hgb  <LLN-10.0 g/dL;  
(<LLN-6.2 mmol/L; 
<LLN-100 g/L) 
• 
Monitor closely while continuing ICI 
✓ 
2 
Hgb <10.0–8.0 g/dL; 
(<6.2–4.9 mmol/L; 
<100-80 g/L) 
• Monitor closely while continuing ICI 
• Evaluate for possible causes and refer to hematology if no obvious cause if identified 
✓ 
3 
Hgb <8.0 g/dL;  
(<4.9 mmol/L; <80 g/L;) 
transfusion indicated 
• Hold ICI 
• Consider Coombs testing and evaluation for hemolytic anemia 
• Consider re-treating with ICI if hemolytic anemia responds promptly (within a few days) to 
corticosteroids 
✓ 
4 
Life-threatening consequences; 
urgent intervention indicated 
• Permanently discontinue ICI 
✓ 
Notes: 
1. No firm recommendations for corticosteroid management are provided here as treatment should be individualized. 
2. If unexplained anemia does not respond to steroids, consider bone marrow biopsy 
Neutropenia (ANC) 
3 
ANC <1000-500/mm3 
• Dose delay for study treatment-related Grade 3 until resolved to ≤Grade 1 
✓  
4 
ANC <500/mm3 
• Discontinue for study treatment-related Grade 4 >7 days duration 
✓  
Febrile neutropenia 
3 
ANC <1.0x109/L, fever 
≥38.5°C 
• Dose delay for study treatment-related Grade 3 until resolved to ≤Grade 1 
• Discontinue for study treatment-related Grade 4 
✓ 
4 
Thrombocytopenia 
3 
PLT <50,000-25,000/mm3 
• Dose delay for study treatment-related Grade 3 until resolved to ≤Grade 1 
• Discontinue for study treatment-related Grade 3 >7 days or associated with bleeding 
✓ 
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4 
PLT <25,000/mm3 
• Discontinue for study treatment-related Grade 4 
✓ 
Notes:  
Progressive or Grade 3 unexplained thrombocytopenia: consider work up for autoimmune disease and rule out DIC or other cause of thrombocytopenia that may be related 
to underlying disease 
Precipitous development of thrombocytopenia: consider steroid intervention pending clinical condition (brain metastases, colitis, etc.) and evaluate for immune-mediated 
thrombocytopenia 
Permanently discontinue ICI for clinically significant, steroid refractory ICI-associated thrombocytopenia 
Lymphopenia 
3 
<0.5-0.2x109/L 
• Maintain dose level for study treatment-related ≤Grade 3 
 
4 
<0.2x109/L 
• Dose delay for study treatment-related Grade 4 until resolved to ≤Grade 3 
• Study treatment-related Grade 4 lymphopenia or leukopenia does not require discontinuation 
 
RENAL 
Grade 
CTCAE description 
Management 
Specialist referral 
Nephritis (Creatinine increase) 
1 
Creatinine >1.5–2xabove 
baseline;  
>0.3 mg/dL 
• Continue ICI but initiate work-up to evaluate possible causes and monitor closely 
 
2 
Creatinine >2-3xabove baseline  • Dose delay for study treatment-related ≥Grade 2 until resolved to ≤Grade 1 
• Start corticosteroids (Note 3) 
• Discontinue ICI for persistent or recurrent elevation 
3 
Creatinine 
>3xbaseline 
or 
>4 mg/dL 
Hospitalization indicated 
• Hold ICI 
• Consider resuming treatment if Grade 3 resolves (Note 2) and cause of event is confirmed. Timing of 
event and response to treatment should be considered in making a decision 
• Start corticosteroids (Note 3) 
• Discontinue ICI for persistent or recurrent elevation 
4 
Creatinine >6.0xULN 
Life threatening consequences 
dialysis indicated  
• 
Discontinue for study treatment-related Grade 4 
• Start corticosteroids (Note 3) 
✓ 
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Notes: 
1. Grades are those listed under ‘acute kidney injury’ in CTCAE2. 
2. Consider using increase from baseline rather than absolute value for creatinine monitoring, especially in patients with primary renal carcinoma or other baseline renal 
conditions. 
3. For persistent creatinine elevation ≥Grade 2 with no other identifiable cause, start corticosteroids. Dose and schedule should be individualized and based on grade. Taper 
corticosteroids when creatinine improves to Grade 1. 
HEPATIC 
Hepatitis 
Grade 
CTCAE description 
Management 
Specialist referral 
1 
AST, ALT >ULN-3xULN; 
 total bilirubin >ULN-
1.5xULN 
• Continue ICI 
• CMP or hepatic function panel once weekly 
• If liver enzyme and function tests are stable, reduce frequency of blood tests 
 
2 
AST, ALT >3-≤5xULN; 
 total bilirubin >1.5-≤3xULN 
• Hold ICI 
• Rule out viral hepatitis, autoimmune disease, biliary obstruction, new metastasis or thrombosis 
• Start prednisone 0.5-1 mg/kg/day (or equivalent dose of methylprednisolone) with 4-week taper 
• Monitor CMP twice a week 
• Liver biopsy is optional 
• Resume ICI when corticosteroid taper to 10 mg/day (toxicity Grade ≤1) 
 
3 and 
4 
AST, ALT >5xULN;  
total bilirubin >3xULN 
• Permanently discontinue ICI 
• Monitor CMP every 1–2 days 
• Start prednisone 1–2 mg/kg/day 
o 
If refractory after 3 days, consider mycophenolate 
• If liver enzymes improve, taper corticosteroid over 4 weeks 
• Consider liver biopsy 
 
Note: If Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional 
guidelines (eg, review of peripheral blood smear and haptoglobin determination), then reduce one dose level and continue treatment at the discretion of the Investigator. 
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Asymptomatic amylase and/or lipase elevation 
3 
>2.0-5.0xULN 
Any study treatment-related Grade ≥3 isolated amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay or discontinuation. The 
Kymab Medical representative should be consulted for such amylase or lipase abnormalities. 
 
4 
>5.0xULN 
Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 1 week of the first occurrence of any ≥Grade 3 of amylase 
and/or lipase. If asymptomatic Grade 2 elevations of lipase and/or amylase occur again at the reduced dose, patients will be discontinued permanently from study treatment. 
CARDIAC 
Grade 
CTCAE description 
Management 
Specialist referral 
1 
Abnormal cardiac biomarker 
testing, 
including 
abnormal 
ECG 
• Recommend baseline ECG and cardiac biomarker assessment (BNP, troponin) to establish if there is 
a notable change during therapy 
• Mild abnormalities should be observed closely during therapy 
✓ 
if abnormal 
2 
Abnormal screening tests with 
mild symptoms 
• Control cardiac diseases (eg, heart failure, atrial fibrillation) optimally 
• Control cardiac disease risk factors proactively (including hypertension, hyperlipidemia, discontinue 
smoking, and monitor diabetes) 
✓ 
3 
Moderately abnormal testing or 
symptoms with mild activity 
• BNP >500 pg/mL, troponin >99% institutional normal, new ECG findings (QTc prolongation, new 
conduction disease, or ST-T wave changes) 
• Consider withholding ICI 
o 
If a period of stabilization is achieved and definite cardiac toxicity was not identified, it may be 
reasonable to consider re-challenging the patient with ICI, with heightened monitoring. 
• If confirmed cardiac injury or decompensation, hold ICI therapy until stabilized. 
• Optimally treat identified cardiac conditions 
• Consider corticosteroids if myocarditis suspected (Note 2) 
✓ 
4 
Moderate 
to 
severe 
decompensation, 
intravenous 
medication 
or 
intervention 
required, 
life 
threatening 
conditions 
• Permanently discontinue ICI 
• If myocarditis is identified, consider high-dose corticosteroids (1 mg/kg methylprednisolone (IV) for 
at least several days) until improved to Grade ≤1, after that consider at least 4–5 weeks of tapering 
doses (Note 2). 
• Add additional immunosuppressive agents in severe refractory cases. 
✓ 
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• Give additional supportive treatments, including appropriate treatment of heart failure. Additional 
treatment of detected cardiac conditions should be provided.* 
Notes: 
1. Grades outlined here are not drawn from CTCAE (see Putzanov et al “cardiovascular adverse events”3,4) 
2. Patients with confirmed myocarditis (or in cases of reasonable suspicion) should receive emergent high-dose corticosteroids. Until data are available (eg, cut-off levels 
of troponin) to determine when to start corticosteroids in patients with possible (as opposed to confirmed) myocarditis, this decision should be made on a case by case 
basis. The importance of active, ongoing consultation with a cardiologist to discuss the benefit/risk of continuing ICI therapy, starting corticosteroids, or instituting other 
cardiac treatments, cannot be overstated. 
* Other therapies for management of myocarditis or pericarditis (viral based therapy, immunoglobulins, or plasmapheresis) are speculative at this point in time. 
ENDOCRINE 
Hypophysitis 
 
 
Grade 
CTCAE description* 
Management 
Specialist referral? 
1 
Asymptomatic 
or 
mild 
symptoms; 
clinical 
or 
diagnostic observations only; 
intervention not indicated 
• Hold ICI if ≥Grade 2 irAE until work up is completed and appropriate hormone replacement is started 
• If central adrenal insufficiency: start physiologic steroid replacement: Hydrocortisone ~10 mg/m2 
(HC 15 mg am, 5 mg at 3 pm) 
o 
Periodic assessment (eg, every 3 months in the first year, every 6 months thereafter): clinical 
monitoring and repeat hormone levels (am cortisol and ACTH and/or low dose cosyntropin 
stimulation test) to assess recovery 
• If central hypothyroidism: start thyroid hormone (levothyroxine 1 mcg/kg) 
o 
Repeat thyroid function testing 6-8 weeks after initiation of thyroid hormone and then 
periodically (eg, every 3 months in the first year and every 6 months thereafter) to assess 
recovery 
• If central hypogonadism, repeat hormone levels in 2–3 months and consider testosterone in men or 
HRT in women if appropriate for cancer type 
For severe/life-threatening symptoms such as adrenal crisis, severe headache, visual field deficiency: 
• Hospitalize as appropriate. 
• High dose corticosteroid (prednisone 1 mg/kg/day) (or equivalent dose of methylprednisolone) in the 
acute phase, followed by taper over 1 month. 
• Adrenal crisis should be managed per standard guidelines. 
✓ 
2 
Moderate; minimal, local or 
non-invasive 
intervention 
indicated; 
limiting 
age 
appropriate instrumental ADL 
3 
Severe or medically significant 
but 
not 
immediately 
life-
threatening; hospitalization or 
prolongation 
of 
existing 
hospitalization 
indicated; 
disabling; 
limiting 
self-care 
ADL 
4 
Life-threatening consequences; 
urgent intervention indicated 
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• If central hypothyroidism, replace thyroid hormone (see above) after corticosteroids have been 
initiated 
Note: In the uncommon scenario of MRI findings without pituitary deficiency, consider high dose corticosteroids for prevention of hormonal dysfunction. 
* Hypophysitis is not defined in CTCAE Version 4.0. This classification is drawn from the CTCAE category ‘Endocrine disorders - Other’. 
Hypothyroidism 
 
 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Asymptomatic; 
clinical 
or 
diagnostic observations only; 
intervention not indicated 
• Hold ICI for ≥Grade 3 irAEs 
• ICI can be continued after resolution of symptoms to Grade 2 or better. 
• Start standard thyroid replacement therapy: initial dose can be the full dose (1.6 mcg/kg) in young, 
healthy patients, but a reduced dose of 25-50 mcg should be initiated in elderly patients with known 
cardiovascular disease. 
• Repeat TSH and free T4 testing after 6-8 weeks and adjust thyroid hormone dose accordingly. If TSH 
is above reference range, increase thyroid hormone dose by 12.5 mcg to 25 mcg 
• After identification of the appropriate maintenance dose, further evaluation is required every year, or 
sooner if patient’s status changes 
• After identification of the appropriate maintenance dose, further evaluation is required every year, or 
sooner if patient’s status changes 
✓ 
2 
Symptomatic; 
thyroid 
replacement indicated; limiting 
instrumental ADL 
3 
Severe 
symptoms; 
limiting 
self-care ADL; hospitalization 
indicated 
4 
Life-threatening consequences; 
urgent intervention indicated 
Hyperthyroidism 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Asymptomatic; 
clinical 
or 
diagnostic observations only; 
intervention not indicated 
• Hold ICI for ≥Grade 3 irAEs 
• Standard therapy for hyperthyroidism should be followed 
• Thyroiditis is self-limiting and has 2 phases: 
o 
In the hyperthyroid phase, patients may benefit from beta blockers if symptomatic (eg, atenolol 
25-50 mg daily, titrate for HR <90 bpm if BP allows). Monitor closely with regular symptom 
evaluation and free T4 testing every 2 weeks. 
✓ 
2 
Symptomatic; 
thyroid 
suppression therapy indicated; 
limiting instrumental ADL 
3 
Severe 
symptoms; 
limiting 
self-care ADL; hospitalization 
indicated 
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4 
Life-threatening consequences; 
urgent intervention indicated 
o 
Introduce thyroid hormones (see hypothyroidism management) if the patient becomes 
hypothyroid (low free T4/T3, even if TSH is not elevated). 
• Graves’ disease should be treated per standard guidelines. 
Note: High dose corticosteroids (1 mg/kg/day) are not routinely required. 
Type 1 diabetes (CTCAE defines hyperglycemia not diabetes) 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Fasting glucose 
>ULN-160 mg/dL 
(>ULN-8.9 mmol/L) 
• Type 1 DM with diabetic ketoacidosis: Hold ICI; hospitalize and initiate treatment per standard 
guidelines. 
• Type 1 DM without diabetic ketoacidosis: Hold ICI for hyperglycemia ≥Grade 3. Treat with insulin 
and continue ICI when patient recovers to Grade 1. 
• Treat with insulin per standard guidelines and restart ICI when patient recovers to Grade 1. 
• Provide patient education on diet and lifestyle modification, and blood glucose testing 
✓ 
2 
Fasting glucose 
>160-250 mg/dL 
(>8.9-13.9 mmol/L) 
3 
Fasting glucose 
>250-500 mg/dL 
(>13.9-27.8 mmol/L); 
hospitalization indicated 
4 
Fasting glucose >500 mg/dL 
(>27.8 mmol/L); 
life-threatening consequences 
DERMATOLOGIC 
Maculopapular rash/dermatitis 
Grade  CTCAE description 
Management 
Specialist referral? 
1 
Macules/papules 
covering 
<10% BSA with or without 
symptoms 
(eg, 
pruritus, 
burning, tightness) 
• Continue ICI 
• Oral antihistamines 
o 
Cetirizine/loratidine 10 mg daily (non-sedating); hydroxyzine 10-25 mg QID, or at bedtime 
• Topical corticosteroids 
o 
Class I topical corticosteroid (eg, clobetasol propionate, halobetasol propionate, betamethasone 
dipropionate cream or ointment) for body; Class V/VI corticosteroid (eg, aclometasone, 
desonide, hydrocortisone 2.5% cream) for face 
 
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2 
Macules/papules 
covering 
10-30% BSA with or without 
symptoms 
(eg, 
pruritus, 
burning, tightness); limiting 
instrumental ADL 
• Continue ICI 
• Non-urgent dermatology referral 
• Oral antihistamines 
o 
Cetirizine/loratidine 10 mg daily (non-sedating); hydroxyzine 10-25 mg QID, or at bedtime 
• Topical corticosteroids 
o 
See Grade 1 
o 
Cetirizine/loratidine 10 mg daily (non-sedating); hydroxyzine 10-25 mg QID, or at bedtime 
✓ 
3 
Macules/papules 
covering 
>30% BSA with or without 
associated symptoms; limiting 
self-care ADL 
• Hold ICI 
• Same day dermatology consult 
• Rule out systemic hypersensitivity: CBC with differential, CMP 
• Oral antihistamines 
o 
Cetirizine/loratidine 10 mg daily (non-sedating); hydroxyzine 10-25 mg QID, or at bedtime 
• Systemic corticosteroids 
• Prednisone 0.5-1 mg/kg/day (or equivalent dose of methylprednisolone) until rash resolves to 
≤Grade 1 
✓ 
Pruritus* 
Grade  Description 
Management 
Specialist referral? 
1 
Mild 
or 
localized; 
topical 
intervention indicated 
• Emollients with cream or ointment based, fragrance-free products 
o 
Class I topical corticosteroid (eg, clobetasol propionate, halobetasol propionate, betamethasone 
dipropionate) for body; Class V/VI corticosteroid (eg, aclometasone, desonide, hydrocortisone 
2.5%) for face, AND oral antihistamines (eg, cetirizine/loratidine 10 mg daily, hydroxyzine 
10-25 mg QID, or at bedtime 
 
2 
Intense 
or 
widespread; 
intermittent; skin changes from 
scratching 
(eg, 
edema, 
papulation, 
excoriation, 
lichenification, oozing/crusts); 
• Dermatology referral 
o 
Class I topical steroid (eg, clobetasol propionate, halobetasol propionate, betamethasone 
dipropionate) for body; class V/VI steroid (aclometasone, desonide, hydrocortisone 2.5%) for 
face, AND oral antihistamines (eg, cetirizine/loratidine 10 mg daily, hydroxyzine 10-25 mg 
QID, or at bedtime 
✓ 
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oral 
intervention 
indicated; 
limiting instrumental ADL  
• Oral corticosteroids 
o 
Prednisone 0.5-1 mg/kg/day (or equivalent of methylprednisolone) tapered over 2 weeks 
3 
Intense 
or 
widespread; 
constant; 
limiting 
self-care 
ADL 
or 
sleep; 
oral 
corticosteroid 
or 
immunosuppressive 
therapy 
indicated 
• Dermatology referral 
• GABA agonist (eg, pregabalin, gabapentin 100-300 mg TID) 
• Oral corticosteroid 
o 
Prednisone 0.5-1 mg/kg/day (or equivalent of methylprednisolone) tapered over 2 weeks 
✓ 
Notes: 
1. Grade 4 maculopapular rash/dermatitis is not included in CTCAE 
*Recommendations provided are based on case reports, series and expert consensus. Use of suggested therapies must be discussed with medical oncology based on individual 
patient considerations. The impact of these therapies on the anti-tumor immune response and efficacy of cancer treatment is unknown and requires further research. 
GASTROINTESTINAL 
Colitis 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Asymptomatic; 
clinical 
or 
diagnostic observations only; 
intervention 
not 
indicated 
[Grade 1 diarrhea frequency 
≤4/day] 
• Close follow-up within 24-48 h for changes or progression 
• Continue ICI 
• If symptoms persist, start routine stool and blood tests 
• Bland diet advisable during period of acute diarrhea 
• Anti-diarrheal medication is optional but not highly recommended when infectious work-up is 
negative. 
 
2 
Abdominal pain; mucus or 
blood in stool [Grade 2 diarrhea 
frequency 4-6/day] 
• Hold ICI 
• Outpatient stool and blood work; CRP, ESR, fecal calprotectin, lactoferrin, imaging and endoscopy 
are optional 
• If diarrhea only, observe for 2-3 days. If no improvement start prednisone 1 mg/kg/day (or equivalent 
dose of methylprednisolone); anti- diarrheal medication is not recommended 
• If diarrhea and colitis symptoms (abdominal pain ± blood in BM), start prednisone 1 mg/kg/day (or 
equivalent dose of methylprednisolone) immediately 
✓ 
See note 5 
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o 
If no improvement in 48 h, increase corticosteroid dose to prednisone 2 mg/kg/day (or equivalent 
dose of methylprednisolone) 
o 
If patient improves 
− 
Taper corticosteroid over 4–6 weeks may be needed 
− 
Resume ICI when corticosteroid is tapered to ≤10 mg/ day and patient remains 
symptom-free (Grade ≤1) 
− 
Continue ICI monotherapy 
− 
If using combination anti-CTLA-4/ICI immunotherapy, continue ICI agent only 
− 
ICI dose reduction is not recommended 
• If colitis returns on resuming ICI: 
o 
Grade ≤2: temporarily hold ICI 
o 
Grade ≥3: permanently discontinue ICI 
3 and 
4 
Grade 3: Severe abdominal 
pain; change in bowel habits; 
medical intervention indicated; 
peritoneal 
signs 
[Grade 
3 
diarrhea frequency ≥7×/day] 
Grade 
4: 
Life-threatening 
consequences; 
urgent 
intervention indicated 
• Grade 3: withhold ICI; consider resuming ICI when corticosteroid is tapered to ≤10 mg/day and 
patient remains symptom-free (Grade ≤1). Consider hospitalization 
• Grade 4: permanently discontinue ICI and hospitalize 
• Blood and stool infection work-up, inflammatory markers, imaging, endoscopy and GI consult 
• Start intravenous prednisone 1-2 mg/kg/day (or equivalent dose of methylprednisolone) immediately 
o 
If patient improves, follow instructions for ‘If patient improves’ for Grade 2 
• If refractory or no improvement on IV corticosteroid, start prednisone 2 mg/kg/day (or equivalent 
dose of methylprednisolone) for 3 days 
• Consider other anti-inflammatory agents eg, infliximab 5 mg/kg, which can be given again after two 
weeks if a second dose is needed. Vedolizumab may also be used (see Note 4). 
 
Notes.  
1. CBC with differential, CMP, ESR and CRP are recommended before starting immunotherapy, to provide baseline values for comparison over time. 
 
Despite the association between elevated ESR and CRP and colitis, some insurance companies may not cover these tests. 
2. There is no proven role for prophylactic corticosteroids (budesonide) to prevent GI irAEs.5,6 
3. Response to infliximab generally occurs within 1–3 days although some patients benefit from a second dose after 2 weeks. Prolonged oral prednisone taper may be 
required after infliximab administration. Whether infliximab reduces the anti-tumor efficacy of ipilimumab remains unknown.7 
4. Case reports of successful treatment of steroid-dependent immune-related colitis using vedolizumab indicate this may benefit certain patients. 
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5. A GI consult is warranted in any patient who meets criteria for Grade 2 diarrhea/colitis with negative infectious stool work up. 
Fatigue/Asthenia 
Grade 
CTCAE description 
Management 
Specialist referral? 
3 
Fatigue not relieved by rest, 
limiting self-care ADL 
• Dose delay for study treatment-related Grade 3 until resolved to ≤Grade 1 
• Discontinue for study treatment-related Grade 3 lasting >7 days or Grade 4 
 
NEUROLOGIC 
Encephalopathy/Leukoencephalopathy/Reversible posterior leukoencephalopathy syndrome (PRES) 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Mild symptoms 
• Hold ICI and initiate diagnostic work-up 
• Consider permanent discontinuation of ICI if AE worsens or does not improve 
 
2 
Moderate symptoms; limiting 
instrumental ADL 
• Hold ICI 
• Start 0.5-1.0 mg/kg/day methylprednisolone equivalents PO or IV once infection has been excluded 
• Consider permanent discontinuation of ICI if AE worsens or does not improve. 
✓ 
3 
Severe symptoms; limiting 
self-care ADL 
• Permanently discontinue ICI 
• Start 1-2 mg/kg/day methylprednisolone equivalents IV and prophylactic antibiotics 
• Consider plasmapheresis if no improvement or symptoms worsen after 3 days 
✓ 
4 
Life-threatening consequences; 
urgent intervention indicated 
• Permanently discontinue ICI 
• Start 1-2 mg/kg/day methylprednisolone equivalents IV and prophylactic antibiotics 
• Consider plasmapheresis if no improvement or symptoms worsen after 3 days 
• Contact intensive care unit 
✓ 
and contact 
intensive 
care unit 
Notes: CTCAE provides grading criteria for encephalopathy, leukoencephalopathy, and PRES. For all these irAEs, ICI therapy may be continued for Grade 1 irAEs. However, 
≥Grade 2 events require an ICI hold, and referral to neurology. For events of ≥Grade 3 severity, ICI should be permanently discontinued, IV corticosteroids administered, 
and plasmapheresis considered if there is no improvement, or symptoms worsen, after 3 days. 
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OPHTHALMOLOGIC 
Uveitis 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Asymptomatic; 
clinical 
or 
diagnostic observations only 
• Continue ICI 
• Ophthalmology referral within 1 week 
• Start lubrication drops (artificial tears) 
✓ 
2 
Anterior 
uveitis; 
medical 
intervention indicated 
• Hold ICI 
• Ophthalmology referral within 2 days, prior to initiating uveitis treatment 
• Coordinate treatment with ophthalmologist (eg, topical corticosteroids, cycloplegic agents, systemic 
corticosteroids) 
✓ 
3 
Posterior or pan-uveitis (Note) 
• Permanently discontinue ICI 
• In carefully selected cases it may be appropriate to restart treatment, cautiously, depending on 
severity, systemic response to immunotherapy and ocular response to topical, local or systemic 
prednisone (prescribed in coordination with ophthalmologist) 
• URGENT ophthalmology referral (preferably uveitis specialist) prior to initiating treatment. 
Co-ordinate treatment with specialists 
• Consider systemic corticosteroids in addition to intravitreal/periocular corticosteroids/topical 
corticosteroid treatment as recommended by ophthalmologist 
✓ 
URGENT 
4 
Blindness (20/200 or worse) in 
the affected eye 
• Permanently discontinue ICI 
• URGENT ophthalmology referral (preferably uveitis specialist) prior to initiating any treatment. Co-
ordinate treatment with specialists 
• Consider systemic corticosteroids in addition to intravitreal/periocular corticosteroids/topical 
corticosteroid treatment as recommended by ophthalmologist 
✓ 
URGENT 
Note: Unlike anterior uveitis, posterior uveitis can be asymptomatic but nonetheless proceed to visual loss. 
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Episcleritis (CTCAE scleral disorder) 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Asymptomatic; 
clinical 
or 
diagnostic observations only 
• Continue ICI 
• Ophthalmology referral within 1 week 
• Start lubrication drops (artificial tears) 
✓ 
2 
Symptomatic, 
limiting 
instrumental ADL; moderate 
decrease 
in 
visual 
acuity 
(20/40 or better) 
• Hold ICI 
• Ophthalmology referral within 2 days, prior to initiating uveitis treatment 
• Coordinate treatment with ophthalmologist (topical steroids, cycloplegic agents, systemic steroids) 
(See Note) 
✓ 
3 
Symptomatic, 
limiting 
self-care 
ADL; 
marked 
decrease in visual acuity (best 
corrected visual acuity worse 
than 20/40 or more than 3 lines 
of decreased vision from 
known baseline, up to 20/200);  
• Permanently discontinue ICI 
• In carefully selected cases it may be appropriate to restart treatment, cautiously, depending on severity, 
systemic response to immunotherapy and ocular response to topical, local or systemic prednisone 
(prescribed in coordination with ophthalmologist) 
• URGENT ophthalmology referral (preferably uveitis specialist) prior to initiating treatment (See 
Note). Co-ordinate treatment with specialists. 
• Consider systemic steroids in addition to intravitreal /periocular steroids /topical steroid treatment as 
recommended by ophthalmologist 
✓ 
URGENT 
4 
Blindness (20/200 or worse) in 
the affected eye 
• Permanently discontinue ICI 
• URGENT ophthalmology referral (preferably uveitis specialist) prior to initiating any treatment (See 
Note). Co-ordinate treatment with specialists. 
• Consider systemic steroids in addition to intravitreal /periocular steroids /topical steroid treatment as 
recommended by ophthalmologist 
✓ 
URGENT 
Note: IMPORTANT: Starting treatment with steroids prior to conducting an eye exam may worsen ocular conditions that are due to infection (eg, herpetic keratitis/uveitis) 
or may mask accurate diagnosis and severity grading when the patient is examined by an ophthalmologist. 
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Blepharitis 
Grade 
CTCAE diagnosis 
Management 
Specialist referral? 
Not defined in CTCAE 
• Puffy eyelids may indicate early preseptal cellulitis, which requires systemic antibiotic treatment. 
Warning signs (eyelid swelling with pain and erythema, proptosis, pain with eye movements, 
movement restriction/diplopia, vision changes) should prompt urgent ophthalmology referral 
• In the absence of warning signs, start warm compresses and lubrication drops and refer to 
ophthalmology, especially if symptoms do not improve 
✓ 
URGENT if 
warning signs 
PULMONARY 
Pneumonitis 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Asymptomatic; 
clinical 
or 
diagnostic observations only 
• Consider holding ICI 
• Consider pulmonary and infectious disease consultations 
• Reimage at least prior to every cycle of ICI treatment (at least every 3 weeks) 
o 
If repeat imaging shows resolution of radiographic findings, no further CT imaging is necessary; 
resume therapy with close follow-up 
o 
If evidence of progression, treat at higher grade 
o 
If no change, consider continued therapy with close follow-up for new symptoms 
• If symptoms develop, treat at higher grade 
• Self-monitor symptoms and oxygen saturation (using personal pulse oximeter) every 2-3 days; 
weekly clinic visits 
• If chest imaging abnormalities resolve, consider resuming treatment with close follow-up 
✓ 
2 
Symptomatic; 
limiting 
instrumental 
ADL; 
medical 
intervention indicated 
• Hold ICI 
• Consider hospitalization 
• Pulmonary consultation for bronchoscopy with bronchoalveolar lavage. Consider biopsies for 
atypical lesions 
• Initiate methylprednisolone 1 mg/kg/day (IV or oral equivalent) 
✓ 
(pulmonary and 
infectious disease) 
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o 
Day 2-3 of corticosteroids/supportive care: If symptoms improve to ≤Grade 2, start slow steroid 
taper over >1 month. If symptoms do not improve, or worsen, treat as Grade 3-4 
• Consider drug re-challenge if symptoms and imaging abnormalities resolve 
3 
Severe 
symptoms; 
limiting 
self-care 
ADL; 
oxygen 
indicated 
• Permanently discontinue ICI 
• Hospitalize; consider ICU care 
✓ 
4 
Life-threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated 
(eg, 
intubation) 
• Pulmonary consultation for bronchoscopy with bronchoalveolar lavage. Consider biopsies for 
atypical lesions 
• Initiate methylprednisolone IV, 2 mg/kg/day 
• Day 2-3 of corticosteroids/supportive care: 
o 
If no clinical improvement, add infliximab or cyclophosphamide, mycophenolate mofetil or 
IVIG  
o 
If clinical improvement: reduce corticosteroids to 1 mg/kg/day and slowly taper over >2 months. 
• Drug re-challenge: 
o 
Grade 3: Consider drug re-challenge on a case-by-case basis after discussions weighing 
benefit/risk with the patient and only if symptoms and imaging abnormalities resolve 
o 
Grade 4: Permanently discontinue ICI 
✓ (pulmonary and 
infectious disease) 
Notes: 
1. Consider prophylactic antibiotics for PCP for patients receiving at least 20 mg methylprednisolone or equivalent for ≥4 weeks 
2. Consider calcium and vitamin D supplementation with prolonged steroid use 
3. All patients with Grade 2-4 pneumonitis receiving steroids should also be on proton pump inhibitor therapy for GI prophylaxis 
4. T-spot testing should be undertaken to exclude tuberculosis in any patient being considered for anti-TNF therapy, prior to starting anti-TNF treatment. 
Sarcoidosis 
 
 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Not defined in CTCAE 
• Consider holding ICI 
• Close follow-up   
✓ 
≥2 
 
• Consider corticosteroids 
• Hold ICI 
✓ 
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• Consider corticosteroid therapy for patients with sarcoidosis Grade 2 or higher and any of the 
following: 
o 
progressive radiographic change 
o 
persistent and/or troublesome pulmonary symptoms 
o 
lung function deterioration: TLC decline of ≥10%, FVC decline of ≥15%; DLCO decline of 
≥20% 
o 
concomitant involvement of critical extrapulmonary organ systems 
o 
sarcoid-related hypercalcemia 
• Corticosteroid dose: prednisone 1 mg/kg (or IV equivalent of methylprednisolone) for Grade 2 
sarcoidosis or severe cases requiring hospitalization. Taper steroids over 2-4 months, depending on 
response 
Note: To date, there are no studies focusing on management of sarcoidosis as a side effect of checkpoint inhibitor therapy. Current recommendations are based on clinical 
experience and case report publications. 
RHEUMATOLOGIC/MUSCULOSKELETAL8 
Inflammatory arthritis 
Grade 
CTCAE description (Note 1) 
Management 
Specialist referral? 
1 
Mild pain with inflammatory 
symptoms (Note 2), erythema, 
or joint swelling (Note 3) 
• Continue ICI 
• Analgesics: NSAIDs: naproxen 500 mg BID or meloxicam 7.5-15 mg daily orally for 4-6 weeks 
• If NSAIDs ineffective, consider prednisone 10-20 mg daily for 2-4 weeks 
• Consider intra-articular corticosteroid injection only if ≤2 joints affected and low dose prednisone 
(10 mg/day) and NSAIDs not effective 
• If no improvement in 2-4 weeks, escalate to Grade 2 management 
• Conduct serial rheumatologic examinations (2 weeks, 4 weeks, then 4-6 weekly) and functional 
assessment at follow-up 
 
2 
Moderate pain associated with 
signs 
of 
inflammation, 
erythema, or joint swelling; 
limiting instrumental ADL 
• Consider holding ICI 
• Rheumatology referral to confirm inflammatory arthritis, assess need for intra-articular injection and 
examine for signs of early bone damage 
✓ 
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• Prednisone 20 mg daily for 2-4 weeks, increase to 1 mg/kg/ day, or equivalent. If no response in 
2-4 weeks. Escalate to Grade 3 management 
• If symptoms improve, taper corticosteroid over 4-8 weeks or until Grade 1 
3 
Severe pain associated with 
signs 
of 
inflammation, 
erythema, or joint swelling; 
irreversible joint damage (eg, 
erosion); 
disabling; 
limiting 
self-care ADL 
• Hold ICI 
• Rheumatology referral 
• Prednisone 1 mg/kg/day or equivalent for 2-4 weeks, or until symptoms improve to Grade 1 
• Consider additional immunosuppression (Note 4) (eg, methotrexate [Note 5], sulfasalazine, 
leflunomide). Consider anti-cytokine therapy (eg, TNF-inhibition) [Note 6] 
• If symptoms improve, taper corticosteroid over 4-8 weeks/until Grade 1; if symptoms do not improve 
in 4-6 weeks: permanently discontinue ICI 
✓ 
Notes: 
1. CTCAE includes separate listings for arthritis, joint effusion and arthralgia although there is overlap in presenting symptoms such as pain and effects on ADL 
2. Joint stiffness after sleep or inactivity, improvement of symptoms with movement or heat. 
3. Joint swelling refers to the clinical finding on examination, and may encompass soft tissue swelling, joint effusion or synovitis. 
4. Before initiation of these drugs, screening for hepatitis B and C should be performed. 
5. Methotrexate should be administered at a starting dose of 15 mg weekly, with daily folic acid supplementation. Titrate up to a maximum of 25 mg weekly, or switch to 
injectable methotrexate if patient cannot tolerate orally. 
6. Before anti-cytokine therapy, evaluation for latent/active TB should be performed. 
Peripheral motor and sensory neuropathy 
Grade 
CTCAE description 
Management 
Specialist referral? 
1 
Asymptomatic; 
clinical 
or 
diagnostic observations only 
• Continue ICI 
• Consider permanent discontinuation of ICI if AE worsens or does not improve 
 
2 
Moderate symptoms; limiting 
instrumental ADL 
• Hold ICI 
• Refer to neurology 
• Consider permanent discontinuation of ICI if AE worsens or does not improve 
✓ 
3 
Severe 
symptoms; 
limiting 
self-care ADL 
• Permanently discontinue ICI 
✓ 
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4 
Life-threatening consequences; 
urgent intervention indicated 
• Start 1-2 mg/kg/day methylprednisolone equivalents IV, and prophylactic antibiotics 
Note: CTCAE provides grading criteria for peripheral motor neuropathy and sensory motor neuropathy. For all these irAEs, ICI therapy may be continued for Grade 1 irAEs. 
However, ≥Grade 2 events require an ICI hold and referral to neurology. For events of ≥Grade 3 severity, ICI therapy should be permanently discontinued and IV 
corticosteroids administered. 
ACTH=adrenocorticotropic hormone; ADL=activities of daily living; AE=adverse event; ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate transaminase: 
BID=twice daily; BM-bowel movements; BNP=B-type natriuretic peptide; CBC=complete blood count; CMP=comprehensive metabolic panel; CRP=C-reactive protein; CRS=cytokine release 
syndrome; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; DIC=disseminated intravascular coagulation; DLCO=diffusing capacity of the lungs for 
carbon monoxide; DM=diabetes mellitus; ECG=electrocardiogram; ESR=erythrocyte sedimentation rate; FVC=forced vital capacity; GABA=gamma-aminobutyric acid; GI=gastrointestinal; 
HC=hydrocortisone; ICI=immune checkpoint inhibitors; ICU=intensive care unit; IV=intravenous; IVIG=intravenous immunoglobulin; LLN=lower limit of normal; MRI=magnetic resonance 
imaging; NSAIDs=non-steroidal anti-inflammatory drugs; PCP=pneumocystis pneumonia; PLT=platelet; PO=per oral; PRES=posterior leukoencephalopathy syndrome; QID=4 times a day; 
SITC=Society of Immunotherapy of Cancer; TB=Tuberculosis; TLC=total lung capacity; TNF=tumor necrosis factor; TSH=thyroid stimulating hormone; ULN=upper limit of normal.  
1. Lee DW, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-95. 
2. SERVICES., U.S.D.O.H.A.H., Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 27 November 2017. 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf 
3. Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Res. 2008;14(1):14-24. 
4. Lurz P, et al. Diagnostic performance of CMR imaging compared with EMB in patients with suspected myocarditis. JACC Cardiovasc Imaging. 2012;5(5):513-24. 
5. Berman D, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 
2010;10:11. 
6. Weber J, et al. A randomized, double-blind, placebo-controlled, Phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in 
patients with unresectable Stage III or IV melanoma. Clin Cancer Res. 2009;15(17):5591-8. 
7. Pages C, et al. Ipilimumab-induced acute severe colitis treated by infliximab. Melanoma Res. 2013;23(3):227-30. 
8. Naidoo J, et al. Inflammatory arthritis: a newly recognized adverse event of immune checkpoint blockade. Oncologist. 2017;22(6):627-30. 
 
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5.6.3 Atezolizumab Specific Recommendations:  
For detailed specific safety information about atezolizumab, please refer to the atezolizumab 
Investigators Brochure, including any associated addenda. 
As outlined in Section 5.6.1, there will be no dose reductions of atezolizumab however 
atezolizumab may be delayed for toxicity as described in Table 5-5. 
Given the mechanism of action of atezolizumab, immune-mediated reactions are considered a 
potential risk when given in combination with other immunomodulating agents.  
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis and macrophage activation syndrome, which are rare conditions 
characterized by an excessive immune response.  
Immune-mediated reactions should be included in the differential diagnosis for patients who, 
in the absence of an alternate etiology, develop a sepsis-like syndrome after administration of 
atezolizumab, and the initial evaluation should include the following: 
• Complete blood count with peripheral smear 
• Partial thromboplastin, partial thromboplastin time, fibrinogen, and D-dimer 
• Ferritin 
• Triglycerides 
• AST, ALT and total bilirubin 
• LDH 
• Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
If immune-mediated reactions are still suspected after the initial evaluation, contact the Medical 
Monitor for additional recommendations. 
If any irAEs occur and treatment with steroids is required until resolution or improvement of 
the condition to CTCAE v5 Grade 1 or baseline and patients will be tapered off steroids, 
atezolizumab may be withheld for additional time from the last dose until steroids are 
discontinued or reduced to prednisone dose (or dose equivalent) ≤10 mg/day.  
5.7 
Concomitant Medication and Dietary Supplements  
Concomitant therapies and supplements that are permitted, prohibited or restricted during the 
study are summarized in Table 5-6.  All concomitant medications, vaccines (including 
SARS-CoV-2 vaccines) and supplements used during the study must be documented in the 
Prior/Concomitant Medication eCRF.  
For SARS-CoV-2 vaccinations, report the following in the appropriate pages of the eCRF: 
• Information on each administration of SARS-CoV-2 vaccine.  Each injection of 
SARS-CoV-2 vaccine must be reported as separate entries, including the vaccine name, 
dose and date of injection (Prior/Concomitant Medication eCRF). 
• Any observed AE following administration of the SARS-CoV-2 vaccine during the 
study treatment period (Adverse Events eCRF). 
• COVID-19 antibody titers, if measured after vaccination and available (Unscheduled 
Local Lab Results eCRF). 
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Table 5-6: 
Permitted/Prohibited Concomitant Medications  
Medication/class of drug 
Usage guidelines/restrictions 
Erythroid 
stimulating 
agents 
(eg, 
erythropoietin) 
Patients already receiving erythropoietin at the time of 
screening for the study may continue it providing they have 
been receiving it for at least 2 weeks before study treatment is 
started and the patient is on a stable dose.  Prophylactic 
erythropoietin should not be started during Cycle 1 of the 
study but may be started during Cycle 2 and after. 
Immunosuppressive medications (including, 
but not limited to systemic corticosteroids at 
doses beyond 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine and 
TNFα blockers) 
Generally prohibited from the time that patients enter the 
screening period until the last dose of study treatment.  
However, use of immunosuppressive medications for the 
management of investigational product-related AEs and in 
patients with contrast allergies is acceptable.  In these cases, 
such medications may be used when needed and their use 
should be documented. 
Any investigational therapy other than the 
protocol specified therapies 
Prohibited from within 4 weeks prior to the first dose of study 
treatment until the last dose of study treatment. 
Any concurrent chemotherapy, radiotherapy 
(except 
palliative 
radiotherapy), 
immunotherapy, 
biologic 
or 
hormonal 
therapy for cancer treatment 
Prohibited from within 2 weeks prior first dose of study 
treatment until the last dose of study treatment.  For cytotoxic 
agents, that have major delayed toxicity, eg, mitomycin C and 
nitrosoureas, 4 weeks is indicated as washout period 
Herbal preparations/medications (including, 
but not limited to: St. John’s Wort, kava, 
ephedra 
(ma 
huang), 
gingko 
biloba, 
dehydroepiandrosterone, 
yohimbe, 
saw 
palmetto, and ginseng) 
Prohibited from the time that patients enter the screening 
period until the last dose of study treatment.  Patients should 
stop using these herbal medications 7 days prior to first dose 
of study treatment (3 weeks for St John’s Wort) 
Warfarin 
and 
other 
long 
acting 
anticoagulants with a half-life of >12 hours 
Prohibited from the time that patients enter the screening 
period until the last dose of study treatment. 
Vaccines against infectious diseases 
Use of any live or live attenuated vaccine against infectious 
diseases (examples include, but are not limited to, intranasal 
influenza, measles, mumps, rubella, oral polio, Bacillus 
Calmette-Guérin vaccine, rotavirus, varicella, yellow fever, 
TY21a typhoid vaccines etc) are prohibited within 4 weeks 
prior to the first dose of study treatment, during the study, and 
for 3 months after the last dose of study treatment.  
SARS-CoV-2 vaccines authorized for use by the competent 
local regulatory health authorities for active immunization to 
prevent COVID-19 are allowed (unless the vaccine is live or 
live attenuated) and must be given in accordance with the 
prevailing 
immunization 
guidelines. 
 
SARS-CoV-2 
vaccination may be given at least 7 days prior to the planned 
first dose of study treatment. Otherwise, administer 
SARS-CoV-2 vaccine with at least a 7 day period before and 
after study treatment.  Administer study treatment only if 
vaccine-related AEs have improved to Grade ≤1.  Please 
report any SARS-CoV-2 vaccine-related AEs in the Adverse 
Events eCRF as “post-SARS-CoV-2 vaccine AEs” (eg, 
post-SARS-CoV-2 vaccine fever) and/or, SARS-CoV-2 
vaccine site reaction(s) (eg, post-SARS-CoV-2 vaccine site 
pain or post-SARS-CoV-2 vaccine site erythema) (refer to 
Section 7 for further instructions on AE reporting). 
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Medication/class of drug 
Usage guidelines/restrictions 
Inhaled, intranasal, topical and ophthalmic 
and corticosteroids 
Concurrent use is acceptable 
Hormones for noncancer-related conditions 
(eg, insulin for diabetes and hormone 
replacement therapy) 
Concurrent use is acceptable 
Local treatment of isolated lesions for 
palliative intent (eg, by local surgery or 
radiotherapy) 
Concurrent treatment is acceptable 
Low molecular weight heparin  
Concurrent treatment is acceptable 
Blood transfusions 
Allowed at any time during the study 
AE=adverse event; COVID-19=coronavirus disease 2019; eCRF=electronic Case Report Form; TNFα=tumor necrosis factor 
alpha; SARS-CoV-2=Severe Acute Respiratory Syndrome Coronavirus 2. 
5.8 
Lifestyle Restrictions  
The following restrictions (according to the CTFG (Clinical Trial Facilitation Group) 
Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials in 
Women of Childbearing Potential apply while the patient is receiving study treatment and for 
the specified times before and after: 
1. Females of childbearing potential must use two highly effective methods of contraception 
from the time of screening until 5 months after discontinuing study treatment, or longer, 
depending on the PK of KY1044 (contraception must be maintained for at least 
5 half-lives). 
Acceptable methods of contraception include true sexual abstinence when this is in line 
with the preferred and usual lifestyle of the patient, tubal ligation, hormonal contraceptives 
that are not prone to drug-drug interactions (for example Levonorgestrel Intra Uterine 
System [Mirena], medroxyprogesterone injections [Depo Provera]), copper-banded 
intra-uterine devices and vasectomized partner.  Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a trial, and withdrawal are not acceptable methods of contraception.  All 
methods of contraception must be used in combination with the use of a condom by their 
male sexual partner for intercourse.   
2. Male patients must avoid unprotected sex with all sexual partners (by use of condoms) 
during the study, and for a washout period of at least 5 months after the last dose of IMP, 
depending on the PK of KY1044.  A condom is also required to be used by vasectomized 
men in order to prevent delivery of the drug via seminal fluid.  Where a sexual partner of a 
male participant is a woman of childbearing potential, patients must avoid procreation for 
at least 5 months after completion of treatment with IMP.  Patients must refrain from 
donating sperm from the start of dosing until at least 5 months after discontinuing study 
treatment.  If male patients wish to father children during the study period they should be 
advised to arrange for freezing of sperm samples prior to the start of study treatment. 
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5.9 
Patient Numbering and Treatment Assignment  
Patients will be assigned to two treatments groups in this study, KY1044 as single agent or in 
combination with atezolizumab in an open-label manner. Allocation of the IMP kits during the 
study period will be done via IXRS. 
Phase 1: The assignment of a patient to a particular cohort during the Phase 1 dose escalation 
or enrichment components (KY1044 as single agent or in combination with atezolizumab) will 
be coordinated in IXRS in accordance with the Cohort Management Plan. 
Patients will be identified with unique patient numbers assigned by IXRS at the time of 
screening and then at enrolment.  Enrolment number will start with the digit “1” indicating that 
the patient is being treated in Phase 1 of the study, in addition to a digit indicating a cohort to 
which the patient was allocated and an arm of treatment (KY1044 single agent or in 
combination with atezolizumab).  Enrolment number will identify the patient in all study 
databases including eCRF, central laboratory, central imaging and ECG and will be linked to 
the patient’s name in an identification list retained in the Investigator’s Site File.  
Phase 2: The assignment of a patient to a particular group during the Phase 2 will be based on 
tumor indication and history of anti-PD-(L)1 treatment (Figure 3-1).  In the initial Phase 2 dose 
assessment part, two biologically relevant dose levels of KY1044 (as single agent or in 
combination with atezolizumab) that have been determined to be safe in Phase 1 will be 
explored in one or more indication(s).  In the Phase 2 expansion component, patients will 
receive the RP2D of KY1044 as single agent or in combination with atezolizumab that was 
established during the Phase 1 dose escalation and/or enrichment component and/or the initial 
Phase 2 dose assessment part of the study. 
Patients will be identified with unique subject numbers assigned by IXRS at the time of 
screening and then at enrolment.  Enrolment number will start with the digit “2” indicating that 
the patient is being treated in Phase 2 of the study, in addition to a digit indicating an arm of 
treatment (KY1044 single agent or in combination with atezolizumab).  Enrolment number will 
identify the patient in all study databases including eCRF, central laboratory, central imaging 
and ECG and will be linked to the patient’s name in an identification list retained in the 
Investigator’s Site File. 
5.10 Supply, Packaging, Labelling and Storage  
IMPs are KY1044 and atezolizumab, both of which will be provided by the Sponsor to the 
investigational site as open-label liquid solutions in vials.  
KY1044 drug substance has been manufactured in accordance with current Good 
Manufacturing Practice (GMP) at Lonza Biologics plc, Slough, UK, and subsequently KY1044 
drug product has been manufactured by Nova Laboratories Ltd, Leicester, UK.  
Atezolizumab drug product has been manufactured in accordance with current GMP and 
supplied by F Hoffman-La Roche. 
Both IMPs (KY1044 and atezolizumab) will be labelled, packaged and distributed by PCI 
Clinical Services.  Labelling will be done in accordance with GMP guidelines and regulatory 
requirements of each country participating in the study.  Investigational sites will supply all 
ancillary supplies as detailed in the pharmacy manual, including all materials required for the 
preparation and administration of KY1044 and atezolizumab doses. 
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After release procedures have been completed in accordance with regulatory requirements and 
as needed thereafter, IMPs will be shipped with temperature monitoring devices to the 
responsible person at the investigational site pharmacy.  
IMP delivered to sites, and prepared doses, must be maintained at 2 to 8°C and stored in a 
secure environment ie, with restricted access, and in accordance with any locally applicable 
regulations.  Before administration, prepared doses of the IMP need to be brought to room 
temperature at least 1 hour before administration. 
Details of procedures for the receipt, storage, and management of IMP supplies are provided 
in the Pharmacy Manual. 
5.11 IMP Accountability Records  
The Investigator is responsible for accountability of all used and unused supplies of 
KY1044 and atezolizumab at the site. 
IMP accountability forms will be completed by the Investigator and filed in the Investigator 
Site File (ISF).  The IMP accountability forms will be kept current and will contain the dates 
and quantities of drugs received at site, and details of disposition of all drug received and 
preparation of individual doses.  
At the end of the study, a final IMP reconciliation statement must be completed by the 
Investigator and provided to the Sponsor. 
All IMP accountability forms must be made available for inspection by the clinical monitor, 
the Sponsor or representatives of the Sponsor, and regulatory agency inspectors. 
At the end of the study, or at intervals confirmed by the Sponsor, and after the accountability 
has been verified, all IMP supplies including unused, partially used, or empty containers, will 
be destroyed locally according to the site requirements and local regulations or returned as 
directed by the Sponsor.  Proof of delivery, certificates of destruction and/or IMP return 
documentation will be filed in the eTMF. 
5.12 Procedures for Monitoring Patient Compliance  
The Investigator or designee is responsible for the administration of the IMPs. The monitor 
will assess compliance throughout the study by reviewing drug reconciliation/accountability 
records on a periodic basis as outlined in the monitoring plan and guidelines. 
6 
STUDY ASSESSMENTS  
The schedule of procedures and assessments during the study is summarized and presented in 
Table 6-1 (Phase 1) and Table 6-2 (Phase 2).  
 
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A window of 3 days is permissible to complete Day 1 assessments, a window of 1 day is permissible to complete all other assessments
a After receiving the first infusion in Phase 1, patients will be either hospitalized or remain in the clinic for at least 6 to 8 hours until the last assessments. They will be provided with instructions 
for after hour care as per institutional standard and will return to the clinic on C1D2. Patients should remain in the clinic for at least 3 hours at all other visits where infusions are given. 
b IXRS contact can be performed prior to the patient’s CXD1 visit to receive treatment allocation. 
c Medical History including date of diagnosis and dates and extent of cancer, prior antineoplastic therapies (chemotherapies, targeted agents, radiation, surgery) and current concomitant 
medication (including SARS-CoV-2 vaccines).
d Complete physical examination should be performed at screening and at the EOT. This should also include a full dermatological examination (complete skin and mucosal exam). Abbreviated 
physical examination will be performed every cycle (see Section 6.5.2). 
e Vital signs: during Cycles 1 and 2, blood pressure (BP) and HR will be monitored in the clinic every 15 minutes during the infusions of study treatment and every 30 minutes inbetween the 
infusions (for combination therapy) and 60 min after the last infusion of study treatment and before the patients are discharged from the hospital on Cycle 1 Day 2. See Section 6.5.7. 
f 
Cardiac markers at screening will include: Baseline Troponin I for all patients. Additionally, N-terminal pro B-type natriuretic peptide (NT-pro-BNP) will only be taken for patients with a 
history of cardiac disease (according to exclusion criteria). Repeated assessments of cardiac markers during the study will be performed only when clinically indicated . 
g ECGs will be taken pre- and post-dose at Cycles 1, 3 and 6 as close as possible to the relevant PK timepoints (see Section 6.5.8). In the event of abnormal ECG findings and if clinically 
indicated, an unscheduled PK sample should be collected and Troponin I , together with assessments for CK, CK-MB, AST and lactate dehydrogenase (LDH).  NT-pro-BNP should be measured 
together with the other cardiac markers as outlined above only in patients with previous cardiac complications at screening.  
h All samples will be analyzed centrally.  On the occasions marked h only, duplicate samples for immediate access to key safety laboratory parameters (hematology, clinical chemistry and 
coagulation) will be analyzed at local labs as well. 
i 
At screening, clinical chemistry includes collection of a fasting lipid profile sample. 
j 
HbA1c should be measured every 12 weeks throughout the study and will be assessed at EOT only if the previous assessment has not been performed within the last 3 months. 
k Serum pregnancy test (β-HCG) will be performed at screening. Urine dipstick test will be performed at all other visits. 
l
Thyroid function includes free T4 and TSH and the analyses will be repeated every 3 cycles and at EOT.
m Virology testing will be performed at screening for HIV, HBV and HCV. In patients, who are known to be positive for HBV and HCV, tests will be repeated every cycle pre-dose and a 
confirmatory sample should be taken when clinically indicated. See Section 6.5.9 for more details. 
n Auto-antibodies include: anti-DNA, anti-nuclear, anti-mitochondrial and anti-phospholipid antibodies and Rheumatoid factor (RF) and  acetyl-choline receptor antibodies (AChR). When a 
blood sample is positive for ANA (ie, titer >40) it will be tested for antibodies against extractable nuclear antigens. Samples for auto-antibody analyses will be collected at screening, every 
second cycle pre-dose for the first six cycles (C2, C4, C6), then every 12 weeks up to 48 months of treatment, when clinically indicated and at EOT.  
o
ADA samples should be collected at every cycle at pre-dose on Day 1 and unscheduled at any time, when clinically indicated. For detailed ADA sample collection schedule see Section 6.4.2. 
p PK samples will be taken pre- and post-dose during all cycles and unscheduled at any time, when clinically indicated. For detailed PK analysis timings please refer to Section 6.4.2. 
Note: On days and timepoints when biomarker and pharmacokinetic blood samples are being collected, the PK sample must be drawn first. For further details please see schedule 
of PK assessments in Section 6.4.2 and biomarker assessments in Section 6.3.1. 
q In patients with measurable disease, a fresh tumor biopsy should be taken once other screening investigations strongly suggest the patient is likely to be eligible, to avoid unnecessary risk of 
biopsy for a patient who is not going to be eligible. Where a prior (archival) biopsy is available that is less than 3 months old this may be substituted for a fresh tumor biopsy at screening. A 
fresh tumor biopsy is mandatory on treatment (C2D8). Where feasible, collection of a tumor biopsy at progression is encouraged. 
r 
Samples for the analysis of ICOS Receptor Occupancy will be collected from patients on KY1044 single agent only.  
s Plasma sample for cytokine analysis post dose timepoint is 6 to 8 hours post-infusion on C2D1 and C3D1. Unscheduled sample may be collected if required.  
t 
Blood sample for measurement of serological tumor markers will be taken at screening, pre-dose of every cycle and EOT only for those patients that have tumors with correlative serological 
markers. 
u
Tumor Imaging RECIST 1.1 assessment is done every 8 weeks (±7 days) after the start of treatment for the first 16 weeks, after that every 12 weeks (±7 days) for 48 months of treatment 
duration or until objective disease progression; visit window for assessment is ±7 days. In case of progression of disease without clear clinical signs of progression, the patient should continue
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treatment. In this case a confirmatory scan should be scheduled 4 to 8 weeks later as per iRECIST guidelines. The thorax CT/ magnetic resonance imaging (MRI) scan performed at screening 
as part of the RECIST assessment will document the lung parenchyma status. 
v Please see Section 8.1 for details of follow up after end of treatment visit.  
w KY1044 is always to be administered first followed by a saline solution flush to empty the line as described in the pharmacy manual. For the combination part, a slow saline infusion will 
continue (after this saline flush) for approximately 1 hour before starting the atezolizumab infusion at the same infusion site. There should be a period of at least 1 hour after the infusion(s) is 
complete whereby the patient requires close observation as outlined in Section 5.2.2. 
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d Vital signs: during Cycles 1 and 2, BP and HR will be monitored in the clinic every 15 minutes during the infusions of study treatment and every 30 minutes inbetween the infusions (for 
combination therapy), 60 min after the last infusion of study treatment. See Section 6.5.7. 
e Cardiac markers at screening will include: Baseline Troponin I for all patients. Additionally, N-terminal pro B-type natriuretic peptide (NT-pro-BNP) will only be taken for patients with a 
history of cardiac disease (according to exclusion criteria). Repeated assessments of cardiac markers during the study will be performed only when clinically indicated. 
f 
ECGs will be taken pre- and post-dose at Cycles 1, 3 and 6 as close as possible to each of the PK timepoints (see Section 6.5.8). In the event of abnormal ECG findings and if clinically 
indicated, an unscheduled PK sample should be collected and Troponin I, together with assessments for CK, CK-MB, AST and LDH. NT-pro-BNP should be measured together with the other 
cardiac markers as outlined above only in patients with previous cardiac complications at screening.  
g All samples will be analyzed centrally. On the occasions marked g only, duplicate samples for immediate access to key safety laboratory parameters (hematology, clinical chemistry and 
coagulation) will be analyzed at local labs as well.  
h At screening, clinical chemistry includes collection of a fasting lipid profile samplI. 
i 
HbA1c should be measured every 12 weeks throughout the study and will be assessed at EOT only if the previous assessment has not been performed within the last 3 months. 
j 
Urinalysis will include pH, protein, glucose, ketones, blood and urine dipstick pregnancy test. 
k Serum pregnancy test (β-HCG) will be performed on screening. Urine dipstick test will be performed at all other visits. 
l 
Thyroid function includes free T4 and TSH and the analyses will be repeated every 3 cycles and at EOT. 
m Virology testing will be performed at screening for HIV, HBV and HCV. In patients, who are known to be positive for HBV and HCV, tests will be repeated every cycle pre-dose and a 
confirmatory sample should be taken when clinically indicated. See Section 6.5.9 for more details. 
n Auto-antibodies include: anti-DNA, anti-nuclear, anti-mitochondrial and anti-phospholipid antibodies and Rheumatoid factor (RF) and acetyl-choline receptor antibodies (AChR). When a 
blood sample is positive for ANA (ie, titer>40) it will be tested for antibodies against extractable nuclear antigens. Samples for auto-antibody analyses will be collected at screening, every 
second cycle pre-dose for the first six cycles (C2, C4, C6), at EOT and then every 12 weeks up to 48 months of treatment and when clinically indicated. 
o ADA samples should be collected at every cycle on Day 1 and unscheduled at any time, when clinically indicated. For detailed ADA sample collection schedule see Section 6.4.2. 
p PK samples will be taken pre- and post-dose during all cycles and unscheduled at any time, when clinically indicated. For detailed PK analysis timings please refer to Section 6.4.2. 
Note: On days and timepoints when biomarker and pharmacokinetic blood samples are being collected, the PK sample must be drawn first. For further details please see schedule 
of PK assessments in Section 6.4.2.  
q Fresh tumor biopsy should be taken once other screening investigations strongly suggest the patient is likely to be eligible to avoid unnecessary risk of biopsy for a patient who is not going to 
be eligible. Where a prior (archival) biopsy is available no older than 3 months, the archival tissue may be substituted for a fresh tumor biopsy at screening. A fresh tumor biopsy is mandatory 
on treatment (C2D8).  Where feasible, collection of a tumor biopsy at progression is encouraged. 
r 
Plasma sample for cytokine analysis post dose timepoint is 6 to 8 hours post-infusion on C1D1 and C2D1 and C3D1. Unscheduled sample may be collected if required. 
s Blood sample for measurement of serological tumor markers  will be taken at screening, pre-dose of every cycle and EOT only for those patients that have tumors with correlative serological 
markers. 
t 
Tumor Imaging RECIST 1.1 assessment is done every 8 weeks (±7 days) after the start of treatment for the first 16 weeks, after that every 12 weeks (±7 days) for 48 months of treatment 
duration or until objective disease progression; visit window for assessment is ±7 days. In case of progression of disease without clear clinical signs of progression, the patient should continue 
treatment. In this case a confirmatory scan should be scheduled 4 to 8 weeks later as per iRECIST guidelines. The thorax CT/MRI scan performed at screening as part of the RECIST assessment 
will document the lung parenchyma status. 
u Please see Section 8.1  for details of follow up after end of treatment visit.  
v KY1044 is always to be administered first followed by a saline solution flush to empty the line as described in the pharmacy manual. For the combination part, a slow saline infusion will 
continue (after this saline flush) for approximately 1 hour before starting the atezolizumab infusion at the same infusion site. There should be a period of at least 1 hour after the infusion(s) are 
complete whereby the patient requires close observation as outlined in Section 5.2.2.
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6.1 
Screening Assessments  
6.1.1 Written Informed Consent  
Written informed consent for the study will be obtained from each patient before any 
protocol-specific procedures are carried out. 
At the screening visit, the Investigator will explain the aims, methods, anticipated benefits and 
potential risks of participating in the study and should inform the patient that participation is 
voluntary and that they can withdraw from the study at any time.  Each patient will be given a 
study-specific Patient Information Sheet to read as part of the informed consent process and 
will be given adequate time to ask questions.  In accordance with ICH GCP and 21 Code of 
Federal Regulations (CFR) 50, informed consent shall be documented by the use of an 
Informed Consent Form (ICF) approved by the IEC/IRB.  The ICF will be signed and 
personally dated by the patient, and by the site personnel responsible for obtaining consent. 
In addition to the ICF for the study, the patient may be asked to participate in the 
pharmacogenomic sampling section of the study, for which there is a separate ICF and Patient 
Information Sheet. The importance of this assessment should be clearly outlined to all patients.  
The use of genomic test such as FoundationOne (Foundation Medicine Cambridge, MA, USA) 
may be conducted at a later stage to understand the molecular/mutanome profiling of the 
tumors in order to correlate response (or lack of response) with specific genomic profiles (eg, 
tumor mutation burden, EGFR status etc.).  However, lack of informed consent to participate 
in the pharmacogenomic sampling section of the study does not preclude patients from 
participating in the clinical trial. 
Informed consent procedure will be documented in the patient’s medical records.  The patient 
will be given a copy of the Patient Information Sheet and their signed and dated ICF, and the 
original ICF will be filed in the ISF. 
6.1.2 Screening and Enrollment into the Study  
All screening assessments must be performed within the 28-day screening period.  All screened 
patients will be allocated a unique screening number (See Section 5.9). 
Assessment of inclusion and exclusion criteria must be checked during the screening period 
and finally confirmed prior to patient admission on C1D1.  Emergency cards will be handed 
out to patients prior to first administration of IMP (IMPs). After receiving the first infusion in 
Phase 1, patients will be either hospitalized or remain in the clinic for at least 6 to 8 hours until 
the last assessments. They will be provided with instructions for after hour care per institutional 
standard and will return to the clinic on C1D2.  In Phase 2, patients will be admitted prior to 
the first dose and will remain in the clinic for 6 to 8 hours after the first dose administration for 
all assessments to be performed.  
6.1.3 Screen Failures  
A patient who signed an ICF but failed to be started on-treatment for any reason will be 
considered a screen failure.  The reason for screening failure will be entered into the eCRF.  
The demographic information, informed consent, and inclusion/exclusion pages must also be 
completed for screen failure patients.  No other data will be entered into the clinical database 
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for patients who are screen failures, unless the patient experienced an SAE during screening or 
died or withdrew consent, when the appropriate eCRF pages should be completed. 
6.1.4 Demographic Information  
Demographic information will be collected at the screening visit as follows: 
• Age 
• Year of birth 
• Sex 
• Race 
• Ethnicity 
6.1.5 Medical History  
The Investigator will be responsible for review of the medical history of patients to ensure that 
they meet the criteria for eligibility for the study. Data to be collected will include relevant 
medical, surgical and radiation history and current medical conditions, diagnosis, including 
date and extent of tumor, details of prior anti-neoplastic treatments, current concomitant 
medication, SARS-CoV-2 vaccines, current significant non-drug therapies and other important 
molecular tumor characteristics. Medical history will be taken at screening and concomitant 
medications and vaccines, including SARS-CoV-2 vaccines, will be assessed throughout the 
study according to the schedules in Table 6-1 and Table 6-2.  
For SARS-CoV-2 vaccinations, report the following in the appropriate pages of the eCRF: 
• Information on each administration of SARS-CoV-2 vaccine. Each injection of 
SARS-CoV-2 vaccine must be reported as separate entries, including the vaccine name, 
dose and date of injection (Prior/Concomitant Medication eCRF). 
• Any observed AE following administration of the SARS-CoV-2 vaccine during the 
study treatment period (Adverse Events eCRF). 
• COVID-19 antibody titers, if measured after vaccination and available (Unscheduled 
Local Lab Results eCRF). 
6.2 
Assessment of Efficacy  
6.2.1 Tumor Assessments  
Tumor response will be determined locally according to two sets of criteria: 
• RECIST 1.1: Appendix 1 (51, 52) 
• iRECIST: Appendix 2 (53) 
The Investigator’s assessment according to both RECIST 1.1 and iRECIST will be used for the 
analysis of response and for treatment decisions (study discontinuation due to progressive 
disease as per iRECIST).  During the course of the study, the Sponsor may decide to have a 
central review of the radiological assessments performed.  In such case, the Investigator’s staff 
will be instructed on how to send data from these radiological assessments to a CRO for central 
review when needed. 
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RECIST 1.1 guidelines for measurable, non-measurable, target lesions (TLs) and non-target 
lesions (NTLs) and the objective tumor response criteria are presented in Appendix 1 of this 
protocol. 
Screening tumor assessments will include CT of the thorax and abdomen (including liver and 
adrenal glands) and pelvis and should encompass all areas of known predilection for metastases 
in the disease under evaluation and will additionally investigate areas that may be involved 
based on signs and symptoms of individual patients.  Brain magnetic resonance imaging (MRI) 
is mandatory for patients with known or suspected brain metastases.  
If a patient is intolerant to iodine-based contrast agents, CTs may be performed without 
contrast.  MRI may be used to evaluate sites of disease where a CT without IV contrast is not 
adequate or to evaluate sites of disease that are not adequately imaged by CT.  Ultrasound 
should not be used to measure sites of disease. 
Screening assessments should be performed no more than 28 days before the start of study 
treatment, and ideally should be performed as close as possible to the start of study treatment.  
Scans obtained as part of standard clinical practice, prior to informed consent, but within the 
28-days prior to treatment are acceptable. 
The methods of assessment used at screening should be used at each subsequent follow-up 
assessment every 8 weeks (±7 days) after the start of treatment for 16 weeks, after that every 
12 weeks (±7 days) for 48 months of treatment of duration or until objective disease 
progression as defined by RECIST 1.1/iRECIST (see Table 6-3).  Scans confirming 
progression should preferably not be conducted within 1 week of a progression biopsy to allow 
for reduction in inflammation.  
Any other sites at which new disease is suspected should also be appropriately imaged.  If an 
unscheduled CT/MRI scan is performed and the patient has not progressed, every attempt 
should be made to perform subsequent assessments at the scheduled visits whilst the patient 
remains on study treatment.  
Table 6-3: 
Disease Assessment Collection Plan  
Procedure 
Screening 
During treatment/Follow-up 
CT with (or without) contrast 
enhancement 
or MRI 
(Thorax, Abdomen, Pelvis) 
Mandated 
During treatment: Every 8 weeks (+7 days) 
for the first 16 weeks and then every 12 weeks 
until progression of disease as per iRECIST or 
patient withdrawal. 
Brain CT or MRI with contrast 
Mandated (for 
patients with known 
or suspected brain 
metastases) 
If disease was detected at screening, or if 
clinically indicated. 
CT=computed tomography; iRECIST=immune-related response evaluation criteria in solid tumors; MRI=magnetic resonance 
imaging 
6.2.1.1 RECIST 1.1  
Categorization of objective tumor response at each visit will be based on the 
RECIST 1.1 guidelines for response: CR, PR, SD and progression of disease.  For ORR, a visit 
response of CR or PR must be confirmed by a later scan conducted at least 4 weeks after the 
initial response is observed. 
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Target lesion progression will be calculated in comparison to when the tumor burden was at a 
minimum (ie, smallest sum of diameters previously recorded on study).  In the absence of 
progression, tumor response (CR, PR, SD) will be calculated in comparison to the baseline 
tumor measurements obtained before starting treatment. 
If the Investigator is in doubt as to whether progression has occurred, particularly with response 
to NTLs or the appearance of a NL, it is advisable to continue treatment and reassess the 
patient’s status at the next scheduled assessment or sooner if clinically indicated. 
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more NTLs is usually not 
sufficient to qualify for unequivocal disease progression status. 
If repeated scans confirm progression, then the date of the initial scan should be declared as 
the date of progression.  
All RECIST 1.1 assessment images will be reviewed at site.  Duplicates may be collected, 
stored and can be sent for independent central RECIST 1.1 review, if deemed appropriate. 
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
Schedule of Assessments see Section 6. 
6.2.1.2 iRECIST  
RECIST 1.1 has been modified to take into consideration the unique response kinetics which 
have been observed with immunotherapy in some patients where responses to immune 
therapies may occur after progression has been assessed (53).  Therefore patients should be 
treated and followed up post initial progression until subsequent disease progression 
(confirmed progression).  Note: patients with rapid tumor progression or with symptomatic 
progression that requires urgent medical intervention will not be eligible to continue to receive 
treatment. 
In this study a confirmation of progression scan is required at no less than 4 weeks and 
preferably at the next scheduled visit after first overall visit response of progression of disease.  
Confirmed progression is defined as: 
• ≥20% increase in sum diameters of target lesions compared to the nadir at 2 consecutive 
visits 
• And/or significant progression (worsening) of NTLs or NLs at the confirmatory 
progressive disease timepoint compared with the first timepoint where progression of 
NTLs or NLs identified 
• And/or additional new unequivocal lesions at the confirmatory progressive disease 
timepoint compared with the first timepoint NLs identified 
If progression is not confirmed then the overall visit response should be assessed as SD/PR or 
CR and the patient should continue scheduled RECIST 1.1 CT/MRI scans.  If progression is 
confirmed the overall visit response should be assessed as progressive disease. 
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6.3 
Assessment of Pharmacodynamics  
6.3.1 Biomarkers  
Biological samples (eg, archived and fresh tumor samples or blood samples) will be collected 
and may be analyzed for exploratory predictive or responsive biomarkers (see Section 6.3.2 
and Section 6.3.3).  
There is a high need to identify and validate biomarkers with the aim of selecting indications 
and patients who will best respond to KY1044 as single agent and/or to the combination with 
atezolizumab and also to correlate the PD effects of the treatments with clinical outcomes such 
as efficacy and toxicity.  Such biomarkers will be explored at the soluble (plasma), cellular, 
and transcriptomic levels.  
In addition, it is proposed to use PD readouts to contribute to the process of RP2D decision. 
These biomarkers/PD markers include immune cell profiling (to be analyzed by RNA and/or 
Protein) in the blood and in the TME (TRegs quantification, ICOS expression, number of CD8, 
TILs contents) pre and post treatment.  Diagnostic and prognostic gene signatures derived from 
pre-clinical in vitro and in vivo models will also be examined using relevant patient samples 
(PBMC and Tumor) where appropriate consent has been provided.  
Finally, cytokines such as IFN, TNF and GM-CSF will be assessed in the plasma of the 
patients.  
Alternative biomarkers may be evaluated as determined by additional data associated with 
safety, disease progression or response to KY1044 as single agent or in combination with 
atezolizumab.  The results obtained from this study may be pooled with biomarker data from 
other studies to test existing hypotheses or to generate hypotheses to be tested in future studies 
where KY1044 may be combined with other agents.  A summary of the biomarker samples is 
provided in Table 6-4. 
Table 6-4: 
Biomarker Sample 
Collection 
Plan (Tumor/Blood Samples) 
for 
Phase 1 and 2  
Sample type 
Visit/ Timepointa 
Approx. 
volume (blood 
samples) 
Markerb 
Purpose 
Tumor samplesc 
Newly obtained 
tumor sample  
Screening and 
during treatment 
C2D8 
N/A 
IHC expression of 
markers such as: 
ICOS, CD8, FOXP3 
(secondary endpoint) 
and other markers such 
as CD163, CD68, 
PD-L1 etc. (exploratory 
endpoint) 
Assess 
expression 
status of 
potential 
predictors of 
efficacy.  
PD markers  
Transcriptomic analysis 
of immune-related 
genes (exploratory 
endpoint)  
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Sample type 
Visit/ Timepointa 
Approx. 
volume (blood 
samples) 
Markerb 
Purpose 
Analysis of 
pharmacogenomics 
markers  
Blood samples 
Blood sample 
(Plasma) for 
cytokine analysisb 
C1D1 (pre-infusion) 
C1D2, C1D8, 
C2D1 
(pre-infusion), 
C2D1 (6-8 hours 
post-infusion), 
C2D8  
C3D1(pre-infusion), 
C3D1 (6-8 hours 
post-
infusion),C3D8  
and unscheduledd  
1 x 5 mL of 
blood per 
timepoint 
Cytokine analysis (eg, 
IFNγ, TNFα, GM-CSF) 
(exploratory endpoint) 
PD effect 
Blood sample 
(PBMC) for 
Immunoprofilling 
C1D1 
(pre-infusion), 
C1D8, C2D1 
(pre-infusion), 
C2D8 and 
unscheduled 
1 x 4 mL of 
blood per 
timepoint 
Phenotypic 
characterization of 
circulating ICs by 
FACS/ChipCytometry 
(eg, CD8, CD4, TRegs 
and B cells) 
(exploratory endpoint)  
PD effect 
Blood sample 
(PBMC) for 
pharmacogenomics 
testing 
C1D1 (pre-infusion), 
C1D8, C2D1 
(pre-infusion), C2D8 
and unscheduled 
1 x 8 mL of 
blood per 
timepoint 
Transcriptomic analysis 
of PBMC using 
customized IO360 
panel from Nanostring 
(exploratory endpoint) 
PD effect 
Samples will 
be taken only 
if PGx ICF is 
signed 
Analysis of 
pharmacogenomics 
markers  
Blood Samples 
(PBMC) for 
receptor 
occupancy 
(KY1044 single 
agent in Phase 1 
only) 
C1D1 
(pre-infusion), 
C1D8, C2D1 
(pre-infusion), 
C2D8 and 
unscheduled 
1 x 8 mL of 
blood per 
timepoint 
KY1044 binding to 
CD4/CD8 cells by 
FACS (exploratory 
endpoint) 
Target 
engagement 
Samples will 
be taken only 
from patients 
receiving 
monotherapy 
FACS=fluorescence-activated cell sorting; FOXP3=forkhead box; GM-CSF=granulocyte-macrophage colony-stimulating 
factor; 
ICF=informed 
consent 
form; 
ICOS=inducible 
T 
cell 
costimulatory; 
IFNγ=interferon 
gamma; 
IHC=immunohistochemistry; PBMC=peripheral blood mononuclear cells; PD= pharmacodynamics; PD-L1=Programmed 
Cell Death-Ligand 1; PGx=pharmacogenomics; PK=pharmacokinetic; TNFα=tumor necrosis factor alpha.  
a On days and timepoints when biomarker and pharmacokinetic blood samples are being collected, the PK sample must 
be drawn first. For further details please see schedule of PK assessments in Section 6.4.2. 
b Patients need to stay in the clinic for as long as possible (6 to 8 hours) for collection of plasma cytokine samples (see 
schedule of assessments in Section 6) in Phase 1: C2D1 and C3D1 in Phase 2: C1D1, C2D1 and C3D1 at pre-infusion 
and 6 to 8 hours post-infusion. 
c At screening where a prior (archival) biopsy is available that is less than 3 months old this may be substituted for a fresh 
tumor biopsy 
d In Phase 2 - No C1D2, but instead C1D1 +6 to 8 hours post-infusion. 
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6.3.2 Tumor Samples  
Fresh tumor biopsies for biomarker analysis will be collected during the screening period once 
other screening investigations strongly suggest the patient is likely to be eligible, to avoid 
unnecessary risk of biopsy for a patient who is not going to be eligible.  Biopsies are mandatory 
except if associated with unacceptable clinical risk and after discussion with the Medical 
Monitor.  Where a prior (archival) biopsy is available that is less than 3 months old this may 
be substituted for a fresh tumor biopsy at screening.  A further biopsy will be obtained at C2D8. 
Where feasible, collection of a tumor biopsy at progression is encouraged.  This sample will 
be used to investigate changes in target expression and immune cell contexture and potential 
mechanisms of resistance (ie, change in immune cell contents, genetic alterations/new 
mutations, evidence of alternative pathway activation), RNA and protein. 
6.3.2.1 Collection of Fresh Tumor Samples for Pharmacodynamic and Exploratory 
Biomarker Assessments  
Tumor samples provided should be in a quantity sufficient to allow for analysis (see the 
Laboratory Manual). Tumor samples will preferably be in the form of a formalin-fixed paraffin 
embedded (FFPE) block.  If this is not possible, 20 slides of freshly prepared unstained 5 m 
sections from the tumor block should be provided. 
If clinically practical, dependent to accessibility of the tumor lesion and disease indication, and 
within the same procedure, patients may undergo up to four core biopsies, (ideally minimum 
of at least two).  The core biopsies will be placed in formalin and processed for FFPE. 
Tumor biopsies will be stored at an appropriate vendor selected by the Sponsor.  Core biopsies 
may be used for correlative studies such as IHC, transcriptomic analysis, proteomic analysis 
and tumor mutation analysis.  Samples will be collected, labelled, stored and shipped as 
detailed in the Laboratory Manual.  
6.3.2.2 Archival Tumor Samples  
An unstained, archived tumor tissue sample (FFPE) in a quantity sufficient to allow for analysis 
(see the Laboratory Manual) will be requested, if available, from all enrolled patients.  Any 
biopsy samples taken following previous lines of therapy will also be requested, if available.  
In each case the previous patient treatment must be clearly indicated for each sample provided.  
Tumor samples will preferably be in the form of a FFPE block.  If this is not possible, 20 slides 
of freshly prepared unstained 5 m sections from the archival tumor block should be provided. 
6.3.2.3 Tumor Sample Analysis  
The biomarkers to be investigated using the tumor samples may be assessed by IHC and 
transcriptomic analysis of RNA expression levels and may include but are not limited to ICOS, 
PD-L1, CD8, FOXP3.  Tissue samples may also be analyzed for the presence of viral 
DNA/RNA or the presence of other pathogens associated with cancer (eg, helicobacter pilori) 
and for specific mutations where appropriate consent has been provided. 
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6.3.2.4 Assessment of Gene Signatures in Tumor Samples  
Slides from FFPE biopsies will also be used to extract mRNA and monitor changes in gene 
signatures previously identified in pre-clinical work (ICOS co-regulated genes signature, 
KY1044 response signature).  IFN signature and genes will be assessed using the Nanostring 
nCounter (PanInflammatory panel or the IO360 panel). 
6.3.2.5 Tumor Samples for Pharmacogenomics  
If a patient is eligible for enrollment into the study and has consented to provide DNA for 
genetic analysis, the baseline tumor sample may be used for pharmacogenomic analysis with 
The FoundationOne CDx™.  This next generation sequencing based in vitro diagnostic device 
for detection of substitutions, insertion and deletion alterations (indels), and copy number 
alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures 
including MSI and tumor mutational burden (TMB) is using DNA isolated from FFPE tumor 
tissue specimens.  Handling and shipping of pharmacogenomic samples is described in the 
Laboratory Manual.  
6.3.3 Blood Samples  
Blood samples for biomarker analysis will be collected at C1D1 pre-dose and the times 
indicated in Table 6-1 (Biomarker sample collection plan (Section 6.3.1) and the table of blood 
volumes and timings in the laboratory manual).  Samples will be used for the biomarker 
analysis listed below.  
6.3.3.1 Collection of Samples for Circulating Soluble Factors  
Plasma samples will be obtained for profiling of a variety of circulating soluble factors related 
to immune status including but not limited to cytokines such as IFN, TNF and GM-CSF. 
EDTA plasma samples will be analyzed using ultra-sensitive protein detection SIMOA or other 
appropriate, qualified methods. 
For post-dose sample collection the patients need to stay in the clinic for as long as possible (6 
to 8 hours) for biomarker assessments.  
• In Phase 1 on C2D1 and C3D1 
• In Phase 2 on C1D1, C2D1 and C3D1 
6.3.3.2 Collection of Samples for PBMC  
Peripheral blood mononuclear cells will be isolated from whole blood and will be preserved 
(direct fixation on ChipCytometry slides or stored as frozen as described in the Laboratory 
Manual), and used for subsequent functional analysis such flow cytometry or ChipCytometry 
(immune cell profiling and receptor occupancy), transcriptomic analysis (Nanostring), to 
correlate the PD changes with the clinical responses. 
6.3.3.3 Receptor Occupancy on PBMC  
In patients receiving KY1044 as single agent in Phase 1, receptor occupancy will be determined 
by flow cytometry on CD4 and CD8 T cells using frozen PBMC.  
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6.3.3.4 Immune Cell Phenotyping in PBMC  
Blood samples will be collected for analysis of immune cell subsets, such as T-cells subsets, 
B-cells, by flow cytometry or ChipCytometry (Zellkraftwerk, Leipzig, Germany).  Markers 
may include but not be limited to CD3, CD4, CD8, CD25, FOXP3, CD45RA, ICOS, CD14, 
CD45, CD56, ICOSLG and CD19. 
6.3.3.5 Assessment of Gene Signatures and Pharmacogenomics in PBMC  
PBMCs will be isolated and used for extraction of mRNA for the Nanostring analysis as 
described for tumor samples in Section 6.3.2.4 and extraction of deoxyribonucleic acid (DNA) 
with the aim to determine which FCGRIIIA and FCGRIIB variant is expressed in the patient.  
Handling and shipping of PBMCs samples for mRNA and DNA is described in the Laboratory 
Manual. 
6.3.4 Storage, Re-use and Destruction of Biological Samples  
The number of samples taken, as well as the volume required for each analysis, are specified 
in the laboratory manual.  Requirements may change during the study as emerging data on 
study treatments become available. 
The Investigator will ensure that all biological samples are stored labelled and shipped in 
accordance with the Laboratory Manual.  Records must be maintained of all samples collected 
and their disposition. 
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last 
Visit, after which they will be destroyed.  During this time samples may be used to evaluate 
emerging target related PD markers.  The results of biomarker research may be reported either 
in the Clinical Study Report for this study, or as an addendum, or separately in a scientific 
report or publication.  The results of this biomarker research may be pooled with biomarker 
data from other studies with IMP to generate hypotheses to be tested in future research.  
6.4 
Pharmacokinetic and Anti-drug Antibody Procedures  
6.4.1 Pharmacokinetic Procedures  
Blood samples will be withdrawn periodically for KY1044 and atezolizumab assay.  Samples 
should not be taken from the arm that has recently (12 hours) been infused with the study 
treatment (KY1044 or atezolizumab) that is to be measured.  Samples should not be taken from 
an arm that has any IV infusion running.  If atezolizumab is to be administered into the arm 
opposite that used for infusing KY1044, KY1044 sample will be collected before the start of 
atezolizumab infusion. 
6.4.2 Pharmacokinetic and Anti-drug Antibody Sampling Schedule  
Serum concentrations of KY1044 and atezolizumab and detection of ADA will be assessed 
from blood samples taken during the study using validated bioanalytical methods.  Assay 
methodologies and procedures will be described in analytical plans to be finalized before the 
start of sample analysis.  
Multiple samples for concentration-time profiles for KY1044 will be taken in Cycles 1, 3 and 
6 (see Table 6-5, Table 6-6, Table 6-7).  For other cycles, samples will be taken for KY1044 
serum concentrations and for atezolizumab serum concentrations at each cycle pre-infusion, 
end of infusion, End of Treatment and End of Study. 
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Anti-Drug Antibody samples will be drawn pre-infusion at all cycles and at the End of Study. 
Samples will be collected at the timepoints specified in Table 6-5, Table 6-6, Table 6-7.  
Tolerances for deviation from the nominal time of sampling are provided in the tables below. 
These tolerances indicate the best time to allow interpretation of data.  However, samples taken 
outside these tolerances will be evaluated so should be taken.  The exact date and time of 
sampling will be recorded.  Samples may also be drawn for serum concentration and/or ADA, 
with prior agreement with the Sponsor, at unscheduled times. Additionally, these blood 
samples may be used for ad hoc biomarker analysis (ie, safety and efficacy analyses). 
Table 6-5: 
KY1044 PK Sampling Times  
Cycle 
Day relative to most 
recent infusion 
Scheduled timepoint and tolerance 
Phase 1  
1 
1 
Pre-infusion of Cycle 1 
1 
1 
End of KY1044 infusion (up to 5 min delay allowed) a 
1.5 h post-infusion start (±5 min) a 
2.5 h post-infusion start (±5 min) a 
8 h post-infusion start (±1 h) a 
1 
2 
24 h post-infusion start (±2 h) 
1 
8 
168 h post-infusion start (±8 h) 
1 
11 
240 h post-infusion start (±24 h) 
1 
15 
336 h post- infusion start (±24 h) 
2 
1 
Pre-infusion of Cycle 2 (up to 24 h before 2nd infusion) 
End of KY1044 infusion (up to 5 min delay) a 
3 
1 
Pre-infusion of Cycle 3 (up to 24 h before 3rd infusion) 
End of KY1044 infusion (up to 5 min delay) a 
1.5 h post-KY1044 infusion start (±5 min) a 
3 
8 
168 h post-KY1044 infusion start (±8 h) 
3 
11 
240 h post-KY1044 infusion start (±24 h) 
3 
15 
336 h post-KY1044 infusion start (±24 h) 
4 
1 
Pre-infusion of Cycle 4 (up to 24 h before 4th infusion) 
End of KY1044 infusion (up to 5 min delay) a 
5 
1 
Pre-infusion of Cycle 5 (up to 24 h before 5th infusion) 
End of KY1044 infusion (up to 5 min delay) a 
6 and all 
other cycles 
1 
Pre-infusion of Cycle 6 (up to 24 h before 6th infusion)  
End of KY1044 infusion (up to 5 min delay) a 
1.5 h post-KY1044 infusion start (±5 min) a, b 
EOT 
within 21 days of the 
last dose 
EOT 
End of safety 
follow-up 
90 days after the last 
dose 
End of safety follow-up 
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Cycle 
Day relative to most 
recent infusion 
Scheduled timepoint and tolerance 
Phase 2  
1 
1 
Pre-infusion of Cycle 1 
End of KY1044 infusion (up to 5 min delay) a 
1.5 h post-KY1044 infusion start (±5 min) a 
2 
1 
Pre-infusion of Cycle 2 (up to 24 h before 2nd infusion) 
End of KY1044 infusion (up to 5 min delay) a 
3 
1 
Pre-infusion of Cycle 3 (up to 24 h before 3rd infusion) a 
End of KY1044 infusion (up to 5 min delay) 
1.5 h post-KY1044 infusion start (±5 min) a 
4 
1 
Pre-infusion of Cycle 4 (up to 24 h before 4th infusion) a 
End of KY1044 infusion (up to 5 min delay) 
5 
1 
Pre-infusion of Cycle 5 (up to 24 h before 5th infusion) a 
End of KY1044 infusion (up to 5 min delay) 
6 and all 
other cycles  
1 
Pre-infusion of Cycle 6 (up to 24 h before 6th infusion)  
End of KY1044 infusion (up to 5 min delay) a 
1.5 h post-KY1044 infusion start (±5 min) a, b 
EOT 
within 21 days of the 
last dose 
EOT 
End of safety 
follow-up 
90 days after the last 
dose 
End of safety follow-up 
Optional, Phase 1 or 2  
Unscheduled 
 
Anytime 
EOT=end of treatment; PK=pharmacokinetic 
a Samples will be collected from the arm opposite of the KY1044 infusion site for the first 12 hours following infusion 
b This sample will only be taken during Cycle 6 
Table 6-6: 
Atezolizumab PK Sampling Times  
Cycle 
Day relative to most 
recent infusion 
Scheduled timepoint and tolerance 
Phase 1 and 2 patients receiving KY1044 in combination with atezolizumab  
1 
1 
Pre-KY1044 infusion of Cycle 1* 
End of atezolizumab infusion (up to 5 min delay) a 
2 
1 
Pre-KY1044 infusion of Cycle 2 (up to 24 h before 2nd infusion) 
End of atezolizumab infusion (up to 5 min delay) a 
3 
1 
Pre-KY1044 infusion of Cycle 3 (up to 24 h before 3rd infusion) 
End of atezolizumab infusion (up to 5 min delay) a 
4 
1 
Pre-KY1044 infusion of Cycle 4 (up to 24 h before 4th infusion) 
End of atezolizumab infusion (up to 5 min delay) a 
5 
1 
Pre-KY1044 infusion of Cycle 5 (up to 24 h before 5th infusion) 
End of atezolizumab infusion (up to 5 min delay) a 
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Cycle 
Day relative to most 
recent infusion 
Scheduled timepoint and tolerance 
6 and all 
other cycles 
1 
Pre-KY1044 infusion of Cycle 6 (up to 24 h before 6th infusion) 
End of atezolizumab infusion (up to 5 min delay) a 
EOT 
within 21 days of the 
last dose 
EOT 
End of safety 
follow-up 
90 days after the last 
dose 
End of safety follow-up 
Optional, Phase 1 or 2 patients 
Unscheduled 
 
Anytime 
EOT=end of treatment; PK=pharmacokinetic 
a All baseline atezolizumab PK samples are to be taken before infusion with KY1044. Samples (ie, end of atezolizumab 
infusion) will be collected from the arm opposite of the atezolizumab infusion site for the first 12 hours following infusion. 
Table 6-7: 
ADA Sampling Times (KY1044 and Atezolizumab)  
Cycle 
Day relative to most 
recent infusion 
Scheduled timepoint and tolerance 
Phase 1 and 2 patients 
1 
1 
Pre-KY1044 infusion of Cycle 1 for anti-KY1044 and for 
combination therapy patients, anti-atezolizumab 
2 
1 
Pre-KY1044 infusion of Cycle 2 (up to 24 h before 2nd infusion) 
for anti-KY1044 and for combination therapy patients, 
anti-atezolizumab 
3 
1 
Pre-KY1044 infusion of Cycle 3 (up to 24 h before 3rd infusion) 
for anti-KY1044 and for combination therapy patients, 
anti-atezolizumab 
4 
1 
Pre-KY1044 infusion of Cycle 4 (up to 24 h before 4th infusion) 
for anti-KY1044 and for combination therapy patients, 
anti-atezolizumab 
5 
1 
Pre-KY1044 infusion of Cycle 5 (up to 24 h before 5th infusion) 
for anti-KY1044 and for combination therapy patients, 
anti-atezolizumab 
6 and all 
other cycles 
1 
Pre-KY1044 infusion of Cycle 6 (up to 24 h before 6th infusion) 
for anti-KY1044 and for combination therapy patients, 
anti-atezolizumab 
End of safety 
follow-up 
90 days after the last 
dose 
End of safety follow-up for anti-KY1044 and for combination 
therapy patients, anti-atezolizumab 
Optional, Phase 1 or 2 patients 
Unscheduled 
 
Anytime for either/both anti-KY1044 and anti-atezolizumab 
6.4.3 Pharmacokinetic and Anti-drug Antibody Sample Preparation and Shipment  
The details of blood volume, type of tube, sample handling, storage and dispatch are described 
in the Laboratory Manual. 
Up to 11 mL of whole blood will be collected at each sampling timepoint. Blood will be drawn 
into a Serum Separator Tube, spun down and aliquoted into a minimum of two labelled sample 
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tubes.  Separate PK and ADA samples are needed for the KY1044 and atezolizumab assays.  
These samples must be stored on site at <-60°C and will periodically be shipped in a staged 
fashion.  The Investigator will maintain a log of samples stored and dispatched. 
KY1044 samples (for KY1044 serum concentration and for anti-KY1044 antibody) will be 
shipped to Intertek Pharmaceutical Services.  Atezolizumab samples (for atezolizumab serum 
concentration and for anti-atezolizumab antibody) will be shipped and analyzed as outlined in 
the laboratory manual. 
6.5 
Assessment of Safety and Tolerability  
The Investigator will review results of safety assessments on a regular basis and the Sponsor 
must be kept fully informed of any clinically significant findings either at screening or 
subsequently during study conduct. 
6.5.1 Physical Examination  
The Investigator will perform physical examinations, which will consist of assessment of: 
general appearance, ears, eyes, nose, throat, mouth, neck, thyroid, complete skin and mucosal 
assessment, cardiovascular, respiratory, abdomen, neurological, musculoskeletal, lymph nodes 
and extremities. 
6.5.2 Abbreviated Physical Examination  
The Investigator will perform the abbreviated physical examination. The extent of the 
abbreviated examination will be based in the findings of the baseline medical history (including 
physical examination) and adverse events.  This examination must include assessments of 
baseline abnormalities in physical examination that might have changed, an examination for 
changes based on adverse events and for changes related to study procedures such as 
venipuncture and biopsies for example. 
6.5.3 ECOG Performance Status  
ECOG scoring of general well-being will be assessed as follows: 
Grade 
ECOG performance status (54) 
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, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more 
than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
ECOG=Eastern Cooperative Oncology Group 
ECOG grade will be recorded in the eCRF at screening, at the beginning of every cycle and at 
EOT. 
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6.5.4 Body Weight and Height  
Body weight will be measured in kilograms (kg) and height in meters (m), with patients in light 
clothing and without shoes.  
Body mass index (BMI) will be calculated as follows: 
BMI = Weight (kg)/Height (m)2 
6.5.5 Adverse Events  
Investigators must carefully monitor patients for the occurrence of AEs, including clinical 
laboratory, vital signs and ECG variables.  Assessments must be made of the seriousness, 
severity and relationship to the administration of study medication (causality).  Serious Adverse 
Events (SAE) and specific Adverse Events of Special Interest (AESI) will require expedited 
reporting.  For details on definitions and reporting procedures see Section 7.  
Adverse event assessments must be made by the Investigator or delegated to an appropriately 
trained and experienced physician.  The Investigator is required to record the assessments in 
the eCRF and patient medical notes.  Any AEs already recorded and designated as “continuing” 
should be reviewed at each subsequent assessment. 
During and following a patient’s participation in this study, the Investigator has to ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory values, related to the trial. 
Patients will be monitored for AEs at all study visits beginning at screening until completion 
of the 90 day safety follow-up. 
6.5.6 Safety Laboratory Tests  
All laboratory parameters assessed will be evaluated centrally.  However, laboratory tests for 
safety evaluation, such as hematology, clinical chemistry and coagulation parameters will also 
be assessed locally at indicated times during each cycle. In exceptional circumstances, the use 
of local labs may also be considered for assessment of screening laboratory values, after 
approval by the medical monitor. 
Refer to the Schedule of Assessments (Table 6-1, Table 6-2 and Table 6-8) for a summary of 
the parameters to be evaluated. 
More frequent evaluations may be performed at the Investigator’s discretion if medically 
indicated; results should be recorded as unscheduled laboratory assessments. 
Laboratory tests will be performed as described below and according to the schedule of 
assessments.  
• All laboratory reports should be reviewed, signed and dated by Investigators. Any 
clinically significant changes will be recorded as AEs. 
• Any single laboratory abnormality without clinical signs or symptoms needs to be 
repeated before qualifying as an AE. 
• All clinically relevant abnormal laboratory tests occurring during the study may be 
repeated at appropriate intervals until they return to baseline or to a level deemed 
acceptable by the Investigator or until the abnormality is explained by an appropriate 
diagnosis. 
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Full details relating to the methodology of analysis, sample processing, labelling, storage, 
shipment and destruction procedures will be documented in a laboratory manual. 
Table 6-8: 
Local/Central Clinical Laboratory Parameters Collection Plan  
Test category 
Test name 
Time of assessment 
Approx. mL 
per cycle 
(central assessment 
only) 
Phase 1 and 2 (unless otherwise specified) 
Hematology 
• 
Hematocrit (HCT), Hemoglobin 
(Hgb), Reticulocytes, red blood cell 
count (RBCC), mean cell 
hemoglobin (MCH), mean 
hemoglobin concentration (MCHC) 
and mean cell volume (MCV) 
• 
Platelets  
• 
White blood cells with Differential 
(Basophils, Eosinophils, 
Lymphocytes, Monocytes, 
Neutrophils)  
• 
Screening a,  
• 
C 1 b: D1 pre-dose, D2 c, 
D8, D15 
• 
C 2 b: D1 pre-dose, D8, 
D15 
• 
C 3 b: D1 pre-dose, D8 
• 
From Cycle 4 b: 
Day 1 pre-dose (CxD1) 
• 
EOT 
2 mL/sample 
 
2 mL = Screening  
8 mL = C1 
6 mL = C2 
4 mL = C3 
2 mL = C4 -EOT 
• 
HbA1c 
• 
Screening a 
• 
Every 12 weeks: pre-dose 
(C5D1 etc.). 
• 
EOT d 
Clinical chemistry 
• 
Alkaline phosphatase (ALP), 
alanine aminotransferase (ALT), 
aspartate-aminotransferase 
(AST), -glutamyltransferase 
(GGT), Total Bilirubin (also 
measure direct and indirect bilirubin 
if total bilirubin is >Grade 1), LDH, 
total CK, CK-MB 
• 
High sensitivity CRP (hsCRP)  
• 
Amylase, Lipase, 
• 
Total protein, Albumin 
• 
Bicarbonate, Calcium, Chloride, 
Sodium, Potassium Inorganic 
Phosphate, Magnesium, Ferritin, 
• 
Iron 
• 
Glucose, Cholesterol, Triglycerides, 
HDL, LDL 
• 
Creatinine, Blood Urea Nitrogen 
(BUN) or Urea 
• 
Screening a 
• 
C1- 2 b: D1 pre-dose, D8, 
D15 
• 
C 3 b: D1 pre-dose, D8 
• 
From Cycle 4 b: Day 1 
pre-dose (CxD1) 
• 
EOT  
3.5 mL/sample 
 
3.5 mL = Screening 
10.5 mL = C1, C2 
7 mL = C3 
3.5 mL = C4 -EOT 
• 
Fasting lipid profile, Glucose, 
Cholesterol, Triglycerides, HDL, 
LDL 
• 
Creat Clear (Est) 
Screening a 
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Test category 
Test name 
Time of assessment 
Approx. mL 
per cycle 
(central assessment 
only) 
Coagulation 
• 
Prothrombin time (PT) or INR,  
• 
Activated partial thromboplastin 
time (aPTT) 
• 
Thrombin time 
• 
Fibrinogen 
• 
D-Dimer 
• 
Screening a 
• 
Every cycle on Day 1b 
pre-dose (CxD1) 
• 
EOT 
4.5 mL/sample: 
 
4.5 mL  
per visit 
Cardiac markers 
• 
Serum Troponin I 
At screening a and when 
clinically indicated 
3.5 mL/sample: 
• 
N-terminal pro B-type natriuretic 
peptide (NT-pro-BNP) (only for 
patients with previous cardiac 
history or when clinically indicated) 
At screening a (for patients with 
cardiac history only) and when 
clinically indicated 
2 mL/sample 
Thyroid 
• 
Free T4  
• 
TSH (Thyroid Stimulation 
Hormone) 
• 
Screening a 
• 
Every 3 cycles pre-dose 
(C3D1, C6D1, C9D1 etc.) 
• 
EOT 
3.5 mL/sample: 
 
3.5 mL 
per visit 
Serological 
exam: Tumor 
markers e 
PSA, CEA, CA125, AFP,  neuro 
specific enolase (NSE), CA15-3, 
CA19-9, serum mesothelin 
(SMRP)Thyroglobulin, Calcitonin, 
Chromogranin A, human 
choriogonadotropin 
• 
Screening a 
• 
Every cycle on Day 1 
pre-dose (CxD1) 
• 
EOT 
5 mL/sample: 
5 mL 
per visit 
Serology exam: 
Auto-antibodies 
• 
Anti-DNA antibodies (abs) 
• 
Anti-nuclear abs (ANA) 
• 
Anti Cardiolip. IgG, IgM 
• 
Anti Cardiolip. IgA (USA only) 
• 
Beta2-Glycoprotein I IgG, IgM 
• 
Partial thromboplastin time-Lupus 
anticoagulant (PTT-LA) Screen with 
Hexagonal Phase Confirm. As reflex 
(USA only) 
• 
Lupus-Anticoagulant and Lupus 
sens. PTT-LA (EU and APAC only) 
• 
Anti-mitochondrial abs (AMA; and 
AMA titer) 
• 
Rheumatoid factor (RF) 
• 
Acetyl-choline receptor antibodies 
(AChR) 
• 
Anti-La (Anti-SSB), Anti-Ro (anti-
SSA), Anti-Sm-Ab (anti-Smith) 
(new SmDP assay), anti U1RNP 
antibodies, anti-Jo-1 
(anti-histidyl-tRNA synthetase), 
Scl-70 (topoisomerase) Ab (only if 
ANA 1:80 is positive) 
• 
Screening a 
• 
Every 2 cycles pre-dose 
until Cycle 6 (C2D1, 
C4D1, C6D1) 
• 
Every 12 weeks thereafter 
for 48 months of treatment 
duration 
• 
EOT 
18 mL/sample:  
 
18.0 mL  
per visit 
 
(Rheumatoid factor is 
part of chemistry 
sample) 
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Test category 
Test name 
Time of assessment 
Approx. mL 
per cycle 
(central assessment 
only) 
Virology 
Serology 
• 
(HBeAg, Anti-Hbe, HBcAb, 
HBsAb, HBsAg, HCV Ab, HIV-1/2 
Ab) 
• 
Screening a 
3.5 mL/sample 
• 
(HIV-Ab, HBV DNA and HCV 
RNA) 
• 
Screening a (if required) 
• 
CxD1 pre-dose 
8.5 mL/sample 
8.5 mL per visit 
Pregnancy  
• 
Serum samples only for women of 
childbearing potential at screening 
(-HCG) 
• 
Screening a 
Part of the clinical 
chemistry sample 
Urinalysis 
• 
Bilirubin, Blood (hemoglobin) , 
Glucose, Ketones, pH, Protein, 
Specific Gravity, White Blood Cells 
(Leucocyte Esterase) 
• 
Microscopy f (WBC, RBC; Hyaline 
Casts,  Granular Casts,  Waxy Casts, 
WBC Casts. RBC Casts, Epithelial 
Cells, Crystals, Mucous Threads, 
Bacteria, Yeast) 
• 
Urine dipstick pregnancy test 
(-HCG) (not at Screening) 
• 
Screening a 
• 
Every cycle pre-dose 
(CxD1) 
• 
EOT 
 
a In exceptional circumstances, the use of local labs for screening values may be considered. 
b Parameters are also assessed at local laboratories. 
c In Phase 2, no sample will be taken at C1D2. 
d Only if the previous assessment has not been performed within the last 3 months. 
e To be performed in Central laboratory only, where applicable. 
f 
 Only if clinically indicated.  
6.5.7 Vital Signs  
Vital signs, including heart rate (HR), blood pressure (BP), respiratory rate, and temperature 
will be assessed at the screening visit and periodically during the treatment period as described 
in the Schedule of Assessments.  
Heart rate and BP need to be established as a standard assessment (after 5 minutes in the supine 
position and after 5 minutes standing) during screening only. For all other visits supine position 
will be used. 
During Cycles 1 and 2, BP and HR will be monitored in the clinic every 15 minutes during the 
infusions of study treatment and every 30 minutes in between the infusions (for combination 
therapy) and after the last infusion of study treatment for 1 hour and, during Phase 1, before 
the patients are discharged from the hospital on C1D2. In Phase 1, if the patient does not stay 
in the clinic for 24 hours on C1D1 (and instead may be released into after hour care per 
institutional standard), BP and HR need also to be monitored at 6 to 8 hours after the last 
infusion and/or before the patient is discharged into after hour care. This schedule maybe 
altered depending on emerging data.  
Any changes from baseline in BPs and HR findings judged to be clinically significant by the 
Investigator will be recorded as AEs. In such cases, vital signs will be repeated at appropriate 
intervals until they return to baseline or to a level deemed acceptable by the Investigator or 
until the abnormality can be explained by an appropriate diagnosis. 
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6.5.8 12-lead ECG  
At the timepoints indicated in Table 6-9, a triplicate 12-lead ECG will be performed at 
screening and in accordance with PK measurements (the ECG should be recorded as close as 
possible to the timepoint, when the PK sample is drawn).  At each timepoint three ECG 
recordings should be taken one after another.  
Before the ECG, the patient should be supine for at least 10 minutes.  All ECGs should be 
recorded with the patient in the same physical position.  ECG traces are to be reviewed by a 
qualified physician at the study site (physician to sign, date and record interpretation on ECG 
trace).  The Investigator will enter a signed and dated clinical interpretation of the ECG trace 
in the eCRF.  
Any clinically significant abnormalities will be recorded as an AE.  In such cases, triplicate 
ECGs will be repeated at appropriate intervals until they return to baseline or to a level deemed 
acceptable by the Investigator, or until the abnormality can be explained by an appropriate 
diagnosis. 
Table 6-9: 
12-lead ECG Collection Plan for Phase 1 and 2  
Cycle 
Day 
Timea 
Screening 
-28 to -1 
Twiceb 
1 
1 
Pre-infusion 
1 
1 
1.5 hours (±5 min) post-infusion start 
3 
1 
Pre-infusion 
3 
1 
1.5 hours (±5 min) post-infusion start 
6 
1 
Pre-infusion 
6 
1 
1.5 hours (±5 min) post-infusion start 
EOT 
- 
Anytime 
Unscheduledc 
- 
Anytime 
ECG=electrocardiogram; EOT=end of treatment. 
a 
All ECGs will be performed in triplicates  
b 
ECGs will be taken twice during the screening period, at least 3 days apart 
c 
In case an ECG is performed due to an unexpected cardiac signal then an additional PK sample should be collected at 
the same time 
The Investigator or designated physician will review the ECGs and may refer to a local 
cardiologist if appropriate.  All ECG data will also be collected digitally and will potentially 
be transferred electronically as described in the ECG manual for central analysis of QTc data.  
If an abnormal ECG finding at screening is considered by the Investigator to be clinically 
significant, it should be reported as a concurrent condition.  During the study, clinically 
significant abnormal ECG findings not present at screening should be reported as an AE.  
Troponin I  and additionally other cardiac markers, ie, CK, CK-MB, BNP (only for patients 
with a history of cardiac disease), AST and lactate dehydrogenase (LDH) depending on the 
Investigators decision and if clinically indicated should also be assessed on identification of 
abnormal ECG findings, eg, new repolarization abnormalities, found to be possibly clinically 
significant by Investigators judgement.  A repeat cardiac marker assessment should also be 
performed 24 hours later.  The same Troponin isoform I should be assessed at each of the visits. 
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6.5.9 Virology Tests  
Blood samples for HIV and hepatitis virology tests will be taken at screening.  For those who 
have seropositivity of any markers indicating current or previous HBV (any seropositivity of 
HB s-Antigen, HB s-Antibody, HB c-Antibody, HB e-Antigen or HB e-Antibody, and/or 
detectability of HBV DNA) and/or HCV infection (seropositivity of HCV antibody and/or 
detectability of HCV RNA), relevant virology tests (ie, serum HBV DNA load for HBV 
infected patients and/or serum HCV RNA load for HCV infected patients) will be repeated 
pre-dose of every cycle, additionally, as clinically indicated (eg, a 2 to 3xULN rise in ALT). 
Active HBV infection is defined as HBV viral load ≥2000 IU/mL (104 copies/mL). Active 
HCV infection is defined as anti-HCV positive  and detectable HCV RNA. 
Methods of assessment 
For patients seropositive in HBV and/or HCV, virus replication status will be assessed by 
serum HBV DNA and/or HCV RNA in International units per milliliter (IU/mL) over time. 
Derivation or calculation of outcome variable 
For HBV/HCV seropositive patients, changes in virus replication will be measured by changes 
from baseline in HBV DNA level or in HCV mRNA levels on log scale, and HBV DNA/HCV 
mRNA status will be further categorized into detectable and undetectable.  
6.5.10 Monitoring for Drug Induced Liver Damage  
Patients will be monitored for clinical signs of liver impairment according to the FDA 
guidelines for drug induced liver injury (DILI) (55).  The levels of acceptable AST and ALT 
values must be adapted accordingly for patients with liver metastases or HCC.  Re-challenge 
of patients who developed DILI will be carefully explored by assessing the benefit/risk 
situation for each individual patient by the Safety Review Committee, taking the FDA 
guidelines into consideration.  
6.5.11 Oxygen Saturation  
Oxygen saturation will be measured at screening and when clinically indicated using pulse 
oximetry.  
6.5.12 Imaging for Interstitial Lung Disease (Pneumonitis)  
A thorax computed tomography (CT) (or MRI scan) taken at screening as part of the RECIST 
assessment (see Section 6.2.1) will also be able to document the lung parenchyma status at 
screening and can be used for comparison with another follow-up scan (with the same 
methodology as at baseline (CT or MRI), in case clinical symptoms of interstitial lung disease 
would occur during the trial. 
High resolution CT scan/MRI should be performed if clinically indicated by pulmonary 
symptoms any time during the study. 
For any new respiratory symptoms (cough, dyspnea, lower respiratory infection) not clearly 
explained by other factors (eg, dyspnea associated with substantial drop in hemoglobin), 
patients should have oxygen saturation measured. If <92%, the high resolution CT /MRI scan 
of the thorax should be repeated and pulmonary function tests should be performed. 
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6.6 
Total Blood Volume  
The maximum volume to be drawn in the 3-week periods for Cycles 1 and 2 will not exceed 
200 mL. In screening, later cycles and at EOT, volumes drawn will not exceed 100 mL. At the 
safety follow-up visit, the volumes drawn will not exceed 50 mL. 
7 
SAFETY MONITORING AND REPORTING  
7.1 
Definition of an Adverse Event  
The ICH E6(R2) GCP guideline defines an AE as any untoward medical occurrence in a patient 
or clinical investigation volunteer administered a pharmaceutical product, which does not 
necessarily have to have a causal relationship with this treatment.  An AE can, therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product. 
During the screening period, adverse events include only AEs, which are related to study 
specific procedures.  After enrolment into the study, an AE can include an undesirable medical 
condition occurring at any time, even if no IMP has been administered.  This includes an 
exacerbation of pre-existing conditions or events, intercurrent illnesses, drug interaction, 
SARS-CoV-2 vaccines (or any other vaccine) related AEs, or the significant worsening of the 
indication under investigation that is not recorded elsewhere on the eCRF under specific 
efficacy assessments. Anticipated fluctuations of pre-existing conditions, including the disease 
under study, that do not represent a clinically significant exacerbation or worsening will also 
be considered AEs. 
The AE definition includes events occurring from the time of the patient giving informed 
consent until the safety follow-up 90 days after last study treatment dose. 
Any SARSCoV2 vaccine related AEs should be recorded in the Adverse Events eCRF using 
the following terminology in the verbatim term: 
• For general reactions considered to be SARS-CoV-2 vaccine-related, report as 
“post-SARS-CoV-2 vaccine AEs” (eg, post SARS-CoV-2 vaccine fever).  
• For site reactions considered to be SARS-CoV-2 vaccine related, include the words 
“site” and “post-XX vaccine” (eg, post-SARS-CoV-2 vaccine site pain or 
post-SARS-CoV-2 vaccine site erythema). 
7.1.1 Toxicity Management Algorithms (According to SITC)  
Management algorithms have been developed to assist Investigators in assessing and managing 
specific groups of AEs.  The Consensus recommendations from the Society for Immunotherapy 
of Cancer (SITC) Toxicity management working group will be applied, which will include 
monitoring of organ systems, known to be potentially affected by immune activation. (See 
Table 5-5). 
7.1.2 Severity of Adverse Events  
Adverse events will be classified for severity by the Investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 (Table 7-1). 
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Table 7-1 
Common Terminology Criteria for Adverse Events v5.0  
Grade 
Description of severity 
0 
No change from normal or reference range 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities of daily living 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE 
AE=adverse event 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of severity to be performed.  Adverse events characterized as 
intermittent require documentation of onset and duration of each episode and their resolution 
or outcome. 
7.1.3 Causality of Adverse Events  
The relationship of an AE to administration of IMPs will be classified by the Investigator (or 
medically qualified designee) according to the following: 
• Related: The temporal relationship of the AE to IMP administration makes a causal 
relationship possible, and other medications, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the observed event. 
• Not related: The temporal relationship of the AE to IMP administration makes a causal 
relationship unlikely or remote, and other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the observed event. 
7.1.4 Follow-up of Adverse Events  
During the course of the study all AEs/SAEs will be proactively followed-up for each patient. 
Every effort should be made to obtain a resolution for all events, even if the events continue 
after the patient discontinued the study.  
Patients will undergo safety assessment at the end of study visit 90 days after the last dose of 
study treatment. 
If any AE remains unresolved after the patient’s last visit to the study, detailed evaluation and 
follow-up should be attempted until the AE has been resolved or a reasonable explanation for 
its persistence is found. 
7.1.5 Serious Adverse Event Assessment and Reporting to the Sponsor  
The Investigator (or medically qualified designee) must pursue and obtain information 
adequate both to determine the outcome of the AE and to assess whether it meets criteria for 
classification as a serious AE (SAE) requiring immediate notification to PRA Drug Safety. 
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• Description of the SAE, including criteria for seriousness. 
The additional information included in the SAE form must be provided to PRA Drug Safety as 
soon as it is available. The Investigator must provide an assessment of causality for each event 
reported. Upon receipt of the initial report, the Investigator’s causality assessment will be 
requested if it was not provided with the initial report. 
The Investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The Investigator must only report AEs that contribute to the seriousness 
criterion/criteria. Non serious but medically relevant sequelae and the treatments of AEs must 
be recorded separately, in the narrative section of the SAE report. 
A disease progression will not be considered an SAE and will be reported only as a progressive 
disease in eCRF, and not as an AE/SAE however if there are adverse events related to disease 
progression, then they along with disease progression should also be reported and recorded as 
per AE/SAE reporting conventions for this study.  
7.1.6 Adverse Events of Special Interest  
Adverse events of special interest (AESIs) for atezolizumab are outlined in Appendix 3.  
The Investigator must report AESIs in -atezolizumab treated patients, regardless of suspected 
relationship to IMPs, to PRA Drug Safety within 24 hours of knowledge of the event.  
Adverse events of special interest for KY1044: Infusion related reactions (IRRs) of Grade 3 
severity or above are deemed as Adverse events of special interest (AESIs) with KY1044 and 
they must also be reported, regardless of suspected relationship to IMPs, to the PRA Drug 
Safety within 24 hours of knowledge of the event. All other IRRs (Grade 1 and Grade 2) must 
also be captured in the eCRF as any other AEs recording and reporting conventions.  A periodic 
reassessment of AEs will be conducted as much as possible.  
Overdose (please refer to Section 7.2.2 Guidance for Overdose) and pregnancy are considered 
AESIs with both IMPs. 
7.1.7 Deaths  
All deaths and all AEs resulting in death during the study treatment period or 90 days follow-up 
period must be reported as SAE. 
The convention for recording death is as follows: 
• S/AE term: the disease or condition directly leading to death including the most precise  
cause of death such as hepatic failure or any other cause of death (World Health 
Organization Medical Certification of Cause of Death, 1979) 
• Outcome: fatal 
• CTCAE v5 Grade 5 
• All relevant clinical and safety information related to death including its time 
The only exception is if the cause of death is unknown (ie, sudden or unexplained death), in 
which case the AE term may be “death” or “sudden death” until the cause of death is 
determined or if the cause of death will not be possible to be determined. In all these cases, 
every effort must be made to provide appropriate medical history around the event and 
pertinent records relating to the fatal outcome. 
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7.1.8 Reporting to Competent Authorities, IECs/IRBs and Other Investigators  
The Sponsor will ensure that processes are in place for submission of reports of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring during the study to the 
Competent Authorities (CAs), IECs and other Investigators concerned by the IMP.  
Suspected AEs are any AEs for which there is a reasonable possibility that the IMPs caused 
the AE.  
As there is no clinical experience yet with KY1044, all SAEs will be reported as unexpected.  
Reporting will be done in accordance with the applicable regulatory requirements. 
Details of procedures and responsibilities will be documented in the SAE management plan for 
the study. 
7.2 
Important Medical Procedures to be Followed  
7.2.1 Medical Emergencies and Sponsor Contacts  
Each patient will be given a card at the enrolment visit and asked to carry it with them at all 
times in case of an emergency.  The card will include the following study information as a 
minimum: a patient identifier, IMP name and name and 24-hour telephone number of the 
Investigator (or medically qualified designee).  
If the Investigator needs urgent advice a 24/7 telephone line will be available to contact the 
Medical Monitor. The phone number will be provided in a separate manual. 
7.2.2 Guidance for Overdose  
Symptomatic overdose (serious or nonserious) with Investigational Medicinal Products (IMPs) 
• An overdose of IMP (KY1044) is defined as: increase of at least 30% of the dose to be 
administered in the specified duration or if the dose is administered in less than half the 
recommended duration of administration.   
• An overdose (accidental or intentional) with the IMP (atezolizumab) is an event 
suspected by the Investigator or spontaneously notified by the participant and defined 
as at least twice the intended dose within the intended therapeutic interval, adjusted 
according to the tested drug. 
In the unlikely event that an overdose of KY1044 is administered, the patient will be observed 
and treated symptomatically.  
KY1044 is expected to have a very slow clearance leading to a half-life (t½) of approximately 
3 weeks. If severe adverse reactions occur after an overdose of KY1044, then plasmapheresis 
to reduce the drug exposure may be considered. 
There is no information on atezolizumab overdose. Treat as clinically indicated. 
Cases of overdose should be documented as protocol deviations in the protocol deviation log. 
7.2.3 Protocol Deviations  
Any inadvertent protocol deviations that occur during the conduct of the study must be fully 
documented by the Investigator and the Sponsor notified. 
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7.2.4 Pregnancy  
All pregnancies and their subsequent outcome (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth or congenital abnormality) should be reported to PRA Drug 
Safety. 
7.2.4.1 Maternal Exposure  
If a patient becomes pregnant during the course of the study IMP should be discontinued 
immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the study 
treatment under investigation (IMP), may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages will be reported and handled as SAEs.  Elective abortions without complications 
should not be handled as AEs.  The outcome of a pregnancy should be followed up and 
documented even if the patient is withdrawn from the study. 
If a pregnancy occurs during exposure to study treatment or in the 90 days after discontinuing 
study treatment, then Investigators or other site personnel inform PRA Drug Safety within one 
day ie, immediately but no later than the end of the next business day of when he or she 
becomes aware of it. 
PRA Drug Safety works with the Investigator to ensure that all relevant information is provided 
to PRA Drug Safety as soon as it is available for SAEs (see Safety Management Plan) and 
within 30 days for all other pregnancies not considered to be SAEs. 
The same timelines apply when outcome information is available. 
7.2.4.2 Paternal Exposure  
Pregnancy of a patient’s partner is not considered to be an adverse event. However, any 
conception occurring from the date of dosing until 90 days after dosing will be reported to PRA 
Drug Safety and followed up for its outcome. 
8 
WITHDRAWAL OF PATIENTS FROM TREATMENT AND/OR 
THE STUDY  
Patients are free to withdraw from participation in the study at any time, without prejudice to 
their further care. In some circumstances, patients may be discontinued from study treatment 
but continue certain study assessments, as described in Section 8.1.  
The Investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being. 
Study treatment may be discontinued and/or patients may be withdrawn from the study under 
the following circumstances: 
1. Withdrawal of consent (see Section 8.1.1) 
2. Severe non-compliance with the protocol as judged by the Investigator 
3. Patients incorrectly initiated on study treatment (eg, patient has been determined to have 
met one or more of the exclusion criteria for study participation at study entry and 
continuing study treatment might constitute a safety risk). 
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4. AEs that, in the opinion of the Investigator or the Medical Monitor, contraindicate further 
dosing. (Patients on combination therapy who need to discontinue KY1044 due to AEs, 
also need to discontinue atezolizumab. In the case that a patient needs to discontinue 
atezolizumab due to acute infusion reactions or ADAs, KY1044 may be continued after 
discussion with the Medical Monitor)   
5. Pregnancy 
6. Disease progression, (unless, in the opinion of the Investigator, the patient is still receiving 
clinical benefit, whereby the patient will be treated until the confirmatory progressive 
disease per iRECIST (Note: patients with rapid tumor progression or with symptomatic 
progression that requires urgent medical intervention will not be eligible to continue to 
receive treatment) 
7. Study terminated by the Sponsor (see Section 3.7) 
8. 48 months of treatment 
9. Lost to follow-up 
Regardless of the reason for discontinuation, if possible, all patients should undergo End of 
Treatment procedures and enter the 90 days safety follow-up period. After the safety follow-up 
period, patients will have their End of Study visit (Section 8.2). All data available for the patient 
at the time of withdrawal and all reasons for withdrawal, must be recorded in the eCRF.  
8.1 
Follow-up of Patients Off Treatment  
If a patient needs to withdraw from study treatment for AEs or other safety reasons 
(reasons 3 and 4 above), but does not have disease progression, they will continue with tumor 
progression assessments in accordance with the study schedule until they progress as per 
iRECIST or until they start another anti-cancer therapy or when the overall end of the study is 
reached.  Patients who withdraw consent to treatment but who accept continued monitoring 
(see Section 6.2.1) will also continue in the same way.  Continuation of patients who stop 
treatment for reasons of non-compliance should be discussed between the Investigator and the 
Medical Monitor.  
All patients (all reasons 1 to 6 listed above) will be followed up at 3 monthly intervals 
(telephone followup is acceptable) to obtain survival information after the start of treatment. 
These data will be recorded in eCRF. 
8.1.1 Withdrawal of Informed Consent  
A patient who withdraws consent will always be asked about the reason(s) and assessed for the 
presence of any AEs.  If possible, AEs will be followed up as described in Section 7.  However, 
it is at the patient’s discretion to withdraw from treatment or from the study without giving any 
reason.  
If consent is withdrawn, the patient will not receive any further study treatment.  The patient 
will be specifically asked if they are withdrawing consent to further participation in the study 
including any further assessment for disease progression or follow-up of survival information.  
Note that the patient may be offered additional tests or tapering of certain treatments 
(co-medication) if withdrawn for safety.  
The Sponsor will continue to retain and use all research results that have already been collected 
for the study evaluation.  All biological samples that have already been collected may be 
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retained and analyzed at a later date for the fulfilment of the assessments defined in this 
protocol.  
8.1.2 Lost to Follow-up  
If a patient fails to return for study assessments for unknown reasons, every effort (eg, 
telephone calls, e-mail, letter) should be made to contact them.  Patients will be considered lost 
to follow-up only if no contact has been established by the time the study is completed such 
that there is insufficient information to determine the patient’s status at that time. 
Note: patients who refuse to continue participation in the study, including phone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.”  Investigators 
should document attempts to re-establish contact with missing patients throughout the study 
period.  
8.2 
End of Treatment and End of Study Procedures  
Patients discontinuing treatment or withdrawing from the study should return for the End of 
Treatment (EOT) assessments as soon as possible and latest within 21 days of the last dose of 
study treatment or within 21 days of the decision to discontinue study treatment, and then enter 
the follow-up period as indicated in (Section 8.2.1).  
If the decision to discontinue the patient occurs at a regular scheduled visit, that visit may 
become the EOT visit rather than having the patient return for an additional visit.  The eCRF 
should be completed, giving the reason for stopping the study treatment. 
8.2.1 Safety Follow-up Visit  
If possible, all patients will return for the safety follow-up visit 90 days after the last dose of 
study treatment.  Assessments will be performed as per schedule of assessments (see Table 6-1 
and Table 6-2). 
8.2.2 Follow-up Period  
All patients must have 90 days safety follow-up evaluations after the last dose of study 
treatment, including tumor or survival assessments.  Evaluations should be performed 
according to the schedule of assessments, and data collected added to appropriate eCRF pages. 
Patients who discontinue study treatment and do not have progressive disease per 
RECIST 1.1/iRECIST, but continue with study assessments will return for tumor assessments 
(Section 6.2.1) according to the study schedule.  Any relevant adverse event data reported 
during study visits will be recorded.  No other study procedures will be performed.  Tumor 
assessments will stop when disease progression is confirmed (RECIST 1.1), the patient 
commences further treatment for their malignancy, or when the overall end of the study is 
reached.  The date at which tumor monitoring is discontinued must be recorded. After 
discontinuation of tumor assessments patients will continue to be followed up for survival 
status at 3-monthly intervals. 
All patients who do not withdraw consent for the study will be followed up for survival unless 
they are lost to follow-up or the overall end of the study has been declared.  
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8.2.3 End of Study for Individual Patients  
The end of study for each patient will be either:  
• At the end of the 90 day safety follow-up period after stopping treatment, for the last 
patient in the study  
• At the overall end of the study for all patients, who are still in follow-up- for PFS and 
or survival as determined by the Sponsor, is defined as the date of the last visit of the 
last participant in the study or last scheduled procedure shown in the Schedule of 
Activities for the last participant in the trial globally. 
The end of the study will be recorded in the eCRF. 
8.3 
Replacement Policy  
8.3.1 Phase 1 Dose Escalation Parts:  
Patients will not be replaced on study. However, if a patient is considered to be non-evaluable 
for the dose escalation, enrolment of a new patient to the current cohort will be considered if 
there is less than the required number of evaluable patients (see Section 5.4.5.1).  Enrolment 
of new patients may be considered until at least the minimum number or at most the maximum 
number of evaluable patients is achieved within the cohort.  Minimum and maximum numbers 
of evaluable patients per cohort are defined in Section 4.1.1. 
8.3.2 Phase 2 Part:  
During the Phase 2 part no replacements of patients will be needed. 
9 
STATISTICAL CONSIDERATIONS  
9.1 
Modified Toxicity Probability Interval (mTPI-2) Design  
9.1.1 Rationale for mTPI-2 Design  
The rationale for deciding the starting dose and investigational dose range are discussed in the 
previous Section 5.4.1. In the trial, dose escalation/de-escalation decisions will use predefined 
DLT criteria (Section 5.5) and be based on the mTPI-2 design (49) with precalculated decisions 
that are displayed in Figure 9-1 (obtained via U-Design v1.0, udesign.laiyaconsulting.com).  
Figure 9-1 consists of all the dose-escalation rules for the trial. The trial is conducted aiming 
at a target 30% DLT rate (pT=30%) for the MTD with an acceptable DLT range of 25% to 
35%, and a maximum sample size of 36 patients with a cohort size of 3. To begin the trial, treat 
three patients on the starting dose. After observing all the outcomes of each cohort (or as 
specified in Section 5.4.3 if cohort modification is required), dose-escalation, de-escalation or 
staying at the current dose will be guided by the decision table and the SRC.  
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Figure 9-1: 
mTPI-2 Decision Table  
Sample size=36, Target toxicity probability=0.3, epsilon 1=0.05, epsilon 2=0.05 
 
 
* Column indicates the number of patients treated. Row indicates the number of patients with DLTs 
* E: Escalate to the next higher dose; S: Stay at the same dose; D: De-escalate to the previous lower dose; DU: De-escalate to 
the previous lower dose and the current dose will never be used again in the trial. Two parameters e1 and e2 are set at default 
values (Guo. et al. 2017) of 0.05.  
The mTPI-2 design is chosen for this trial because it has demonstrated superior operating 
characteristics when compared with standard methods, such as the 3+3 design, and is easy to 
implement with precalculated dose decision rules (56).  
Section 9.1.2 presents comprehensive simulation results of mTPI-2 and its operating 
characteristics. See Appendix 4 for the detailed technical summary of the design and 
simulations. 
9.1.2 Simulation Results  
Simulations were performed via U-Design v1.0 to assess the performance of mTPI-2 based on 
the setting of this trial.  There are seven prespecified doses and the stating dose is 0.8 mg. The 
sample size is 36 and patients are enrolled in cohorts of size 3. The MTD target toxicity 
probability is pT=0.3 and the choices of e1 and e2 are both 0.05.  Six different scenarios were 
investigated in the simulation studies, as shown in Table 9-1 and Figure 9-1.  For each scenario, 
5000 simulated trials were conducted.  
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Table 9-1: 
Six Scenarios Used in Simulation Results  
Index 
pT 
nsim 
Dose (mg) 
0.24 
0.8* 
2.4 
8 
24 
80 
240 
1 
0.3 
5000 
0.001 
0.005 
0.022 
0.0831 
0.269 
0.599 
0.858 
2 
0.3 
5000 
0.668 
0.832 
0.924 
0.968 
0.987 
0.995 
0.998 
3 
0.3 
5000 
0.002 
0.008 
0.039 
0.168 
0.500 
0.832 
0.961 
4 
0.3 
5000 
0.001 
0.018 
0.269 
0.881 
0.993 
0.9997 
0.99998 
5 
0.3 
5000 
0.063 
0.083 
0.109 
0.142 
0.182 
0.231 
0.289 
6 
0.3 
5000 
0.039 
0.083 
0.168 
0.310 
0.500 
0.690 
0.832 
*starting dose 
The simulation results are presented in Figure 9-2 and Table 9-2.  
Figure 9-2 illustrates the performance of mTPI-2 in terms of the probability of selecting the 
MTD, probability of toxicity, probability of selecting a dose higher than the MTD, and the 
probability of no selection. 
Table 9-2 provides a summary of these results.  The full details of each of the six simulations 
is presented in Appendix 4.  
Figure 9-2: 
mTPI-2 Performance Across the Six Scenarios  
 
 
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Table 9-2: 
Summary of mTPI-2 Performance  
 
mTPI-2 
Probability of Selecting the MTD 
0.712±0.223 
Probability of Toxicity 
0.318±0.199 
Probability of Selecting Dose-over-MTD 
0.031±0.04 
Probability of No Selection 
0.167±0.408 
MTD=maximum tolerated dose; mTPI-2=Modified Toxicity Probability Interval Design No 2 
9.2 
Sample Size Determination  
Sample Size Determination Phase 1: 
A maximum of 36 patients will be used for each Phase 1 dose escalation component (single 
agent and combination therapy).  The total number of patients included across all cohorts in 
the Phase 1 dose escalation and enrichment parts will be approximately 150. 
Phase 2: 
The initial Phase 2 dose assessment part in one or more specific indication(s) (see 
Section 3.1.4) will include approximately 20 patients (ie, 15 anti-PD-(L)1 naïve and where 
feasible five anti-PD-(L)1 pre-treated patients) at each of two dose levels of KY1044 (as single 
agent or in combination with atezolizumab).  
Once the RP2D is established, Phase 2 may be extended and approximately 15 patients will be 
enrolled initially in each tumor type in the anti-PD-(L)1 naïve subgroup per each indication in 
either the single agent cohort or the combination cohort.  
The full sample size of specific indications in Phase 2 of the study will be based on early 
evaluation of ORRs and only indications with promising response rates will be expanded 
further (up to 40 per subgroup).  The Go-no-go decision criteria for cohort expansion will be 
based on historical ORR rates and a target ORR response rate for KY1044 treatment. No formal 
statistical testing will be performed. Instead, confidence intervals will be constructed around 
the objective response rate observed in each cohort, and this will enable decisions to be made 
around the likely success of future studies.  
Historical response rates for monotherapy with ICI in the second line metastatic setting are in 
the region of 15% to 25% for anti-PD-(L)1 inhibitors as monotherapy across the different 
indications and will be even lower in more advanced stages of disease (≥3 lines of anti-cancer 
treatment in the metastatic setting).  
In order to illustrate the impact of sample sizes of 15 or expansion to 40 on the width of the 
confidence intervals, example evaluations are given for these 3 situations (ORR of 13% (3 and 
more lines of prior therapies in the advanced metastatic setting and 20% and 33% ORR for 
2nd line metastatic setting) for cohort sizes of either 15 or 30 patients are given below:   
• If the observed response rate is 13% (2/15), the 2-sided 80% confidence interval will 
be (4%, 32%). 
• If the observed response rate is 20% (3/15), the 2-sided 80% confidence interval will 
be (8%, 39%). 
• If the observed response rate is 33% (5/15), the 2-sided 80% confidence interval will 
be (17%, 53%). 
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• If the observed response rate is 13% (5/40), the 2-sided 80% confidence interval will 
be (6%, 22%). 
• If the observed response rate is 20% (8/40), the 2-sided 80% confidence interval will 
be (12%, 30%). 
• If the observed response rate is 33% (13/40), the 2-sided 80% confidence interval will 
be (23%, 44%). 
In the anti-PD-(L)1 pre-treated subgroup, initially up to 10 patients will be recruited in each 
indication in either the single agent cohort or the combination cohort. These patients will have 
already progressed on previous immunotherapy; hence any individual response would indicate 
a proof of mechanism in these patient groups. If signs of efficacy have been observed in at least 
one patient any of these anti-PD-(L)1 pre-treated indications a further expansion up to 
40 patients per cohort will be considered. 
This number of patients, also offers the opportunity to evaluate further the safety and PK/PD 
of the chosen MTD/RP2D of KY1044 as single agent or in combination with atezolizumab. 
Overall a maximum of 412 patients may be enrolled into the study (Phase 1 and 2). 
9.3 
Analysis Set  
9.3.1 Full Analysis Set  
The full analysis set (FAS) will consist of all patients who are allocated to study drug, 
regardless of treatment ultimately received. The FAS will generally be the primary population 
of interest for efficacy endpoints. 
9.3.2 Safety Set  
The safety set will consist of all patients who take at least one dose of study drug. 
Any additional analysis sets will be defined in the Statistical Analysis Plan (SAP). 
9.4 
Statistical Analyses  
Full details of the statistical analyses of the data will be documented in an agreed SAP, which 
will be finalized prior to locking the database. There will be a preliminary analysis of the study 
data according to the requirements defined in Section 3.5. Final data analysis will be performed 
at the end of the study. 
Phase 1 will be reported by dose group(s) within KY1044 single agent and KY1044 
combination groups. 
Phase 2 of the study will be reported by indication and dose group(s) within KY1044 single 
agent and KY1044 combination groups, split by anti-PD-(L)1 naïve and pre-treated groups. 
Wherever possible, patients with the same tumor type who have received the recommended 
dose(s)/schedule(s) of KY1044 as single agent or in combination with atezolizumab will be 
pooled for analysis. 
In general, continuous variables will be summarized by number of patients, mean, standard 
deviation (StD), median, and minimum, maximum. Categorical variables will be summarized 
by frequency counts and percentages. 
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9.4.1 Demographic and Baseline Characteristics  
Demographic variables (age, gender and race), medical history, physical examination and 
ECOG performance status will be summarized. Body weight, height and BMI will also be 
summarized. 
9.4.2 Efficacy Analysis  
9.4.2.1 Analysis of Primary Endpoints  
The primary endpoint in Phase 2 is ORR per RECIST 1.1. ORR will be assessed using 
descriptive statistics for categorical data by indication along with the associated 2-sided exact 
80%  and 95% CIs . The primary endpoints in Phase 1 are safety endpoints (see Section 9.4.3). 
9.4.2.2 Secondary Analysis of Secondary Endpoints  
Secondary efficacy endpoints include: 
• ORR per RECIST 1.1 (Phase 1 only) 
• ORR and PFS per iRECIST (Phase 1 and Phase 2) 
• Best Overall Response (BOR), PFS and DOR per RECIST 1.1  
• Survival rate at 12 and 24 months 
Response endpoints will be summarized using descriptive statistics for categorical data by 
treatment group along with the associated 2-sided exact 95% CIs. 
Time-to-event endpoints (eg, DOR, PFS) will be summarized using the Kaplan-Meier method 
and displayed graphically where appropriate.  Median event times and 2-sided 95% confidence 
interval for each median will be provided. For survival rate at 12 and 24 months, Kaplan-Meier 
estimates with 95% CIs will be presented. 
Pharmacodynamic endpoints include: 
• Presence and/or concentration of anti-KY1044 and anti-atezolizumab antibodies 
• Presence of TILs as determined by expression of ICOS, FOXP3 and CD8 cells (IHC) 
Continuous endpoints, eg, the concentration of anti-KY1044 and anti-atezolizumab antibodies 
will be summarized using summary statistics, number of patients (n), mean, StD, median, 
minimum and maximum values. 
Categorical endpoints, eg, Presence of anti-KY1044 and anti-atezolizumab antibodies will be 
summarized using frequency counts and percentages. 
The association between expression of ICOS and other immunological markers with efficacy 
endpoints will be explored graphically.  
9.4.2.3 Analysis of Exploratory Endpoints  
The following exploratory endpoints will be evaluated using summary statistics and frequency 
counts as applicable. Full details of exploratory analyses including graphical presentations will 
be described in the Statistical Analysis Plan. 
• Expression of immune- and response-related markers such as (but not limited to) 
PD-L1, CD163, CD68 by IHC  
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• mRNA gene signature (transcriptomics/ Nanostring) with special interest in IFN gene 
signature (PanInflammatory panel and/or IO360 panel) 
• Peripheral, soluble ligands and cytokine levels (eg, IFNγ, TNFα, GM-CSF) contingent 
on availability of assay (ie, SIMOA) 
• Phenotype and markers of IC activation in peripheral blood (eg, CD3, CD8, CD4, TRegs, 
CD4 memory cells, CD25, FOXP3, CD45RA, ICOS, CD14. CD45, CD56, CD19 and 
ICOSLG) (FACS or ChipCytometry) 
• PBMCs gene signature (RNA) (transcriptomics Nanostring) 
• ICOS Receptor Occupancy (RO) in PBMCs (KY1044 as single agent in Phase 1 only) 
9.4.3 Safety Analysis  
The Phase 1 primary and Phase 2 secondary safety endpoints include: 
• Safety: Incidence and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and ECGs 
• Tolerability: Dose interruptions, reductions and dose intensity 
For Phase 1, the primary endpoints will also include: 
• The incidence of DLTs with KY1044 as single agent during the first 21 days of 
treatment  
• The incidence of DLTs with KY1044 in combination with atezolizumab during the first 
21 days of treatment 
All AEs in the clinical trial database will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 21.0 or higher, which will be used to summarize 
AEs by primary system organ class (SOC) and preferred term (PT).  All AEs will be displayed 
in listings. 
A treatment emergent adverse event (TEAE) is defined as an AE observed after starting 
administration of the specific treatment.  If a patient experiences an event both prior to and 
after starting administration of a treatment, the event will be considered a TEAE (of the 
treatment) only if it has worsened in severity (ie, it is reported with a new start date) after 
starting administration of the specific treatment, and prior to the start of another treatment, if 
any.  All TEAEs collected during the investigational period will be summarized. 
Treatment-related AEs/SAEs coded by primary SOC and PT will be summarized in those 
receiving at least one infusion of KY1044.  
Additional summaries by severity of AEs/SAEs will also be produced. 
 Actual and change from baseline data for vital signs and ECG parameters will be reported 
using summary statistics.  
  
When relevant, for laboratory variables, descriptive statistics for results and changes from 
baseline will be provided during the on-treatment period. These analyses will be performed 
using local measurements for laboratory variables. Clinical laboratory results will be graded 
according to NCI CTCAE version 5.0, when applicable. Number (%) of participants with 
laboratory abnormalities (all grades and by grade) using the worst grade during on-treatment 
period will be provided for the all-treated population. 
  
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When the NCI CTCAE version 5.0 scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
The number of dose interruption, reductions and incidence of DLTs will be summarized. 
Continuous endpoints, will be summarized using summary statistics, number of patients (n), 
mean, StD, median, minimum and maximum values. 
Categorical endpoints, will be summarized using frequency counts and percentages. 
9.4.4 Pharmacokinetic Analysis  
The serum PK of KY1044 as a single agent, in combination with atezolizumab and for 
atezolizumab alone will be characterized using no compartmental analysis. The following PK 
measures will be calculated, whenever possible, from serum concentrations: 
• Cmax: Maximum concentration (for atezolizumab - only one timepoint of serum 
concentration at the end of infusion) 
• tmax: Time of the maximum concentration (obtained without interpolation) 
• Cmin: Trough concentrations 
• λz: Terminal elimination rate constant (whenever possible) 
• AUC0-last: Area under the concentration-time curve calculated using 
• Linear trapezoidal summation from time 0 to time last, where “last” is the time of 
• The last measurable concentration 
• AUC0-inf: Area under the concentration-time curve from 0 to infinity, 
• Calculated using the formula: AUC0-inf = AUC0-last + Clast/ λz, where λz is the apparent 
terminal elimination rate constant 
• Clearance 
• Volumes of distribution 
• t½: Half-life  
For both KY1044 and atezolizumab, all peak (end-of-infusion) and trough (pre-infusion) 
concentrations will be tabulated. For KY1044 peak and trough concentrations will be tabulated 
separately for use as a single agent and for combination with atezolizumab. 
Besides listings of pharmacokinetic measures for individual patients, all measures will be 
summarized. The summaries will include estimates of not only central tendency but variability 
such as Standard Error. For concentrations, geomeans will be provided. For tmax median (and 
range) and for half-lives, arithmetic means will be provided. Besides listings of concentrations, 
noncompartmental analysis (NCA) tables, charts illustrating the concentration-time profiles 
will be generated. 
Additional pharmacokinetic analyses may be undertaken. For instance, if the tables of peak and 
trough concentration (or anti-drug antibody) indicate some kind of interaction between 
KY1044 and atezolizumab, pharmacokinetic modelling of these data may be undertaken.   
Exploratory analyses may also be conducted to estimate dose proportionality and accumulation 
ratio on relevant parameters. 
Population PK analysis may be performed if deemed relevant and applicable, and the results 
will be summarized in a stand-alone report if deemed relevant. In this context, further 
exposure-response analyses may also be conducted. 
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9.4.5 Handling of Withdrawals and Missing Data  
There will be no imputation of missing data values. Data on patients who withdraw early will 
be summarized up until the time of withdrawal.  
9.4.6 Protocol Deviations  
Any inadvertent protocol deviations that occur during the conduct of the study must be fully 
documented by the Investigator and the Sponsor notified. The statistical impact of significant 
protocol deviations will be assessed, and the details provided in the SAP. 
10 
QUALITY CONTROL AND QUALITY ASSURANCE  
10.1 Monitoring  
The Sponsor and its selected CRO(s) will ensure the assignment of appropriately qualified 
monitors who will be responsible for visiting sites at regular intervals throughout the study in 
order to verify adherence to the protocol, completeness and accuracy of the data entered in the 
eCRFs and to perform Source Data Verification (SDV) of data recorded in the eCRFs, in 
accordance with applicable regulations, standard operating procedures (SOPs) and the 
monitoring plan. 
The Investigator is responsible for the validity of all data collected at the site. 
The eCRF is expected to be completed an ongoing basis to allow regular review by the study 
monitor, both remotely and during site visits, and to ensure information is available for safety 
reviews in a timely fashion. 
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the Investigator who should ensure that appropriate action designed to prevent 
recurrence of the detected deviations is taken and documented. Additionally, the monitor will 
provide a written report, including copies of correspondence with the Investigator and site 
study staff, to the Sponsor, following each visit. 
The frequency and nature of monitoring will be determined by the Sponsor prior to 
commencement of the study. The monitor must have direct access to patients medical records 
and other study-related source documents. The Investigator and study staff will be expected to 
co-operate with the monitor, to be available during the monitoring visit to answer questions 
and to ensure that any problems detected are resolved in a timely manner. 
10.2 Audits and Inspections  
In accordance with ICH E6(R2) GCP guidelines and applicable regulations, the Sponsor may 
decide to conduct audits at investigational sites participating in this study. During the audit, the 
Sponsor auditors or their representative will assess site’s facilities (eg, pharmacy, drug storage 
areas, laboratory), meet with the Investigator and study personnel and review study-related 
records in order to evaluate the study compliance with the Sponsor/vendor SOPs, protocol, ICH 
E6(R2) GCP guideline and applicable parts of 21 CFR and local regulations. The Investigator 
must also agree to inspection of all study documents by regulatory authorities and the IEC/IRB.  
The Investigator and site personnel should be available to provide information and answer 
questions as necessary. Should the Investigator be notified of a regulatory inspection involving 
this study, they must notify the Sponsor immediately. 
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10.3 Data Quality Assurance  
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system (ISF) of all study-related (essential) documentation, suitable for 
review and inspection at any time by representatives of the Sponsor and/or applicable 
regulatory authorities. The ISF must consist of those documents that individually or 
collectively permit evaluation of the conduct of the study and the quality of the data produced. 
Quality assurance and quality control systems will be implemented and maintained using 
written SOPs to assure that the trial is conducted, and that the data are generated, recorded and 
reported in compliance with the protocol, GCP and the applicable regulatory requirements. 
Quality control procedures will be applied to each stage of data handling to ensure that all data 
are reliable and have been processed correctly. 
11 
REGULATORY AND ETHICAL CONSIDERATIONS  
This study will be conducted in compliance with the protocol, ICH E6(R2) GCP guideline, the 
applicable regulatory requirement(s) and the general principles of the Declaration of Helsinki. 
11.1 IEC/IEB Approval  
The study protocol, Patient Information Sheet, Informed Consent Form, Investigator Brochure, 
available safety information, patient recruitment procedures (eg, advertisements), information 
about payments and compensation available to the patients and documentation evidencing the 
Investigator’s qualifications should be submitted to the IEC/IRB for ethical review and 
approval as required by local regulations, prior to the study start. The written approval should 
identify all documents reviewed by name and version. 
The Investigator/Sponsor will follow all necessary regulations to ensure appropriate, initial, 
and ongoing, IEC/IRB study review. The Investigator/Sponsor (as appropriate) must submit 
and, where necessary, obtain approval from the IEC/IRB for all subsequent protocol 
amendments and changes to the patient information sheet or informed consent documents. 
Investigators will be advised by the Sponsor whether an amendment is considered substantial 
or non-substantial and whether it requires submission for approval or notification only to an 
IEC/IRB. 
The Investigator or the Sponsor as applicable will notify the IEC/IRB of the end of the study 
or early termination if the study within required timelines. A reason for the early termination 
will be provided.  
Safety updates for KY1044 will be prepared by the Sponsor as required, for submission to the 
relevant IEC/IRB. 
11.2 Regulatory Approval  
As required by local regulations, the Sponsor will ensure approval of the appropriate regulatory 
bodies is obtained prior to study initiation. If required, the Sponsor will also ensure that the 
implementation of substantial amendments to the protocol and other relevant study documents 
happens only after approval by the relevant regulatory authorities. 
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The Sponsor will notify the relevant regulatory authorities about end of study or early study 
termination within required timelines and in case of early termination will provide the reasons 
for it. 
Safety updates for KY1044 will be prepared by the Sponsor as required, for submission to the 
relevant regulatory authority. 
11.3 Patient Confidentiality  
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other trial-related data. Personal 
information will be treated as confidential, but may need to be reviewed by authorized 
representatives of the Sponsor (eg, monitor or auditor) or the regulatory authorities. The 
patient’s consent to direct access to his/her original medical records for data verification 
purposes must be obtained prior to a patient’s participation in the trial. 
For all patients enrolled into the trial, the Investigator must maintain a list of names and 
identifying information (eg, date of birth, patient identification code, date of study enrollment). 
The patient identification code list will be kept by the Investigator in the Investigator Site File. 
11.4 Protocol Amendments  
The Investigator will not implement any changes to the protocol without approval from the 
Sponsor, the regulatory authority and IRB/IEC (and other approving bodies), if required, except 
where necessary to eliminate immediate hazards to the trial patients, or when the changes 
involve only logistical or administrative aspects of the trial. 
The Sponsor will not permit or approve any waivers from the approved protocol. 
Modifications to the protocol will be made as a protocol amendment. 
Substantial amendments to the protocol are those likely to have a significant impact on: 
• The safety, or physical or mental integrity of the patients; 
• The scientific value of the trial. 
Non-substantial amendments (eg, changes in telephone numbers, etc.) will not require prior 
submission to the regulatory authority and the IRB/IEC or other approving body unless 
requested. 
11.5 Principal Investigator Responsibilities  
Principal Investigator (Investigator) responsibilities are set out in the ICH E6(R2) Guideline 
for GCP and in the local regulations. Sponsor staff or an authorized representative will evaluate 
and approve all Investigators who in turn will select their staff. 
The Investigator must ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions. 
The Investigator will maintain a list of sub-Investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties. 
If the Investigator contracts any vendors to work on the study he/she must inform the Sponsor 
or an authorized Sponsor’s representative and ensure appropriate oversight of said vendors. 
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The Investigator is responsible for the validity, maintenance and archiving of all data collected 
at site. 
12 
DATA HANDLING AND RECORD KEEPING  
12.1 Data Capture  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. The PI is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported and should ensure that study staff are adequately trained and 
have sufficient time to fulfil their responsibilities.  
An eCRF Medidata RAVE, Version 2017.2.3, a 21 CFR Part 11-compliant data capture system 
provided by Medidata will be used for this study.  
The results from screening and data collected during the study will be entered into MediData 
RAVE by the Investigator. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate. The Investigator will electronically sign the eCRF indicating that the data in the 
eCRF have been assessed and agreed.  
At the Sponsor’s discretion, SDV may be performed on all data items or a percentage thereof. 
12.2 Data Management  
Detailed data entry instructions will be provided in the eCRF Completion Guidelines. 
Computerized data cleaning checks will be used in addition to manual review to check for 
discrepancies and to ensure consistency of the data. The data entered are subsequently verified. 
An electronic audit trail system will be maintained within the data capture system to track all 
data changes in the database once the data have been saved initially into the system or 
electronically loaded. 
Regular backups of the electronic data will be performed. 
12.3 Record Archiving and Retention  
All original source documents supporting entries in the eCRF must be included in the patient’s 
medical file and retained so that integrity and accessibility are maintained.  
The Sponsor will inform the Investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements. The minimum retention time will meet the 
strictest standard applicable to that study center for the study, as dictated by any institutional 
requirements or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The ISF must be retained in accordance with ICH E6(R2) GCP, 21 CFR 312.62(c) or longer if 
required by applicable regulatory requirements or by the Sponsor. The PI or his/her institution 
should retain essential documents until written instructions for their destruction are obtained 
from the Sponsor. If the PI wishes to assign the study records to another party or to another 
location, they must obtain prior approval in writing from the Sponsor. Any transfer of records 
must be fully documented. 
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13 
FINANCING AND INSURANCE  
This study will be financed by Kymab Ltd who are the Sponsor of the study.  Individual site 
financing and insurance will be subject to a separate written agreement between the Sponsor 
and applicable parties. 
14 
PUBLICATION POLICY  
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential. The Sponsor is committed to 
publish the data arising from this study at a suitable time irrespective of the study outcome. 
Results from the study will be published/presented as per the Sponsor’s publication policy. 
The Sponsor will ensure that any applicable requirements to register the study or publish the 
results arising are met. 
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15 
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patients with advanced cancers. NCT02904226. ASCO 2018 Annual Meeting; 2018; 
Chicago, Illinois.  
49. Guo W, Wang S-J, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design 
addressing Ockham’s razor: mTPI-2. Contemp Clin Trials. 2017 Jul;58:23-33. 
50. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response 
Criteria. Clin Cancer Res. 2009 Dec 1;15(23):7412-20.  
51. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009 Jan;45(2):228-47.  
52. Schwartz LH, Litière S, de Vries E, Ford R, Gwyther S, Mandrekar S, et al. RECIST 1.1-
Update and clarification: From the RECIST committee. Eur J Cancer. 2016 Jul;62:132-7. 
53. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 
2017 Mar;18(3):e143-52.  
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54. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 
Dec;5(6):649-55.  
55. Food and Drug Administration. Guidance for Industry. Drug Induced Liver Injury: 
Premarketing Clinical Evaluation. Maryland: Food and Drug Administration; 2009 p. 28.  
56. Ji Y, Wang S-J. Modified Toxicity Probability Interval Design: A Safer and More 
Reliable Method Than the 3 + 3 Design for Practical Phase I Trials. J Clin Oncol. 2013 
May 10;31(14):1785-91.  
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16 
APPENDICES  
 
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16.1 Appendix 1 - RECIST 1.1 (Eisenhauer et al., 2009) and Update 2016 
(Schwarz et al., 2016)  
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16.2 Appendix 2 - iRECIST  
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16.3 Appendix 3 - Adverse Events of Special Interest  
Atezolizumab Adverse Events of Special Interest 
Adverse Events of Special Interest (Immediately Reportable to the Sponsor): 
Adverse events of special interest are required to be reported by the investigator to the Sponsor 
immediately (ie, no more than 24 hours after learning of the event). Adverse events of special 
interest for this study are as follows: 
• Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either 
an elevated bilirubin or clinical jaundice, as defined by Hy's Law (see reference and 
definition of Hy’s Law in KY1044-CT01 protocol, Section 6.5.10): 
• Suspected transmission of an infectious agent by the study treatment, as defined below: 
Any organism, virus, or infectious particle (eg, prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a medicinal product.  
This term applies only when a contamination of study treatment is suspected. 
• Pneumonitis 
• Colitis 
• Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis 
• Hepatitis, including AST or ALT 10  ULN 
• Systemic lupus erythematosus 
• Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis and meningoencephalitis 
• Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, influenza-like illness, systemic inflammatory response syndrome and 
immune-mediated reactions 
• Nephritis 
• Ocular toxicities (eg, uveitis, retinitis, optic neuritis) 
• Myositis 
• Myopathies, including rhabdomyolysis 
• Grade 2 cardiac disorders (eg, atrial fibrillation, myocarditis, pericarditis) 
• Vasculitis 
• Autoimmue hemolytic anemia 
• Severe cutaneous reactions (eg, Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
 
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16.4 Appendix 4 - Modified Toxicity Probability Interval Design No 2 
(mTPI2) Design and Simulations  
The mTPI-2 design 
The modified toxicity probability interval design no 2 (mTPI-2) design1 is an extension of the 
modified toxicity probability interval design (mTPI) design 2 , which uses a Bayesian 
hierarchical model and a decision framework for dose finding.  In mTPI, decision rules are 
based on calculating the unit probability mass (UPM) of three intervals (0, pT - e1), 
(pT - e1, pT + e2) and (pT + e2, 1) that correspond to under-, proper-, and over-dosing intervals, 
respectively.  Here, pT is the target toxicity probability, and e1 and e2 are small fractions, such 
as 0.05, to account for the uncertainty around the true target toxicity.  The proper-dosing 
interval (pT - e1, pT + e2) is also called the equivalence interval.  Assume at a given moment of 
the trial, a dose is used to treat patients.  That dose is referred to as the “current dose”.  Given 
an interval and a probability distribution, the unit probability mass (UPM) of that interval is 
defined as the probability of the interval divided by the length of the interval.  Under an optimal 
Bayesian decision framework2, the mTPI design calculates the UPMs for the three dosing 
intervals given the observed toxicity data at the current dose and selects the one with the largest 
UPM.  The selected interval is associated with a decision of escalation (E), stay (S), or 
de-escalation (D), respectively, if it is the under-dosing interval, the equivalence interval, or 
the over-dosing interval.  
Because of its simplicity and transparency as 3+3 (all decisions could be pre-tabulated for 
examination as 3+3), and also its better performance than 3+33, the mTPI design has been 
applied in real-world trials, including trials sponsored by Merck4,5, Pfizer6, and Bristol-Myers 
Squibb7.  
The mTPI-2 design extends mTPI with a refined decision framework1.  It further partitions the 
under-dosing interval (0, pT - e1) and the over-dosing interval (pT + e2,1) into adjacent 
subintervals with equal length of (e1 + e2), the length of the equivalence interval.  As a result, 
it is nimbler, with fewer “Stay” decisions than mTPI (Figure 16-1).  For example, mTPI gives 
decision “Stay” when three out of six patients have dose limiting toxicity (DLT) and if pT=0.3; 
whereas, mTPI-2 gives decision “De-escalation”.  As a result, mTPI-2 yields safer and more 
ethical decisions, with similar accuracy in identifying the maximal tolerated dose (MTD) 
compared to mTPI1. 
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Figure 16-1: Example mTPI-2 Decision Table  
 
Column indicates the number of patients treated. Row indicates the number of patients with DLTs. 
Decisions for both mTPI and mTPI-2.  For each column (the number of patients treated), there are two 
sub-columns listing the decisions of mTPI and mTPI-2 side by side.  Here, the target toxicity probability 
pT=0.30, e1=0.05 and e2=0.05.  
mTPI-2 Simulation Results 
Simulations were performed via 
to assess the performance of mTPI-2 based on 
the setting of this trial.  There are seven prespecified doses and the stating dose is 0.8 mg. The 
sample size is 36 and patients are enrolled in cohorts of size 3.  The MTD target toxicity 
probability is pT=0.3 and the choices of e1 and e2 are both 0.05.  Six different scenarios were 
investigated in the simulation studies, as shown below (Table 16-1).  For each scenario, 
5000 simulated trials were conducted.  
Table 16-1: 
Six Scenarios used in Simulation Results  
Index 
pT 
nsim 
Dose (mg) 
0.24 
0.8* 
2.4 
8 
24 
80 
240 
1 
0.3 
5000 
0.001 
0.005 
0.022 
0.0831 
0.269 
0.599 
0.858 
2 
0.3 
5000 
0.668 
0.832 
0.924 
0.968 
0.987 
0.995 
0.998 
3 
0.3 
5000 
0.002 
0.008 
0.039 
0.168 
0.500 
0.832 
0.961 
4 
0.3 
5000 
0.001 
0.018 
0.269 
0.881 
0.993 
0.9997 0.99998 
5 
0.3 
5000 
0.063 
0.083 
0.109 
0.142 
0.182 
0.231 
0.289 
6 
0.3 
5000 
0.039 
0.083 
0.168 
0.310 
0.500 
0.690 
0.832 
 
*starting dose 
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3. 
Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable 
method than the 3 + 3 design for practical phase I trials. J Clin Oncol 2013 
May;31(14):1785-91. 
4. 
Atkins MB, Hodi FS, Thompson JA, McDermott DF, Hwu WJ, Lawrence DP, et al. 
Pembrolizumab plus pegylated interferon alfa-2b or ipilimumab for advanced melanoma 
or renal cell carcinoma: dose-finding results from the Phase 1b KEYNOTE-029 study. 
Clin Cancer Res 2018 Apr;24(8):1805-15. 
5. 
Brana I, Berger R, Golan T, Haluska P, Edenfield J, Fiorica J, et al. A parallel-arm phase 
I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT 
inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor 
MK-0752, in patients with advanced solid tumours. Br J Cancer 2014 
Nov;111(10):1932-44. 
6. 
Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, et al. 
Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: 
a non-randomised, open-label, dose-finding, and dose-expansion Phase 1b trial. Lancet 
Oncol 2018 Mar;19(3):405-15. 
7. 
Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. 
Nivolumab in combination with platinum-based doublet chemotherapy for first-line 
treatment of advanced non-small-cell lung cancer. J Clin Oncol 2016 Sep;34(25), 
2969-79. 
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16.5 Appendix 5 - Protocol Amendments  
This is the seventh version of the protocol. To date, there have been six protocol amendments. 
Details of the key changes made in each version are provided in the table below. 
Protocol 
version 
Effective 
date 
Section 
Change 
1.0 
24th Aug 
2018 
All 
No change - new protocol 
2.0  
14th Nov 
2018 
FDA requested changes 
Section 1.6.2 
Start of corticosteroid therapy was clarified 
Section 4.2 
Clarification of terminology “standard therapy” and 
protocol in and exclusion criteria (#4) 
Clarification if patients will be enrolled who are eligible to 
receive therapies with known clinical benefit 
Section 5.5 
Update DLT criteria 
Section 3.3 
Define pre-specified stopping rules to pause enrolment 
Section 5 
Revise protocol to align management of toxicities according 
to Appendix 1 and Table 5-5 of protocol 
Section 5 
Table 5-2 revised for administration sets 
Section 6 
Addition 
of 
antiacetyl-choline 
receptor 
(AChR) 
autoantibodies to autoantibody panel 
IRB requested changes 
Section 3.1.2 
Consistency of description of antitumor activity 
Section 9.2 
Consistency of number of patients enrolled throughout the 
entire study 
Section 4.2 
Change age of participants to ≥18 years for all countries 
(excluding Taiwan) 
Kymab internal changes 
 
Various changes for correction of typographical errors and 
clarifications 
3.0  
24th Jan 
2019 
MHRA requested changes 
Section 5.2.3 
The observation period of the sentinel patient in the 
combination cohort 1 of KY1044 with atezolizumab has 
been prolonged to 72 hours instead of 48 hours. 
Section 3.3 
Specific wording has been added to clarify the detailed 
communication process, in the event that the study needs to 
be put on hold  
Section 5.7  
Table 5-6 has been updated to clarify the duration for when 
and how long, life attenuated vaccines are prohibited 
Protocol synopsis 
Section 4.2 
Section 5.8 
The duration required for contraception of females and 
males (barrier contraception) have been changed to at least 
5 months after discontinuing study treatment, or longer if 
the half-life of KY1044 is observed to exceed that of 
atezolizumab. 
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Protocol 
version 
Effective 
date 
Section 
Change 
Kymab internal changes 
Section 4.1.1 
The number of patients required in each cohort in Phase 1 
has been clarified 
Section 5.4.2 
Table 5-2 has been updated and corrected for dose level -1 
Section 5.4.4  
The requirements for the assessment of DLT data based on 
three patients has been clarified 
Section 6 
Table 6-8 has been amended according to the changes in the 
Lab manual 
Table 6-1 and Table 6-2 have been amended according to 
changes in Table 6-8 
Section 6.5.8 has been amended to specify Troponin I 
according to changes in the laboratory manual 
4.0 
08 May 
2019 
Section 1.4.3.1 
Updated date relating to atezolizumab approvals. 
Section 4.3 
Updated to clarify the requirements for use of anticoagulant 
treatment. 
Section 5.6.3 
Updated as Appendix 5 atezolizumab guidance for 
investigators removed. 
Section 6 
Section 6.5.6 revised to enable use of local labs if necessary 
Appendix 3 
Updated list of atezolizumab adverse events of special 
interest. 
Appendix 5 
Atezolizumab guidance for investigators removed. 
5.0 
28 Jul 2020 
Protocol Synopsis: 
Study design; 
Protocol Synopsis: 
Study population; 
Sections 1.5.2; 3.1; 
3.1.2; 3.1.4; 5.2.1; 
5.9; 9.2 
The study design for Phase 2 has been changed to introduce 
an initial Phase 2 dose assessment part in one or more 
specific indication(s) to compare the efficacy and biomarker 
readouts of two biologically relevant dose levels of KY1044 
(as single agent or in combination with atezolizumab) in a 
more homogeneous patient population. 
Protocol Synopsis: 
Sample size; 
Sections 1.5.2; 
3.1.3; 4.1; 9.2 
The number of patients in Phase 1 has been increased from 
112 to approximately 150.  The number of patients in 
Phase 2 has been decreased from a maximum of 300 to a 
maximum of 262. 
Protocol Synopsis: 
Study population; 
Protocol synopsis: 
Key inclusion 
criteria; Sections 
1.5.2; 3.1.4; 4.2; 
5.4.7 
Clarification that patients will be treated with KY1044 as 
single agent in Phase 2 only if evidence of anti-tumor 
activity is detected in the dose escalation/enrichment 
Phase 1 parts. 
Protocol Synopsis: 
Key exclusion 
criteria; 
Section 4.3 
Update to Exclusion criterion 5 in the Protocol Synopsis and 
Exclusion criterion 6 in Section 4.3 to exclude patients with 
any severe infection within 4 weeks of initiation of study 
treatment to align with the atezolizumab required exclusion 
criteria. 
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Protocol 
version 
Effective 
date 
Section 
Change 
Protocol Synopsis: 
Statistical 
analysis; Protocol 
Section 9.4 
Text was updated to account for multiple dose groups and 
schedules. It was clarified that Phase 2 will be reported by 
dose group(s) in addition to indication. 
Section 1.6.5 
Addition of benefit/risk of KY1044 as single agent and in 
combination 
with 
atezolizumab 
regarding 
potential 
infections with SARS-Cov-2. 
Section 3.1.4 
Amendments have been made to the study design figure to 
include the total patients in Phase 1 and Phase 2, to clarify 
that approximately 36 patients will be enrolled in the 
Phase 1 dose escalation part (KY1044 monotherapy and in 
combination with atezolizumab), and to increase the number 
of patients in the enrichment pool from 40 to approximately 
78.  An initial Phase 2 dose assessment part has been added, 
and it has been clarified that patients will be treated with 
KY1044 as a single agent in Phase 2 only if evidence of 
anti-tumor activity is observed in the Phase 1 dose 
escalation/enrichment parts.  A footnote has been added to 
clarify that, for the tumor types selected for Phase 2, the 
number of patients enrolled per group could be reduced, 
depending on enrolment feasibility in the ongoing study. 
Section 3.3; 5.4.4 
It was clarified that, in addition to continuing until 
identification of the MTD and/or the RP2D, dose escalation 
may also continue until completion of all defined dose 
levels, or a decision that further increase of dose is not 
warranted. 
Section 5.2.2 
The infusion schedule has been updated so that, when given 
in combination, both IMPs are to be administered within 
24 hours. 
Section 5.2.4 
A sentence has been added to clarify that if an infusion 
reaction is caused by KY1044, the atezolizumab infusion 
may be delayed until the next day and/or until recovery from 
the event. 
Section 5.6.1 
Active SARS-Cov-2 infections should be treated as AEs, as 
should any other concurrent illnesses, and treatment 
interruption should be considered on an individual patient 
basis. 
Section 5.6.3; 
Appendix 3 
In alignment with Addendum 2 of the atezolizumab IB 
Version 15, “Systemic immune activation” has been 
amended to ‘immune-mediated reactions’. 
Section 6 
The atezolizumab PK sampling schedule was clarified in 
Table 6-1 for Phase 1 and Table 6-2 for Phase 2. 
Section 6.3.1 
Safety analysis has been added to the alternative biomarkers 
to be able to explore biomarkers for infusion reactions. 
Blood volumes for PBMCs for pharmacogenomic testing, 
immunoprofiling and receptor occupancy have been 
clarified in Table 6-4. 
Section 6.4.2 
A sentence has been added to allow PK samples to be used 
for analysis of alternative biomarkers of safety and efficacy. 
The PK sampling timetable has been clarified in Table 6-5. 
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Protocol 
version 
Effective 
date 
Section 
Change 
Section 6.5.8 
The electrocardiogram collection plan timetable has been 
clarified in Table 6-9. 
Addendum 1 
A finalized addendum dated 21 April 2020 summarizing 
potential adjustments for protocol visits and assessments 
due to circumstances created by the COVID-19 pandemic 
has been incorporated into the protocol. 
6.0 
07 May 
2021 
Protocol Synopsis: 
Study design; 
Protocol Synopsis: 
Duration of the 
Study; Sections 
3.1, 3.2, 3.4, 3.6, 
5.3, 6, 6.2.1, 6.5.6, 
8.1, 8.2.2, 8.2.3 
The study has been amended to allow study treatment 
beyond 24 months up to 48 months for patients that are 
deriving clinical benefit without safety concerns.  The 
requirements for survival follow-up have been updated 
accordingly. 
Protocol Synopsis: 
Key exclusion 
criteria; Sections 
4.3, 5.7, 6, 6.1.5, 
7.1 
The study design has been updated with respect to the 
management of SARS-CoV-2 vaccination in subjects 
participating in non-COVID-19 clinical trials. 
7.0 
10 Nov 2021 
See Section Protocol Amendment Summary of Changes 
 
 
 
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17 
ADDENDA  
17.1 Addendum 1  
This addendum is applicable only where national/local restrictions due to COVID-19 are 
implemented and may therefore be in force at variable times and in certain sites only.  
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SAP_001.pdf: 
Protocol Number: KY1044-CT01 
 
Official Title: A Phase 1/2, Open-Label, Multi-Center Study of the Safety and Efficacy of KY1044 As 
Single Agent and in Combination with Anti-PD-L1 (Atezolizumab) in Adult Patients with Selected 
Advanced Malignancies 
 
NCT Number: NCT03829501 
 
Document Date: 24 May 2024 




Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
PRA-QMS-02745
9.0
Page 2 of 31
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Table of Contents


Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
PRA-QMS-02745
9.0
Page 3 of 31
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Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
PRA-QMS-02745
9.0
Page 4 of 31
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Purpose
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Kymab Ltd. Protocol KY1044-CT01.
Scope
The SAP outlines the following:
Study Objectives
Study Design
Study Endpoints
Applicable Study Definitions
Statistical Methods for analysis of all endpoints
Introduction
This SAP describes the statistical methods to be used during the reporting and analyses of data collected 
under Kymab Ltd Protocol KY1044-C01. It should be read in conjunction with the current study protocol 
and case report form (CRF). This version of the plan has been developed using protocol version 7.0 dated 
18-Nov-2021 and CRF version 4.1 dated 06-Jul-2021. Any changes to the protocol or CRF may necessitate 
updates to the SAP.
Changes following approval of the first version of the SAP will be tracked in the Document History section 
of this document and a final version of the updated SAP will be approved prior to database lock.
Study Objectives
5.1 Primary Objectives
Phase 1:
To characterize the safety and tolerability of KY1044 as single agent and in combination with atezolizumab 
and to identify recommended doses for future studies.
Phase 2:
To estimate the anti-tumor efficacy of KY1044 as single agent and in combination with atezolizumab.
5.2 Secondary Objectives
To evaluate the preliminary anti-tumor activity of KY1044 as single agent and in combination with 
atezolizumab (Phase 1 only).
To characterize the safety and tolerability of KY1044 as single agent and in combination with 
atezolizumab (Phase 2 only).
To characterize the pharmacokinetic (PK) profile of KY1044 as single agent and in combination 
with atezolizumab.
To assess emergence of anti-KY1044 and anti-atezolizumab antibodies following one or more 
intravenous (i.v). infusions of KY1044 as single agent and/or in combination with atezolizumab, 
respectively.
To assess changes in biomarkers from baseline in tumor tissue as potential predictors of efficacy 
of KY1044 as single agent and in combination with atezolizumab.
To describe the survival rate at 12 and 24 months of patients treated with KY1044 as single agent 
and in combination with atezolizumab for each disease group.


Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
PRA-QMS-02745
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5.3 Exploratory Objectives
To assess the pharmacodynamics (PD) effect of KY1044 as single agent and in combination with 
atezolizumab in tumor tissue.
To assess the PD effect of KY1044 as single agent and in combination with atezolizumab in 
peripheral blood.
To determine the level of target occupancy in response to KY1044 as single agent (Phase 1 only).
Study Design
This study is a first in human, open-label, Phase 1/2, multi-center study consisting of a Phase 1 dose 
escalation component with KY1044 as single agent and a dose escalation of KY1044 in combination with 
atezolizumab that will start after at least two cohorts of KY1044 as single agent have been considered to 
be safe and tolerable.
KY1044 will be administered i.v. every 3 weeks (Q3W). Atezolizumab will be administered according to 
dosing instructions given in the approved label for marketing (1200 mg i.v. Q3W) until the patient 
discontinues the study for up to 48 months.
Patients should not discontinue treatment based on progressive disease per response evaluation criteria 
in solid tumors version 1.1 (RECIST 1.1) (study discontinuation due to progressive disease as per iRECIST) 
unless clinical deterioration or increase in tumor markers is observed.
Phase 1:
In Phase 1, patients with advanced/metastatic malignancies (all comers) and with preferred indications will 
be enrolled. Preferred indications are: head and neck squamous cell carcinoma (HNSCC), 
gastric/esophageal cancer, hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), 
melanoma, cervical cancer, renal cell cancer, pancreatic cancer and triple negative BC.
Dose escalation part - KY1044 single agent
In the Phase 1 part of the study, cohorts of patients with advanced/metastatic malignancies, preferentially 
those with indications which are expected to have a high expression of inducible T cell costimulator (ICOS), 
will be treated with KY1044 as single agent Q3W until the maximal tolerated dose (MTD) is reached or a 
lower recommended phase 2 dose (RP2D) is established. It is expected that a RP2D based on safety, PK, 
and PD data may be established before the MTD is reached, as this has been the case with other 
checkpoint inhibitors.
The dose escalation will be guided by the Modified Toxicity Probability Interval Design (mTPI-2 design, Guo 
et al 2017 (1)), which is an adaptive dose-finding method that allows dose escalation and de-escalation 
according to the pre-calculated decision table in Appendix 14.1 of the SAP. The maximum sample size for 
dose escalation in each Phase 1 component (single agent and combination therapy) will be 36 patients, 
using cohorts of a minimum of three patients (Section 4.1.1 of the protocol).
Dose escalation part 
KY1044 in combination with atezolizumab
The combination part of the study will commence after at least two cohorts of KY1044 as single agent have 
been considered to be safe and tolerable and the data suggest that it is reasonable to begin treatment in 
combination. The combination dose escalation will follow a Q3W dosing schedule. Treatment in 
combination will escalate until the MTD is reached or a lower RP2D is established based on safety, PK and 
available PD data. The dose escalation will be guided by the mTPI-2 design, which is an adaptive 
dose-finding method that allows dose escalation and de-escalation according to the pre-calculated decision 
table. The maximum sample size for dose escalation will be 36 patients using cohorts of a minimum of 
three patients.


Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
PRA-QMS-02745
9.0
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Phase 1: Enrichment cohorts (optional)
An optional enrichment part may include the testing of additional patients at one or more dose levels to 
better understand the safety, tolerability, biomarkers, PK, preliminary anti-tumor efficacy and /or PK/PD
relationships of KY1044 as single agent and/or in combination with atezolizumab.
The enrichment part of the study will only use doses that have already been explored in the Phase 1 dose 
escalation part of the study, and have been determined to be safe.
Total number of patients in Phase 1
The total number of patients included across all cohorts in the Phase 1 dose escalation and enrichment 
parts will be approximately 150.
Phase 2:
In Phase 2, patients will be enrolled
in one or more specific indication(s), in which efficacy has been observed in Phase 1 to support 
definition of the RP2D for future indications and
in tumor indications, where signs of anti-tumor activities were detected during Phase 1 (indications, 
where complete response (CR), partial response (PR) or durable stable disease (SD) with tumor 
shrinkage that does not qualify for PR have been observed) and
in selected indications, HNSCC, NSCLC, gastric/esophageal cancer, cervical cancer,
In the absence of identifying an MTD or single efficacious dose in Phase 1, an initial Phase 2 dose 
assessment part in one or more specific indication(s) will be opened to compare the efficacy and biomarker 
readouts of two biologically relevant dose levels of KY1044 (as single agent or in combination with 
atezolizumab) in a more homogeneous population. Up to 20 patients (i.e. 15 anti-programmed cell death 
ligand 1 [PD-(L)1] naïve patients and where feasible five anti-PD-(L)1 pre-treated patients) will be included 
at each dose level and indication. Together with safety, efficacy and biomarker data from Phase 1, data 
from this part will assist with the selection of the RP2D. Once the MTD and/or RP2D has been identified, 
Phase 2 may be extended to explore efficacy at the RP2D in additional selected indications as described 
below.
KY1044 as Single Agent
A Phase 2 part will be opened should signs of anti-tumor activity (defined as CR, PR or SD with tumor 
shrinkage that does not qualify for PR) be seen in at least one subject in the Phase 1 dose escalation parts 
in any indication (in either anti-PD-(L)1 naïve or pre-treated patients). Initially up to 15 anti-PD-(L)1 naïve 
patients will be enrolled and depending on early efficacy additionally up to 30 patients will be enrolled per 
each indication. In the anti-PD-(L)1 pre-treated group of patients, initially five patients will be enrolled per 
indication and depending on early efficacy in these patients, additionally up to 15 patients will be enrolled 
in certain indications.
KY1044 in Combination with Atezolizumab
Patients will be enrolled in the Phase 2 part in selected indications (HNSCC, NSCLC, TNBC, 
gastric/esophageal and cervical cancers and any indication showing activity in the Phase 1 dose escalation 
of the combination) in order to assess preliminary anti-tumor efficacy. These patients will either be
anti-PD-(L)1 treatment naïve or
pre-treated with anti-PD-(L)1
In the anti-PD-(L)1 treatment naïve group, initially approximately 15 patients will be enrolled in a defined 
indication and depending on response rates, certain indications may be further expanded to up to 30 
patients.


Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
PRA-QMS-02745
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In the anti-PD-(L)1 pre-treated group, initially a minimum of five patients will be enrolled in each of the 
defined indications which may be further expanded to up to 15 patients, depending on emerging efficacy 
data.
Should enrolment for any of these disease indications not be feasible, or if the early response assessment 
(see below) suggests that there is only limited benefit in one or more of these indications, then enrolment 
to that group may be closed before the target is met.
Early Response Assessment in Phase 2: 
The early assessment of objective response rate (ORR) will compare observed response rates to historical 
controls, to define a minimum number of objective responses (CR, PR or durable SD with tumor shrinkage 
that does not qualify for PR) per RECIST 1.1 per each indication in the initial Phase 2 phase, in order to 
decide if enrolment should be further extended up to 40 patients.
6.1 Study Flow Chart
*Note: Additional provisions may be made for patients who are ongoing on treatment and are still receiving 
clinical benefit at 48 months for continuation of treatment.  
6.2 Sample Size Considerations
Phase 1:
A maximum of 36 patients will be used for each Phase 1 dose escalation component (single agent and 
combination therapy). The total number of patients included across all cohorts in the Phase 1 dose 
escalation and enrichment parts will be approximately 150.
Phase 2:
The initial Phase 2 dose assessment part in one or more specific indication(s) (Section 3.1.4 in the protocol) 
will include approximately 20 patients (that is 15 anti-PD-(L)1 naïve and where feasible five anti-PD-(L)1 
pre-treated patients) at each of two dose levels of KY1044 (as single agent or in combination with 
atezolizumab).
Once the RP2D is established, Phase 2 may be extended and approximately 15 patients will be enrolled 
initially in each tumor type in the anti-PD-(L)1 naïve subgroup per each indication in either the single agent 
cohort or the combination cohort.


Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
PRA-QMS-02745
9.0
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The full sample size of specific indications in Phase 2 of the study will be based on early evaluation of 
ORRs and only indications with promising response rates will be expanded further (up to 40 per subgroup). 
The Go-no-go decision criteria for cohort expansion will be based on historical ORR and a target ORR for 
KY1044 treatment. No formal statistical testing will be performed. Instead confidence intervals will be 
constructed around the ORR observed in each cohort, and this will enable decisions to be made around 
the likely success of future studies. 
Historical ORR for monotherapy with immune checkpoint inhibitors in the second line metastatic setting are 
in the region of 15% to 25% for anti-PD-(L)1 inhibitors as monotherapy across the different indications and 
will be even lower in more advanced stages of d
-cancer treatment in the metastatic 
setting).
In order to illustrate the impact of sample sizes of 15 or expansion to 40 on the width of the confidence 
intervals, example evaluations are given for these 3 situations (ORR of 13% (3 and more lines of prior 
therapies in the advanced metastatic setting and 20% and 33% ORR for 2nd line metastatic setting) for 
cohort sizes of either 15 or 30 patients are given below:
If the observed response rate is 13% (2/15), the 2-sided 80% confidence interval will be (4%, 32%).
If the observed response rate is 20% (3/15), the 2-sided 80% confidence interval will be (8%, 39%).
If the observed response rate is 33% (5/15), the 2-sided 80% confidence interval will be (17%, 
53%).
If the observed response rate is 13% (5/40), the 2-sided 80% confidence interval will be (6%, 22%).
If the observed response rate is 20% (8/40), the 2-sided 80% confidence interval will be (12%, 
30%).
If the observed response rate is 33% (13/40), the 2-sided 80% confidence interval will be (23%, 
44%).
In the anti-PD-(L)1 pre-treated subgroup, initially five patients will be recruited in each indication in either 
the single agent cohort or the combination cohort. These patients will have already progressed on previous 
immunotherapy; hence any individual response would indicate a proof of mechanism in these subject 
groups. If signs of efficacy have been observed in at least one subject any of these anti-PD-(L)1 pre-treated 
indications a further expansion up to 15 patients per cohort will be considered.
This number of patients, also offers the opportunity to evaluate further the safety and PK/PD of the chosen 
MTD/RP2D of KY1044 as single agent or in combination with Atezolizumab. 
Overall a maximum of 412 patients may be enrolled into the study (Phases 1 and 2).
6.3 Randomization and Blinding
Not applicable. This is an open-label study without randomization.






Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
PRA-QMS-02745
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7.2 Analysis Sets
The following analysis sets will be used for presentation of the data. 
For each analysis set, the number and percentage of patients eligible for inclusion will be summarized. A 
listing of reasons for exclusion from analysis sets will be provided by subject.
A subject data-listing of subject analysis set will be provided. 
7.2.1 Screened Set
The patients who have signed informed consent form will be considered as screened subject.
7.2.2 Enrolled Analysis Set
The patients from screened set who have been allocated to study drug regardless of whether the study 
drug was received or not will be included in enrolled set.
7.2.3 Full Analysis Set
The full analysis set (FAS) will consist of all patients who are allocated to study drug, regardless of treatment 
ultimately received. Patients will be grouped according to the study drug they will be allocated to. The FAS 
will be the primary analysis set for efficacy endpoints.
7.2.4 Safety Analysis Set
The safety set will consist of all patients who take at least one dose of study drug within the relevant phase. 
Patients will be grouped according to the study drug received at cycle 1 day 1. The safety set will be the 
analysis set used for safety endpoints.
7.2.5 Dose Limiting Toxicity Evaluable Set
The DLT evaluable set will be patients who have been on study for 1 full cycle (21 days) and have received 
adequate treatment with KY1044 as single agent or in combination with atezolizumab (i.e. have had full 
infusion of planned doses of KY1044 and Atezolizumab if appropriate) or have experienced a DLT in 
Cycle 1. The evaluation of DLTs in Phase 1 of the study will occur in this population.
7.2.6 Pharmacokinetic Evaluable Set
The PK evaluable set will consist of all patients who had sufficient concentration-time data within the 
relevant phase to permit calculation of PK parameters for KY1044. For patients who were noncompliant 
with respect to administration of KY1044, or for patients with incomplete data, a decision as to their inclusion 
in the PK analysis will be made on a case-by-case basis. The PK evaluable set will be used for evaluation 
of PK parameters.
7.2.7 Anti-Drug Antibody Evaluable Set
The anti-drug antibody (ADA) evaluable set will consist of all patients who receive at least one dose of 
KY1044 or atezolizumab and have ADA results available for analysis within the relevant phase. This 
population will be used for the analyses of anti-KY1044 and anti-Atezolizumab antibodies.
7.2.8 Biomarker Evaluable Set
The biomarker evaluable set will consist of all patients who receive at least one dose of study drug and 
have at least one of ICOS, FOXP3 and CD8 cells results available for analysis within the relevant phase. 
This population will be used for the analyses of ICOS, FOXP3 and CD8 cells biomarkers.


Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
PRA-QMS-02745
9.0
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Conventions and Derivations
8.1 Baseline Values
Baseline is defined as the last measurement prior to first study drug administration.
8.2 Change from Baseline
Change from baseline (CFB) will be calculated as (post-baseline value 
baseline value). Change from 
baseline will be calculated for patient who have both a baseline and post-baseline value as applicable.  
8.3 Prior and Concomitant Medication
Medications administered to patients during the study are captured on a log CRF page. Medications are 
considered prior medications if they have a start date prior to the date of first dose of study medication or a 
partial start date which indicates the medication was begun prior to the first dose of study treatment.
Concomitant medications are defined as medications administered to patients on or after the first dose of 
study medication and before the last dose of study medication. 
The medication taken after the last dose of study medication will be considered as post-study and will be 
included in subject data listings.
The medication with start date prior to first dose of study medication and ongoing in the study will be 
included in subject data listing and will be flagged as prior and concomitant.
Collected prior and concomitant medications will be coded using the World Health Organization (WHO) 
medical dictionary.
8.4 End of Study for Individual Patient
The end of study for each patient will be either:
At the end of the 90 day safety follow-up period after stopping treatment, for the last patient in the 
study.
At the overall end of the study for all patients, who are still in follow-up for PFS and or survival as 
determined by the Sponsor.
The end of the study recorded in the CRF will be used to count patients who complete the overall study.
8.5 Time since Initial Diagnosis
The time since initial diagnosis in years will be derived as (date of informed consent 
date of initial 
diagnosis)/365.25. In case of missing or partial date of diagnosis the time since initial diagnosis will be 
missing.
8.6 Efficacy Analysis
8.6.1 Best Overall Response
The BOR for each patient is defined as the best response per RECIST 1.1 or iRECIST among all responses 
recorded from start of treatment until progressive disease, initiation of new anti-cancer therapy, death, or 
analysis cut-off date, whichever comes first, with a response of CR or iCR, PR or iPR, SD or iSD, 
progressive disease or immune-unconfirmed progressive disease (iUPD) or immune-confirmed progressive 
disease (iCPD) and then not evaluable (NE). 
For confirmed responses, an equal or superior response must be observed at a subsequent time point at 
least 4 weeks after the initial assessment.  In the case of SD, measurements must have met the SD criteria 


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at least once no less than 7 weeks after first study drug administration, regardless of whether the endpoint 
is confirmed or unconfirmed responses.
8.6.2 Objective Response Rate
tumor imaging results will be assessed by the Investigator in screening and periodically after start 
of treatment in each study phase for response per RECIST 1.1 and iRECIST. Response categories by 
RECIST as indicated by Investigator will be CR, PR, SD, PD, or NE and by iRECIST will be iCR, iPR, iSD, 
iUPD, iCPD, or NE.
ORR accordingly to RECIST 1.1 is defined as the proportion of patients with a measurable disease at 
baseline and with BOR of CR or PR. The response of CR or PR must be confirmed by a later scan 
conducted at least 4 weeks after the initial response is observed. In case of SD, measurements must have 
met the SD criteria at least once no less than 7 weeks after first study treatment administration.
The ORR for iRECIST is defined as the proportion of patients with a measurable disease at baseline and 
having achieved complete immune-response (iCR) or partial immune-response (iPR) by iRECIST.
8.6.3 Duration of Response
DOR is defined as the time in months from date of the first documentation of objective response (CR or 
PR) per RESIST 1.1 to the first documentation of progression of disease or to death due to any cause in 
the absence of documented progression of disease (i.e., min [progression of disease date, death date] 
date of the first observation of objective response +1) divided 30.4375. DOR will only be calculated for the 
subgroup of patients achieving a BOR of CR or PR.
The censoring rules to be applied to DOR are the same as for PFS.
8.6.4 Progression Free Survival
PFS is defined as the time from the first dose of study drug to the date of progression of disease or death 
(event) due to any cause, whichever occurs first. PFS (in months) will be calculated as: 
(first event/censored date 
first dose date of study drug +1)/30.4375.
The clinical progression without further radiological assessment as corroboration will not be considered as 
progressive disease.
Using iRECIST, PFS is defined as the time from the first dose of study drug to the date of death or the of 
first documented tumor progression (iUPD) provided that iCPD is confirmed at the next assessment, 
whichever is earlier.
The patients who have not progressed or died at the time of analysis will be censored. Following censoring 
rules will be applied for PFS:
Patients with no disease assessment (or only have assessment(s) with response = NE) after first study 
treatment or have baseline or post-baseline assessments where the RECIST criteria cannot be applied 
(e.g. not all baseline lesions assessed) will have their PFS time censored on the date of first dose with 
duration of 1 day unless they die within 2 tumor assessments of baseline, then they will be treated as an 
event with date of death as the event date.
Event time will be censored on the date of the last evaluable assessment documenting absence of 
progression of disease for:
Patients on-study and progression-free at the time of analysis;
Patients who have progression of disease 
ssed tumor 
assessments;
Patients given alternative cancer treatment prior to progression of disease or death on-study.


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8.6.5 Overall Survival
The overall survival (OS) is defined as the time from first dose of study drug to the date of death due to any 
cause. OS
) divided by 
30.4375. Patients who are continuing on study at the time of an analysis, are lost to follow-up or who 
withdraw consent, will have their event time censored on the last date that they were known to be alive. 
The last date that patients are known to be alive can be derived from the clinical database and may include 
the latest Visit date for patients still on study or the latest Date of Contact on the Long-Term Follow-
Up/Survival Status CRF page, whichever occurs latest. For patients with no follow-up after first dose of 
study drug, OS will be censored at the date of first dose. 
8.7 Study Drug Exposure Variables
The exposure for KY1044 and Atezolizumab will generally be presented separately but in addition, the 
study treatment duration will be presented combining both treatments (please see below). 
8.7.1 Study Treatment Duration
Study treatment duration (weeks) for each study drug separately is defined as ((last dose date+21 days
first dose date)+1)/7. For patients in the combination arm, an additional duration of study treatment will be 
calculated using the same formula but which takes the latest KY1044 or Atezolizumab administration for 
the last dose date, and the earliest of either drug for the first dose date. 
8.7.2 Dose Interruption
A dose interruption is defined as any interruption during the administration (infusion) of a dose of study 
drug. Dose interruptions are recorded on the Exposure KY1044- IV/Infusion Administration or the Exposure 
Atezolizumab- IV/Infusion Administration CRF pages in time units of minutes, hours, or days.
8.7.3 Dose Reduction
A dose reduction is defined as any reduction in the dose assigned for infusion and are recorded along with 
the actual dose administered (infused) on the Exposure KY1044- IV/Infusion Administration. Dose 
reductions for Atezolizumab are not permitted.
8.7.4 Cumulative Dose Received
Cumulative dose received (mg) is defined as the total amount of study drug received as recorded on the 
Exposure KY1044- IV/Infusion Administration or the Exposure Atezolizumab- IV/Infusion Administration 
CRF pages, i.e., the sum of actual dose per administration.
8.7.5 Dose Intensity
Absolute dose intensity (mg/week) is calculated as cumulative dose received (mg) / study treatment 
duration (weeks).
Relative dose intensity is calculated as the cumulative dose received (mg) / initial planned cumulative dose 
(mg). Initial planned cumulative dose is calculated as the starting dose (Cycle 1 Day 1 dose) multiplied by 
the scheduled number of administrations within the study treatment duration.
8.8 Safety Variables 
8.8.1 Baseline Signs and Symptoms
treatment dosing are recorded in the CRF as medical history.


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8.8.2 Treatment Emergent Adverse Events
A treatment emergent adverse event (TEAE) is defined as an AE observed after starting administration of 
the specific treatment. If a patient experiences an event both prior to and after starting administration of a 
treatment, the event will be considered a TEAE (of the treatment) only if it has worsened in severity (i.e., it 
is reported with a new start date) after starting administration of the specific treatment, and prior to the start 
of another treatment (if any) or up to 21 days after the last dose.
8.8.3 Post-Treatment Adverse Events
A post treatment adverse event is defined as an AE with start date being up to 21 days after the last study 
dose.
8.8.4 Immune-Related Adverse Events
The Immune-related AEs (irAEs) are defined as follows:
Infusion reactions, Hematological, Cardiological, GI, Renal, Pulmonary, Hepatic, Endocrinopathy, 
Dermatological, Neurological, Ophthalmological, and Rheumatological AEs.
8.8.5 Adverse Events of Special Interest 
Adverse events of special interest (AESI) will be determined during the conduct according to protocol 
Section 16.3 of the study and will be recorded on CRF.
8.8.6 Related Adverse Events 
Related .
8.9 Handling of Missing or Partial Dates
Below are rules for imputing missing or partial dates for analyses of medical history, AEs, and concomitant 
medications. Though imputed for analyses, actual dates (missing or partial) will be reflected in listings. 
Otherwise, there will be no imputation of missing data values. Data on patients who withdraw early will be 
summarized up until the time of withdrawal. 
Missing or partial dates for medical history will be imputed as follows:
If only the day is missing, it will be imputed with the 1st day of the month.
If both the day and month are missing, the month and day will be imputed with January 1st.
If the date is completely missing, no imputation will be performed.
Missing or partial dates for AEs and concomitant medications will be imputed as follows:
Start Date
If only the day is missing and the month and year are the same as the month and year of the 
first dose date, then the day will be imputed with the day of the first dose date. Otherwise the 
day will be imputed with the first day of the event month.
If both the day and month are missing and the year is the same as the year of the first dose 
date then they will be imputed with the month and day of the first dose date. Otherwise they 
will be imputed with the January 1st.
If the start date is completely missing, the date will be imputed with the first dose date.
If the stop date is complete and the imputed start date is after the stop date, then the imputed 
start date will be set to the stop date.
Stop Date


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If only the day is missing and the month and year are the same as the month and year of the 
study discontinuation date, then the day will be imputed with the day of the study 
discontinuation date. Otherwise the day will be imputed with the last day of the event month.
If both the day and month are missing and the year is the same as the year of the study 
discontinuation then they will be imputed with the month and day of the study discontinuation 
date. Otherwise they will be imputed with the December 31st.
If the stop date is completely missing, then it will be imputed with the study discontinuation 
date. 
Note that stop date imputation will not be applied to ongoing AEs. If the imputed stop date is greater than 
last the contact date, then the imputed stop date will be set to last contact date
Interim Analyses
A preliminary analysis of the study data will be performed and reported based on all patients
time when all patients from the Phase 1 part have completed at least six cycles of treatment or discontinued 
the study and the initial patients from the Phase 2 part have had at least one tumor assessment after six 
months of treatment or discontinued the study.
Statistical Methods
There will be no formal statistical testing in this study. Statistical analyses will be limited to descriptive 
summaries.
In general, continuous variables will be summarized by number of patients, mean, standard deviation 
(STD), median, minimum, and maximum. The mean and median will be presented to one more and the 
STD to 2 more decimal places than the precision of the variable, while the minimum and maximum will be 
presented at the same precision. Categorical variables will be summarized by frequency counts and 
percentages. Percentages will be presented to one decimal place. Where relevant, estimates will be 
presented with 95% two-sided confidence intervals (CI).
All tables, figures and listing will be presented separately for Phase 1 and Phase 2 portion of the study. 
The Phase 1 summaries will be reported by dose levels within KY1044 single agent and KY1044 with 
atezolizumab combination groups.
The Phase 2 of the study will be reported by indication within KY1044 single agent and KY1044 in 
combination with atezolizumab, split by anti-PD-(L)1 naïve and pre-treated groups, and dose levels as 
appropriate.
Wherever possible, patients with the same tumor type who have received the recommended dose/schedule 
of KY1044 as single agent or in combination with atezolizumab will be pooled for analysis, respectively.
All analyses will be performed using SAS version 9.4 or higher.
10.1 Subject Disposition
The number and percentage of patients who completed the study, completed the 24 months survival follow-
up, discontinued the study and a breakdown of the corresponding reasons for discontinuation.
The number and percentage of patients who discontinued the treatment prior to 48 months and a 
breakdown of the corresponding reasons for withdrawal from the treatment will be presented. 
The subject disposition will be listed.
10.2 Demographic and Baseline Characteristics
The demographic characteristics will be summarized on the FAS and safety analysis set.


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The demographic variables include age at screening (years), age groups in years (
64, 65 84 and 
85), sex, ethnicity, race, weight (kg), height (m), body mass index (BMI) (kg/m2), and Eastern Cooperative 
Oncology Group (ECOG) status. 
The following baseline characteristics will be summarized in the safety analysis set in both study phases:
Medical history (coded by medical dictionary for regulatory activities [MedDRA] dictionary version 
21.0 or higher and summarized by system organ class (SOC) and preferred term (PT))
Tumor history
Prior anti-cancer therapies 
Prior radiotherapies
Listings of the demographic characteristics, medical history, tumor history, prior anti-cancer therapy, prior 
cancer surgery, and prior radiotherapy will be presented.
10.3 Treatments
10.3.1 Extent of Study Drug Exposure
Exposure to study drug will be summarized for all patients in the safety analysis set. Descriptive statistics 
will be provided for study treatment duration (weeks), the total number of cycles started, number of infusions 
received, cumulative dose received (mg), absolute dose intensity (mg/week), and relative dose intensity.
The number and percentage of patients with at least 1 dose not administered, dose reduction or increase
and at least 1 dose interruption will be presented along with a summary of the reasons for dose not 
administered, dose reductions and interruptions.
The bar plot of time to treatment will be presented for subject in FAS population.
A listing of study drug exposure will also be created. These data can be found on the Exposure 
KY1044- IV/Infusion Administration or the Exposure Atezolizumab- IV/Infusion Administration CRF pages.
10.3.2 Concomitant Medications
The medications received concomitantly with study drug, categorized by medication group and subgroup 
according to WHO Drug Enhanced [Version March 2016], will be summarized. The number and percentage 
of patients using each medication will be displayed together with the number and percentage of patients
using at least one medication with each anatomical therapeutic chemical (ATC) and preferred term (PT).
Prior, concomitant and post study medications will be listed.
10.4 Important Protocol Deviations
Per PRA processes, important protocol deviations data will be entered into our clinical trials management 
system (CTMS). The study team and the Sponsor will conduct on-going reviews of the deviation data from 
CTMS and the resulting set of evaluable patients throughout the study, adjusting the deviation criteria as 
seems appropriate. The evaluable patients set must be finalized at the post-freeze data review meeting (or 
earlier), prior to database lock. 
For each study phase, important protocol deviations for patients in the FAS will be reported by deviation 
category. Important protocol deviations will also be listed.
A separate listing of all COVID-19 related protocol deviations will be provided.


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10.5 Efficacy Analyses
10.5.1 Hypothesis Testing Strategy and Multiplicity
No formal hypothesis testing and no measures will be employed to adjust the primary analysis and key 
secondary analysis for multiplicity are applicable for this study.
10.5.2 Primary Endpoint
Phase 1
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital 
signs and ECGs.
Tolerability: Dose interruptions, reductions and dose intensity
The incidence of DLTs with KY1044 as single agent during the first 21 days of treatment
The incidence of DLTs with KY1044 in combination with atezolizumab during the first 21 days of 
treatment
Phase 2
ORR per RECIST 1.1. 
10.5.2.1 Imputation Methods 
There will be no imputation of missing data values. Data on patients who withdraw early will be summarized 
up until the time of withdrawal.
10.5.2.2 Primary Analysis
The primary endpoints in Phase 1 are safety endpoints (see SAP Section 12.3 and 12.7).
The number and percentage of patients with confirmed CR or PR per RECIST 1.1 will be presented for all 
patients in FAS. The ORR will be accompanied by the 2-sided exact 95% Clopper-Pearson CI.
The waterfall plots of best percent change from baseline and maximum tumor size reduction from baseline 
as assessed by the investigator according to RECIST 1.1 will be provided for the FAS population.
The spider plot for percent change from baseline in tumor size will be provided for the FAS population.
Lesions assessed by the investigator (target, non-target, and new lesions) and investigator-reported overall 
tumor response assessment as per RECIST 1.1 will be presented in listings.
The subject-data listing will be provided for tumor assessment and tumor response.
10.5.2.3 Sensitivity Analyses
No sensitivity analyses is planned for the study.
10.5.2.4 Supplementary Analyses
No supplementary analyses is planned for the study.
10.5.3 Secondary Endpoints
Efficacy measures:
BOR, PFS and DOR per RECIST 1.1
ORR and PFS per immune-related iRECIST (Phase 1 and Phase 2)
ORR per RECIST 1.1 (Phase 1 only)


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Survival rate at 12 and 24 months
Safety measures:
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital 
signs and ECGs (Phase 2).
Tolerability: Dose interruptions, reductions and dose intensity (Phase 2).
PK measures:
KY1044 PK measures (e.g., Cmax, half-life); Serum concentration versus. time profiles.
Anti-drug antibodies:
Presence and/or concentration of anti-KY1044 and anti-atezolizumab antibodies.
Biomarkers:
Presence of tumor-infiltrating lymphocytes (TILs) as determined by expression of ICOS, FOXP3 
and CD8 cells (IHC).
10.5.3.1 Best Overall Response 
The counts and percentages of subject with BOR of CR, PR, SD and PD per RECIST 1.1 will be presented 
for Phase 1 and Phase 2 study phases for all patients in the FAS.
The overall response assessment by investigatory per RECIST 1.1 will be presented for Phase 1 and Phase 
2 study phases for all patients in the FAS.
10.5.3.2 Progression Free Survival
PFS will be summarized using the Kaplan-Meier method. Estimated PFS rates and 95% CIs using 
complementary log-log transformation method will be presented at 12 and 24 months. The median, 25th, 
and 75th percentile of PFS and their two-sided 95% CIs using the Brookmeyer-Crowley method will also be 
presented. Kaplan-Meier curves of the estimated PFS function will also be presented. 
This analysis will be performed according to RECIST 1.1 and iRECIST 1.1 in the FAS for both the study 
phases.
The PFS will be presented in subject-data listing.
10.5.3.3 Duration of Response
DOR per RECIST 1.1 will be summarized with the same approach used for PFS for both the study phases.
The DOR will be presented in subject-data listing.
10.5.3.4 Objective Response Rate
ORR per iRECIST for both the study phases and ORR per RECIST 1.1 for Phase 1 patients in FAS will be 
summarized with the same approach described in SAP section 12.5.2.2.
The subject-data listing will be provided for tumor assessment and tumor response.
10.5.3.5 Survival rate at 12 and 24 months
The OS will be summarized using the Kaplan-Meier method. Estimated OS rates and 95% CIs using the 
complementary log-log transformation method will be presented at 12 and 24 months. Median, 25th, and 
75th percentile of OS and their 95% CIs using the Brookmeyer-Crowley method will also be presented. 
Kaplan-Meier curves of the estimated OS function will also be presented. 
This analysis will be performed in the FAS of both study phases.


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The OS will be presented in subject-data listing.
The analysis of secondary safety endpoints in Phase 2 is detailed in Section 12.7 of the SAP. 
The PK and anti-drug antibodies analysis is detailed in Section 12.6 of the SAP.
10.5.4 Exploratory Endpoints
The following exploratory endpoints will be evaluated:
Tumor tissue:
Expression of immune- and response-related markers such as (but not limited to) PD-L1, CD163, 
CD68 by IHC.
mRNA gene signature (transcriptomics/ Nanostring) with special interest in IFN gene signature 
(PanInflammatory panel and/or IO360 panel).
Peripheral blood:
-CSF) contingent on 
availability of assay (i.e. SIMOA).
Phenotype and markers of IC activation in peripheral blood (e.g., CD3, CD8, CD4, TRegs, CD4 
memory cells, CD25, FOXP3, CD45RA, ICOS, CD14. CD45, CD56, CD19 and ICOSLG) (FACS or 
ChipCytometry).
PBMCs gene signature (ribonucleic acid [RNA]) (transcriptomics Nanostring).
ICOS RO in PBMCs (KY1044 as single agent in Phase 1 only).
All exploratory endpoints will be presented graphically as appropriate.
10.6 Pharmacokinetic and Anti-drug Antibody Analyses
10.6.1 Pharmacokinetic Analyses
The serum PK of KY1044 as a single agent and in combination with atezolizumab  will be characterized 
using non-compartmental analysis (NCA). Nominal times of sample collections will be used for the 
noncompartmental analysis (NCA). All BLQ values will be set to 0 units.
The following PK measures will be calculated, whenever possible, from serum concentrations:
Cmax: Maximum concentration (for atezolizumab 
only one time point of serum concentration at the end of 
infusion)
tmax: Time of the maximum concentration (obtained without interpolation)
Ctrough: Trough concentrations
z: Terminal elimination rate constant (whenever possible) using Linear Up Log Down method of 
determination and Best Fit setting.
AUC0-last: Area under the concentration-time curve calculated using linear trapezoidal summation from time 
last measurable concentration
AUC0-inf: Area under the concentration-time curve from 0 to infinity, calculated using the formula: AUC0-inf = 
AUC0-last + Clast
z
z is the apparent terminal elimination rate constant
Clearance
Volumes of distribution
t½: Half-life


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The following diagnostic criteria will be used to flag individual data in Listings:
%AUCextrap is 30% (criteria for exclusion of parameters: AUCinf, t-half, CL, CLss, Vz, Vss) 
For KY1044, all peak (end-of-infusion) and trough (pre-infusion) concentrations will be tabulated. For 
KY1044 peak and trough concentrations will be tabulated separately for use as a single agent and for 
combination with atezolizumab.
Besides listings of pharmacokinetic measures for individual patients, all measures will be summarized by 
descriptive statistics (N, Mean, SD, SE, Min, Median, Max, CV%, and Geometric Mean (only for ratios). 
The summaries will include estimates of not only central tendency but variability such as Standard Error
(SE). For tmax median (and range) and for half-lives, arithmetic means will be provided. Besides listings of 
concentrations, NCA Mean parameter tables, charts illustrating the mean concentration-time profiles will 
be generated. 
10.6.2 Anti-drug Antibody Analysis
The anti-drug antibody analysis will be performed on anti-drug antibody evaluable set.
The anti-drug antibody results will be analyzed descriptively for patients who develop detectable
anti-KY1044 and anti-atezolizumab antibodies. The titer of anti-KY1044 and anti-atezolizumab antibodies 
will be summarized using summary statistics (n, mean, STD, median, minimum and maximum values). The 
presence of anti-KY1044 and anti-atezolizumab antibodies will be summarized using frequency counts and 
percentage.
The mean (±STD) plot of titer values of anti-KY1044 and anti- atezolizumab antibodies will be presented.
The summary of anti-KY1044 antibodies incidence will be presented. 
The by-subject data listing will be presented.
10.6.3 Biomarker Analysis
The biomarker analysis will be performed on all patients in biomarker evaluable set. 
The descriptive summary of change in following marker will be presented:
number of ICOS positive regulatory T cells (ICOS+FOXP3+) per mm2
in the
tumor
microenvironment.
number of CD8 positive cells per mm2 in the tumor
number of CD8 positive cells per mm2 in the invasive margin
ratio of CD8 T cells per mm2 to the number of ICOS positive regulatory T cells per mm2
CD8 to Regulatory T-cells ratio
ChipCytometry Assay
The biomarkers data will be listed in subject data listing.
10.7 Safety Analyses
Unless otherwise specified all safety analysis will be based on safety analysis set.
10.7.1 Adverse Events
AEs will be coded using the MedDRA Version 21.0 or higher.


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The analysis described in this section will be based on TEAEs and will be tabulated by SOC and/or PT. 
The number and percentage of patients experiencing each event at least once will be summarized. 
A summary of AEs, including the number of events reported, the number of DLTs reported within 21 days 
of treatment (Phase 1 only), and the number and percentage of 
patients reporting at least one TEAE by SOC and PT, 
patients
by SOC and PT,
patients with at least one TEAE by SOC, PT and maximum CTCAE grade
patients with at least one TEAE by PT,
patients with at least one TEAE related to KY1044 by PT,
patients with at least one TEAE related to KY1044 TEAE by SOC and PT,LLOQ
patients with at least one TEAE related to Atezolizumab by SOC and PT,
patients with at least one TEAE related to either study drug by SOC and PT,
patients with at least one greater than or equal to CTCAE grade 3 TEAE related to KY-1044 by 
SOC and PT,
patients with at least one greater than or equal to CTCAE grade 3 TEAE related to Atezolizumab
by SOC and PT,
patients with at least one KY1044-related TEAE by SOC, PT and maximum CTCAE grade,
patients with at least one Atezolizumab-related TEAE by SOC, PT and maximum CTCAE grade,
patients with an TEAE leading to study discontinuation of either study drug by SOC and PT, 
patients with an TEAE leading to discontinuation of KY1044 by SOC and PT, 
patients with an TEAE leading to discontinuation of Atezolizumab by SOC and PT, 
patients with an TEAE leading to interruption of KY1044 by SOC and PT,
patients with an TEAE leading to interruption of Atezolizumab by SOC and PT, 
patients with an TEAE leading to interruption of either study drug by SOC and PT, 
patients with an TEAE leading to reduction of KY1044 by SOC and PT, 
patients with at least one TEAE of special interest by SOC and PT
patients with at least one irAE by SOC and PT
will be presented. In the summary by worst CTCAE grade, the TEAE with the highest or most severe grade 
will be counted when patients have multiple TEAEs, overall, in a SOC or in a PT as appropriate.
A breakdown of the number and percentage of patients reporting each kind of TEAE above, categorized by 
SOC and PT, will be also presented. This breakdown will be sorted by decreasing frequency of PT within 
SOC. Note that counting will be by subject and not by event and patients are only counted once within each 
SOC or PT. This breakdown will be repeated and sorted by decreasing frequency of PTs in the KY1044 
group for patients reporting at least one TEAE and patients reporting at least one CTCAE grade 3 and 
above TEAE. This breakdown will also be repeated by worst CTCAE grade for patients reporting at least 
one TEAE and patients reporting at least one CTCAE grade 3 and above TEAE, sorted by PT within SOC.
All adverse events (including non-treatment-emergent events) recorded on the CRF will be listed.


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10.7.2 Deaths and Serious Adverse Events
A summary of TEAEs, including the number of events reported, the number and percentage of patients
reporting at least one SAE and deaths will be presented.
The following summaries of AEs will be provided for each treatment group by MedDRA primary SOC and 
PT: 
Serious TEAEs
Serious TEAEs related to KY1044
Serious TEAEs related to Atezolizumab
Serious TEAEs of special interest
TEAEs with an outcome of death
TEAEs related to KY1044 with an outcome of death
Post treatment AEs with an outcome of death
The listings of all SAEs and AEs with outcome of death will be provided. A separate listing of all deaths
during treatment will be provided.
10.7.3 Laboratory Data
Actual values, based on central laboratory results, at each planned visit and change in values from baseline 
at each post-baseline planned visit will be summarized. Nominal visits will be used for these summaries but 
unscheduled visits will also be considered when looking at potentially clinically important (PCI) results 
across the entire treatment period.
For parameters that were graded, the worst grade (in the appropriate direction(s)) post-baseline (including 
from unscheduled assessments) and shifts in grade from baseline to worst will be summarized. All 
laboratory results over time will be presented in a listing, including reference ranges and indications of out 
of range values, grading (if done), and an assessment of clinical significance by the Investigator.
Baseline is defined as the last measurement prior to first study drug administration. If the assessment is 
made on the same day as first study drug administration and there are no times to indicate that it was after 
administration, it will be assumed to be prior and therefore qualify as the baseline measurement. 
Potential Hepatotoxicity will be summarized by time point.
To address the impact of global pandemic of COVID-19, the local laboratory results for all assessment time
central laboratory samples are 
collected at a visit due to COVID-19 where local laboratory is collected instead. The separate listing will be 
presented for all local laboratory results obtained from the unscheduled CRF page.
Local laboratory results collected at Screening will be listed separately.
10.7.4 Vital Signs
Vital signs at each scheduled visit will be summarized along with the change from baseline to post-baseline 
visits. A summary of abnormal vital signs will also be presented, where abnormal vital signs are systolic 
blood pressure >140 mmHg, diastolic blood pressure >90 mmHg, heart rate <60 beats/min or >100 
beats/min, or temperature >37.5°C.
Baseline is defined as the last measurement prior to first study drug administration. If the assessment is 
made on the same day as first study drug administration and there are no times to indicate that it was after 
administration, it will be assumed to be prior and therefore qualify as the baseline measurement. 




Statistical Analysis Plan (SAP)
Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
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References
1.
Guo W, Wang S-J, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design addressing 
azor: mTPI-2. Contemporary Clinical Trials. 2017 Jul; 58:23 33.
2.
Ji Y, Wang S-J. Modified Toxicity Probability Interval Design: A Safer and More Reliable Method Than 
the 3 + 3 Design for Practical Phase I Trials. Journal of Clinical Oncology. 2013 May 10;31(14):1785
91.


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Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
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Appendix
12.1 Example mTPI-2 Decision Table
Column indicates the number of patients treated. Row indicates the number of patients with DLTs.
Decisions for both mTPI and mTPI-2. For each column (the number of patients treated), there are two
sub-columns listing the decisions of mTPI and mTPI-2 side by side. Here, the target toxicity probability
pT=0.30, e1=0.05 and e2=0.05.








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Version Date: 24-May-2024
Sponsor: Sanofi
Protocol No: KY1044-CT01
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Additional approvers from Kymab are added in.
In the 
Section 8.0 Study Design
The treatment duration is updated to 48 months as per protocol amendment 
version 6.0.
The figure of study design is added.
Enrollment for patients in Phase 1 and Phase 2 is detailed as in protocol.
Section 9.2 Analysis Sets
The screened subject and enrolled subject are defined separately.
Section10.3 Prior and Concomitant Medications
The medication taken post-study are defined.
Section 10.4 End of Study for Individual Patient is included.
The definition of Time since Initial Diagnosis is included in Section 10.5.
Section 10.6 Efficacy Analysis
The derivation of Duration of Response and Progression-free Survival by 
iRECIST is included.
The confirmatory Stable Disease response criteria is considered of 7 
weeks.
Section 10.8.2 Treatment Emergent Adverse Events
days after the last dose
Section 12.0 Statistical Analysis Method
The tables, figures and listings for the Phase II part of the study will be 
presented by indication and dose group(s) within KY1044 single agent and 
KY1044 combination groups, split by anti-PD-(L)1 naïve and pre-treated 
groups.
Section 12.4 Protocol Deviations
The listing of protocol deviation for all deviations related to COVID-19 is 
included.
Section 12.5 Efficacy Analyses
In this section the endpoints and analysis is separated by primary, 
secondary and exploratory endpoints.
The confidence interval of median, 25th and 75th percentile of progression-
free survival and overall survival is updated to use Brookmeyer-Crowley
method.
-
free survival and overall survival is updated to use complementary log-log 
transformation method.
Section 12.7 Safety Analysis
The definition of treatment emergent adverse is updated to match the 
protocol. 
The definitions of adverse events, dose limiting toxicity are removed as they 
are not need for the analysis.
Section 13 Reference
The references for Bayesian interval dose-finding design and Modified 
Toxicity Probability Interval Design is added in.