First-in-Human Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of M1069 in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors
Phase: PHASE1
Conditions: Metastatic or Locally Advanced Unresectable Solid Tumors
Sponsor: EMD Serono Research & Development Institute, Inc.

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Clinical Study Protocol  
Title Page  
Clinical Study Protocol Title: 
First-in-Human Study to Investigate the Safety, 
Tolerability, Pharmacokinetics, 
Pharmacodynamics and Clinical Activity of 
M1069 in Participants with Metastatic or Locally 
Advanced Unresectable Solid Tumors 
Study Number: 
MS201929_0032 
Merck Compound: 
M1069 
Merck Registered Compound Name in 
Japan: 
Not applicable 
Study Phase: 
Phase 1 
Short Title: 
First in Human Study of M1069 in Advanced 
Solid Tumors 
Coordinating Investigator: 
 
 
 
 
 
PPD

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Sponsor Name and Legal Registered 
Address: 
Sponsor: 
Affiliates of Merck KGaA, Darmstadt, Germany 
For all countries, except the US and Canada: 
Merck Healthcare KGaA, Darmstadt, Germany 
an affiliate of Merck KGaA, Darmstadt, Germany 
Frankfurter Str. 250 
64293, Darmstadt, Germany 
In the US and Canada: 
EMD Serono Research & Development Institute, 
Inc. 
an affiliate of Merck KGaA, Darmstadt, Germany 
45A Middlesex Turnpike 
Billerica, MA, 01821, USA 
Regulatory 
Agency 
Identifying 
Numbers: 
IND: 
 
Protocol Version: 
11 November 2021 / Version 2.0 
Replaces Version: 
24 September 2021 / Version 1.0 
Key Words: 
Adenosine antagonist, A2A/A2B receptors 
- Confidential – 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2021 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved. 
 
 
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Protocol Amendment Summary of Changes 
Protocol History 
 
Version Number 
Type 
Version Date 
1.0 
Original Protocol 
24 September 2021 
2.0 
Global Amendment 
11 November 2021 
Note: No participants were enrolled on version 1.0. 
Protocol Version 2.0 (11 November 2021) 
Overall Rationale for the Amendment 
To incorporate revisions based on feedback from a regulatory agency.  Additionally, changes made 
to Sponsor’s global protocol template implemented. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 
2.3.1 (Risk 
Assessment) 
In Table 3, revise CNS AE to Excitatory AE. 
Correction to align with Investigator’s 
Brochure. 
Section 
5.1 (Inclusion 
Criteria), Criteria #6 
Use only 1 method to establish renal eligibility. 
Simplification. 
Section 
5.3.1 (Meals and 
Dietary Restrictions)  
Clarify sequence for potential SMC 
recommendation to change to fed condition at 
higher doses.  
Clarification. 
Section 
6.6.3 (Definition of 
Dose-limiting 
Toxicity) 
6.6.4 (Dose 
Modification …) 
7.1 (Discontinuation 
of Study 
Intervention) 
8.2.4 
(Ophthalmologic 
Assessments) 
 
Clarification.  
Section  
8.3.1 (Time Period 
and Frequency of 
Collecting ….) 
8.3.4. (Regulatory 
Reporting 
Requirements for 
Serious Adverse 
Events) 
Clarification of Investigator reporting SAEs to 
Merck according to the required timeframe. 
Change to Sponsor’s global standard 
protocol. 
Section 
8.3.8 (Adverse 
Events of Special 
Interest) 
Remove reference to central reader. 
Correction 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 
9.3 (Populations for 
Analysis) 
Add a compliance criterion to DLT population. 
Correction to standard description. 
Appendix 4, 
(Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, Follow-
up, and Reporting) 
Clarification of Investigator reporting SAEs to 
Merck according to the required timeframe. 
Change to Sponsor’s global standard 
protocol. 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor; therefore, have not been 
summarized. 
AE = Adverse event, DLT = Dose limiting toxicity, SAE = Serious adverse event, SMC = Safety 
Monitoring Committee. 

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Table of Contents  
Title Page 
 ..............................................................................................................1 
Table of Contents  ..............................................................................................................5 
Table of Tables 
 ..............................................................................................................9 
Table of Figures 
 ..............................................................................................................9 
1 
Protocol Summary ..............................................................................10 
1.1 
Synopsis ..............................................................................................10 
1.2 
Schema ................................................................................................12 
1.3 
Schedule of Activities .........................................................................12 
2 
Introduction .........................................................................................23 
2.1 
Study Rationale ...................................................................................23 
2.2 
Background .........................................................................................24 
2.3 
Benefit/Risk Assessment ....................................................................25 
2.3.1 
Risk Assessment .................................................................................25 
2.3.2 
Benefit Assessment .............................................................................28 
2.3.3 
Overall Benefit: Risk Conclusion .......................................................28 
3 
Objectives and Estimands ...................................................................28 
4 
Study Design .......................................................................................32 
4.1 
Overall Design ....................................................................................32 
4.2 
Scientific Rationale for Study Design ................................................34 
4.2.1 
Participant Input into Design ..............................................................34 
4.3 
Justification for Dose ..........................................................................34 
4.4 
End of Study Definition ......................................................................37 
5 
Study Population .................................................................................37 
5.1 
Inclusion Criteria ................................................................................37 
5.2 
Exclusion Criteria ...............................................................................40 
5.3 
Lifestyle Considerations .....................................................................42 
5.3.1 
Meals and Dietary Restrictions ...........................................................42 
5.3.2 
Caffeine, Alcohol, Tobacco, and Cannabinoid ...................................43 
5.3.3 
Activity ...............................................................................................43 
5.4 
Screen Failures ....................................................................................44 
6 
Study Intervention(s) ..........................................................................44 

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6.1 
Study Intervention(s) Administration .................................................44 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................44 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................45 
6.3.1 
Study Intervention Assignment ..........................................................45 
6.3.2 
Emergency Blinding ...........................................................................45 
6.4 
Study Intervention Compliance ..........................................................46 
6.5 
Concomitant Therapy .........................................................................46 
6.5.1 
Rescue Medicine .................................................................................46 
6.5.2 
Permitted Medicines ...........................................................................46 
6.5.3 
Prohibited Medicines ..........................................................................47 
6.5.4 
Other Interventions .............................................................................49 
6.6 
Dose Selection and Modification ........................................................49 
6.6.1 
Retreatment Criteria ............................................................................50 
6.6.2 
Safety Monitoring Committee (SMC) ................................................50 
6.6.3 
Definition of Dose-limiting Toxicity ..................................................50 
6.6.4 
Dose Modification Outside of the DLT Period ..................................52 
6.7 
Study Intervention After the End of the Study ...................................54 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................55 
7.1 
Discontinuation of Study Intervention................................................55 
7.1.1 
Treatment Beyond Initial Progression ................................................57 
7.1.2 
Treatment Beyond Confirmed Progression ........................................57 
7.1.3 
Continuation of Study Intervention After Local Treatment of 
Disease Progression ............................................................................57 
7.1.4 
Rechallenge .........................................................................................58 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................58 
7.3 
Lost to Follow-Up...............................................................................59 
8 
Study Assessments and Procedures ....................................................59 
8.1 
Efficacy Assessments and Procedures ................................................60 
8.2 
Safety Assessments and Procedures ...................................................61 
8.2.1 
Physical Examinations ........................................................................61 
8.2.2 
Vital Signs ..........................................................................................61 

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8.2.3 
Electrocardiograms .............................................................................62 
 
 .............................................................62 
8.2.5 
Clinical Safety Laboratory Assessments ............................................63 
8.2.6 
Suicidal Ideation and Behavior Risk Monitoring ...............................63 
8.3 
Adverse Events and Serious Adverse Events .....................................63 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ....................................................64 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ...64 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events ...............64 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .....65 
8.3.5 
Pregnancy ...........................................................................................65 
8.3.6 
Cardiovascular and Death Events .......................................................66 
8.3.7 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ................................................................67 
8.3.8 
Adverse Events of Special Interest .....................................................67 
8.4 
Treatment of Overdose .......................................................................68 
8.5 
Pharmacokinetics ................................................................................68 
 
69 
 
70 
 
.70 
8.9 
Immunogenicity Assessments ............................................................71 
8.10 
Health Economic ................................................................................71 
9 
Statistical Considerations ....................................................................71 
9.1 
Statistical Hypotheses .........................................................................72 
 
72 
9.3 
Populations for Analyses ....................................................................72 
9.4 
Statistical Analyses .............................................................................73 
9.4.1 
Efficacy Analyses ...............................................................................74 
9.4.2 
Safety Analyses ..................................................................................75 
9.4.2.1 
Dose Escalation ..................................................................................76 
 
77 
9.4.3.1 
Pharmacokinetic Profile ......................................................................78 
 
 .......................................................78 
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 ...........................................78 
9.4.4 
Sequence of Analyses .........................................................................78 
10 
References ...........................................................................................79 
11 
Appendices .........................................................................................81 
Appendix 1 
Abbreviations ......................................................................................81 
Appendix 2 
Study Governance ...............................................................................85 
Appendix 3 
Contraception ......................................................................................92 
Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ................................................94 
Appendix 5 
Liver Safety: Suggested Actions and Follow-up Assessments .........100 
Appendix 6 
Clinical Laboratory Tests .................................................................101 
 
 
Appendix 8 
Model for Bayesian Dose Escalation ................................................103 
Appendix 9 
Protocol Amendment History ...........................................................105 
Appendix 10 
Sponsor Signature Page ....................................................................106 
Appendix 11 
Coordinating Investigator Signature Page ........................................107 
Appendix 12 
Principal Investigator Signature Page ...............................................108 
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Table of Tables 
Table 1 
Schedule of Activities .........................................................................13 
Table 2 
Schedule of Electrocardiogram, Pharmacokinetic, and Biomarker 
Assessments during Dose Escalation ..................................................21 
Table 3 
Potential risks of M1069 .....................................................................26 
Table 4 
Objectives, Endpoints and Other Estimand Attributes .......................29 
36 
36 
Table 7 
List of Prohibited Drugs and Drugs To Be Used with Caution ..........48 
Table 8 
Recommended Temporary Treatment Discontinuation for M1069 
for General Toxicity (outside of DLT Period) ....................................53 
Table 9 
Recommended Dose Modifications for Ophthalmological 
Findings on Treatment ........................................................................54 
Table 10 
Assessment of Plasma Pharmacokinetic Parameters ..........................69 
Table of Figures  
Figure 1 
Schema ................................................................................................12 
 
 
 
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1 
Protocol Summary  
1.1 
Synopsis  
Protocol Title: First-in-Human Study to Investigate the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Clinical Activity of M1069 in Participants with Metastatic or Locally 
Advanced Unresectable Solid Tumors 
Short Title: First in Human Study of M1069 in Advanced Solid Tumors 
Rationale: 
A2A and A2B adenosine receptors have been shown to mediate immunosuppressive and 
tumor-promoting signals in the tumor microenvironment. 
 
 
 
 
 
 
 
 
Based on results from nonclinical safety pharmacology and toxicology investigations, the safety 
profile of M1069 is considered adequate for patients with advanced/metastatic solid tumors at the 
projected dose levels. Clinical experience with dual adenosine A2A/A2B antagonism published in 
the literature suggests an acceptable safety profile as a monotherapy and no potentiating toxicities 
in combination with other immunotherapies. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
To determine dose toxicity relationship and 
MTD (if reached) of M1069 as a monotherapy 
in participants with solid tumors. 
x 
Occurrence of DLTs. 
x 
Occurrence of AEs and treatment-related adverse 
events. 
To determine the RDE of M1069 for further 
exploratory clinical development. 
In addition to safety, tolerability, PK, Pd (
 in ex-vivo 
stimulated blood), post-treatment changes in TME in 
available paired tumor biopsies data are considered. 
Secondary 
To characterize the PK profile of M1069. 
PK parameters of M1069 after single dose administration 
and at steady state using non-compartmental analysis.  
To evaluate indicators of clinical activity of 
M1069 in terms of objective response using 
RECIST v1.1. 
Objective response using RECIST v1.1, as assessed by 
Investigator. 
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Objectives 
Endpoints 
To evaluate indicators of clinical activity of 
M1069 in terms of DoR using RECIST v1.1. 
Duration of response according to RECIST v1.1 as 
assessed by Investigator, defined as time from first 
documentation of objective response to PD or death, 
occurring within 2 scheduled tumor assessments after last 
evaluable assessment or start of treatment. 
To evaluate indicators of clinical activity of 
M1069 in terms of PFS using RECIST v1.1. 
Progression-free survival as defined from date of first study 
intervention to PD according to RECIST v1.1 as assessed 
by Investigator or death. Events are considered only if 
occurring within 2 scheduled tumor assessments after last 
evaluable assessment or start of treatment. 
To assess the effect of M1069 on QT interval.  
Change from baseline QTc (ǻQTc) over time. 
AE = Adverse event, DLT = Dose-limiting toxicity, DoR = Duration of response, MTD = Maximum tolerated dose, 
, PD = Progressive disease, 
Pd = Pharmacodynamic, PFS =Progression-free survival, PK = Pharmacokinetic, QTc = QT interval corrected, 
RDE = Recommended dose for expansion, RECIST = Response Evaluation Criteria in Solid Tumors, TME = Tumor 
microenvironment. 
 
Overall Design: 
This is a Phase I First in Human (FIH) dose escalation of M1069, noncontrolled, open label, 
multicenter clinical study designed to determine the safety, tolerability, PK, Pd and early signs of 
efficacy in participants with advanced solid malignancies. A Bayesian study design will be applied, 
using a Bayesian 2-parameter logistic regression model (BLRM). 
The study will include up to 28 days Screening period, a study intervention period consisting of 
consecutive 21-day cycles with twice daily oral administration of M1069, a DLT observation 
period of 21 days, End of Study Intervention Visit and a Safety Follow-up period of 30 ± 7 days 
after the last M1069 intake. Participants who tolerate treatment without significant clinically 
relevant toxicities may continue to receive their assigned dose until progressive disease. 
Participants who discontinue study intervention for any reason will complete the End of Study 
Intervention Visit. 
Disclosure Statement: This is a single group treatment study with 1 arm that is not blinded. 
Number of Arms: 1 
Blinding: Open label. 
Number of Participants: The total sample size will depend on the number of cohorts to be 
evaluated. The planned cohort size is 3 participants. Data observed during the dose escalation (e.g., 
number of DLTs) have an impact on the number of cohorts. The sample size for the RDE and 
MTD dose levels needs to be at least 6. It is anticipated that 21 to 30 participants (5 projected dose 
levels with 3 to 9 participants each) may be needed. 
Study Intervention Groups and Duration: The treatment period will begin at the first dose of 
M1069 with Cycle 1 Day 1 (C1D1) and consists of consecutive 21-days cycles with twice daily 
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oral administration (BID) until disease progression, unacceptable toxicity, withdrawal of consent, 
or any criterion for withdrawal from study intervention. 
For dose cohorts, the SMC will provide recommendations on the dose level and regimen for the 
next cohort. 
The term “cohort” with regards to dose escalation in this protocol is referring to a group of 
participants that are enrolled at the same dose level and evaluated by an SMC before the dosing 
decision for the next cohort is made. There may be more than one cohort on the same dose level, 
if the SMC decides that a further cohort on the same dose level is needed. 
Involvement of Special Committee(s): Yes, Safety Monitory Committee 
1.2 
Schema  
Figure 1 
Schema  
 
DL = Dose level, DLT= Dose-limiting toxicity, FFPE = Formalin-fixed paraffin-embedded, 
MTD= Maximum tolerated dose, RDE = Recommended dose for expansion. 
For additional information on the study design, including adaptability of escalation scheme, see 
Section 4.1. 
1.3 
Schedule of Activities  
Schedules of activities are presented in Table 1 and Table 2. 
 

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Table 1 
Schedule of Activities  
 
Assessments 
and Procedures 
Screening 
D -1 
Intervention Period 
(21-Day Cycles) 
 
EOSI 
Safety 
FU 
Notes 
 
 
Cycle 
1, 2 
Cycles 
3, 4, 5 
Cycles 
≥ 6 
Even cycles 
Cycles 
≥ 7 
Odd 
cycles 
 
 
 
Day  
-28 to -1 
-1 
1 
8 
15 
1 
15 
1 
15 
8 
EOSI 
+7 
Days 
Last 
Dose  
+ 30 
Days 
Visit window 
(days) 
Up to 28 
days 
before 
Day 1 
 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 7) 
 
EOSI within 7 days of 
decision to discontinue 
but before start of 
subsequent anticancer 
treatment. 
Informed 
consent 
X 
 
 
 
 
 
 
 
Inclusion and 
exclusion 
criteria 
X 
 
X 
 
 
 
 
 
 
In- and exclusion criteria 
will be reviewed during 
Screening and must still 
be met prior to initial 
dosing on C1D1. 
Demography 
X 
 
 
 
 
 
 
 
Physical 
examination  
X 
 
X 
Xa 
Xa 
X 
Xa 
X 
Xa 
Xa 
X 
X 
Details in Section 8.2.1. 
Xa Brief physical 
examination including 
peripheral motor and 
sensory nervous 
system. 

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Assessments 
and Procedures 
Screening 
D -1 
Intervention Period 
(21-Day Cycles) 
 
EOSI 
Safety 
FU 
Notes 
 
 
Cycle 
1, 2 
Cycles 
3, 4, 5 
Cycles 
 6 
Even cycles 
Cycles 
 7 
Odd 
cycles 
 
 
 
Day  
-28 to -1 
-1 
1 
8 
15 
1 
15 
1 
15 
8 
EOSI 
+7 
Days 
Last 
Dose  
+ 30 
Days 
 
Visit window 
(days) 
Up to 28 
days 
before 
Day 1 
 
 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
 
(± 7) 
 
EOSI within 7 days of 
decision to discontinue 
but before start of 
subsequent anticancer 
treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
disease history 
(includes 
substance 
usage) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Substances: drugs, 
alcohol, tobacco, and 
caffeine (see Section 
5.3). 
Prior anticancer 
therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(WOCBP only) 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Serum only at Screening 
and urine or serum for all 
other cycles. Details in 
Appendix 6. 
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Assessments 
and Procedures 
Screening 
D -1 
Intervention Period 
(21-Day Cycles) 
 
EOSI 
Safety 
FU 
Notes 
 
 
Cycle 
1, 2 
Cycles 
3, 4, 5 
Cycles 
≥ 6 
Even cycles 
Cycles 
≥ 7 
Odd 
cycles 
 
 
 
Day  
-28 to -1 
-1 
1 
8 
15 
1 
15 
1 
15 
8 
EOSI 
+7 
Days 
Last 
Dose  
+ 30 
Days 
 
Visit window 
(days) 
Up to 28 
days 
before 
Day 1 
 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 7) 
 
EOSI within 7 days of 
decision to discontinue 
but before start of 
subsequent anticancer 
treatment. 
HBV, HCV, HIV 
testing (if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV according to country 
policy. Details in 
Appendix 6. 
Clinical 
laboratory tests 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
72 h-window allowed 
prior to C1D1, refers to 
biochemistry, 
hematology and 
coagulation. Details in 
Appendix 6. 
ECOG PS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
72h-window allowed 
prior to C1D1. 
Urine analysis 
X 
 
X† 
 
 
X† 
 
 
 
X† 
 
 
X† Only in odd Cycles 
Every 6 weeks (± 7 days) 
Details in Appendix 6. 
Vital signs  
X 
 
X 
X† 
X† 
X# 
X 
X@ 
X 
X 
X 
X 
Includes height (collect 
at Screening only) and 
weight. 
See Table 2 for detailed 
timepoint on the 
following cycle days: 
X† Only in Cycle 1 
X# Only in Cycle 4 
X@ Only C6D1 and C8D1 

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Assessments 
and Procedures 
Screening 
D -1 
Intervention Period 
(21-Day Cycles) 
 
EOSI 
Safety 
FU 
Notes 
 
 
Cycle 
1, 2 
Cycles 
3, 4, 5 
Cycles 
≥ 6 
Even cycles 
Cycles 
≥ 7 
Odd 
cycles 
 
 
 
Day  
-28 to -1 
-1 
1 
8 
15 
1 
15 
1 
15 
8 
EOSI 
+7 
Days 
Last 
Dose  
+ 30 
Days 
 
Visit window 
(days) 
Up to 28 
days 
before 
Day 1 
 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 7) 
 
EOSI within 7 days of 
decision to discontinue 
but before start of 
subsequent anticancer 
treatment. 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
To exclude infections, to 
be done before CT for 
RECIST assessment, if 
applicable. 
CT (chest, 
abdomen) or MRI 
X 
 
 
 
 
X† 
 
 
 
X† 
 
 
X† Only in odd Cycles 
At Screening and for 
response assessment 
via RECIST v1.1; tumors 
will be assessed every 
6 weeks (± 7 days) until 
progression. With 
contrast only if renal 
activity allows. 
Holter ECG 
(Holter recorder) 
 
X 
X# 
X# 
 
 
 
 
 
 
 
 
X# Only in Cycle 1 
Detailed timepoints in 
Table 2. 

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Assessments 
and Procedures 
Screening 
D -1 
Intervention Period 
(21-Day Cycles) 
 
EOSI 
Safety 
FU 
Notes 
 
 
Cycle 
1, 2 
Cycles 
3, 4, 5 
Cycles 
≥ 6 
Even cycles 
Cycles 
≥ 7 
Odd 
cycles 
 
 
 
Day  
-28 to -1 
-1 
1 
8 
15 
1 
15 
1 
15 
8 
EOSI 
+7 
Days 
Last 
Dose  
+ 30 
Days 
 
Visit window 
(days) 
Up to 28 
days 
before 
Day 1 
 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 7) 
 
EOSI within 7 days of 
decision to discontinue 
but before start of 
subsequent anticancer 
treatment. 
Triplicate digital 
ECG (Holter 
recorder) 
 
 
Xa 
 
X#a 
X# 
X† 
 
 
 
 
 
 
 
X# Only in Cycle 1. 
X† Only in Cycle 4. 
Xa Included in the Holter 
ECG. 
To be taken before any 
blood sampling; Detailed 
timepoints in Table 2. 
12-lead ECG 
Safety 
(Holter recorder) 
X 
 
X 
X# 
X# 
X† 
 
X† 
 
 
X 
X 
X# Only in Cycle 1 
X† Only in even Cycles 
To be taken before any 
blood sampling; safety 
ECGs to be locally read. 
and extracted from 
Holter recorder; Detailed 
timepoints in Table 2 
PK 
 
 
X 
X† 
X† 
X# 
 
X@ 
 
 
 
 
X† Only in Cycle 1. 
X# Only in Cycle 4. 
X@ Only C6D1 and 
C8D1. 
Detailed timepoints in 
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Assessments 
and Procedures 
Screening 
D -1 
Intervention Period 
(21-Day Cycles) 
 
EOSI 
Safety 
FU 
Notes 
 
 
Cycle 
1, 2 
Cycles 
3, 4, 5 
Cycles 
 6 
Even cycles 
Cycles 
 7 
Odd 
cycles 
 
 
 
Day  
-28 to -1 
-1 
1 
8 
15 
1 
15 
1 
15 
8 
EOSI 
+7 
Days 
Last 
Dose  
+ 30 
Days 
 
Visit window 
(days) 
Up to 28 
days 
before 
Day 1 
 
 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
 
(± 7) 
 
EOSI within 7 days of 
decision to discontinue 
but before start of 
subsequent anticancer 
treatment. 
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Assessments 
and Procedures 
Screening 
D -1 
Intervention Period 
(21-Day Cycles) 
 
EOSI 
Safety 
FU 
Notes 
 
 
Cycle 
1, 2 
Cycles 
3, 4, 5 
Cycles 
 6 
Even cycles 
Cycles 
 7 
Odd 
cycles 
 
 
 
Day  
-28 to -1 
-1 
1 
8 
15 
1 
15 
1 
15 
8 
EOSI 
+7 
Days 
Last 
Dose  
+ 30 
Days 
 
Visit window 
(days) 
Up to 28 
days 
before 
Day 1 
 
 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
 
(± 7) 
 
EOSI within 7 days of 
decision to discontinue 
but before start of 
subsequent anticancer 
treatment. 
Drug dispense  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
C
C
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Assessments 
and Procedures 
Screening 
D -1 
Intervention Period 
(21-Day Cycles) 
 
EOSI 
Safety 
FU 
Notes 
 
 
Cycle 
1, 2 
Cycles 
3, 4, 5 
Cycles 
 6 
Even cycles 
Cycles 
 7 
Odd 
cycles 
 
 
 
Day  
-28 to -1 
-1 
1 
8 
15 
1 
15 
1 
15 
8 
EOSI 
+7 
Days 
Last 
Dose  
+ 30 
Days 
 
Visit window 
(days) 
Up to 28 
days 
before 
Day 1 
 
 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
(± 1) 
 
(± 7) 
 
EOSI within 7 days of 
decision to discontinue 
but before start of 
subsequent anticancer 
treatment. 
M1069 
administration 
 
 
Å========= twice daily oral administration (BID) ========Æ  
 
 
SMC may recommend 
alternative regimens. 
AE & SAE review 
Å====================================================================Æ  
From the time of signing 
ICF to Safety Follow-up 
Visit. 
Concomitant 
medication and 
procedure 
review 
Å====================================================================Æ  
From the time of signing 
ICF to Safety Follow-up 
Visit. 
AE = Adverse event, BID = Twice daily, C = Cycle, CREB = cAMP response element-binding protein, CT = Computed tomography, D = (Study) Day; DL = Dose 
Level; ECG = Electrocardiogram, ECOG = Eastern Cooperative of Oncology Group, EOSI = End of Study Intervenion‚ FU = Follow-up, HBV = Hepatitis B virus, 
HCV = Hepatitis C virus , HIV = Human immunodeficiency virus, ICF = Informed Consent Form, MRI = Magnetic resonance imaging, 
 
 Pd = Pharmacodynamic, PK = Pharmacokinetic, 
, RDE = Recommended dose for 
expansion, RECIST = Response Evaluation Criteria in Solid Tumors, SAE = Serious adverse event, SMC = Safety Monitoring Committee, WOCBP = Women of 
childbearing potential. 
 
 
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See for Table 2 timepoints within visit days for ECG, PK, 
 and 
 assessments. At visits where assessment timepoints coincide 
with each other: (ECG, PK, 
 the following is the order of assessments: 
1. Put the participant at supine position at least 15 min before the PK blood sampling timepoint to allow a 10 min supine rest and 
a 5 min window for ECG data collection. 
2. Perform vital signs assessments first. 
3. ECG assessments slightly before the specific collection timepoint; ECGs have to be taken before any blood sampling. 
4. PK assessments at scheduled collection timepoint. 
5. 
 assessment as last assessment. 
 
Table 2 
Schedule of Electrocardiogram, Pharmacokinetic, and Biomarker Assessments during Dose Escalation  
Cycle/Day 
Hour 
(±min) 
Hour (±min) 
(relative to 
the first 
dose on the 
day) 
Vital 
signs 
Holter 
recorder 
for 
continuous 
ECG 
Holter recorder for 
triplicate digital ECG 
Holter 
recorder 
for safety 
ECG 
 
PK 
Notes 
C1D -1 
 
 
X 
Start Holter 
recording 
 
 
 
 
C1D1* 
Predose 
(within 2h) 
X 
 
 
X 
-15 min 
X 
On C1D-1: set-up Holter recorder and 
encourage normal activity, record continuous 
Holter ECGs until C1D1 8h post-dose. 
On C1D1 and C1D8: Start recording Holter 
ECGs at least 1 hour before the first dose. 
Triplicate digital ECGs will be extracted from 
Holter ECGs at predose (-45, -30, -15min), 1h, 
2h, 4h, 6h and 8h.  
0.5h (±5 min) 
 
 
 
 
X 
1h (±5 min) 
X 
 
 
X 
X 
1.5h (±5 min) 
 
 
 
 
X 
2h (±10 min) 
X 
 
 
X 
X 
4h (±15 min) 
X 
 
 
X 
X 
6h (±15 min) 
X 
 
 
X 
X 
8h (±15 min) 
X 
X 
 
X 
X 
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Cycle/Day 
Hour 
(±min) 
Hour (±min) 
(relative to 
the first 
dose on the 
day) 
Vital 
signs 
Holter 
recorder 
for 
continuous 
ECG 
Holter recorder for 
triplicate digital ECG 
Holter 
recorder 
for safety 
ECG 
 
PK 
Notes 
Stop Holter 
recording 
At indicated timepoints during C1D1 and C1D8 
Holter recorder needs to be used for print out of 
safety ECGs. The safety ECG has to be read 
immediately and locally; for AE management 
see Section 7.1 
X* For C1D1 and C1D8, SMC may recommend 
adjustment of the sample collection timepoints 
with support of human PK data after the first 
cohort (e.g. 24h post-dose, time point close to 
tmax etc.). 
X& These timepoints may be adjusted with 
support of human data after the first cohort. 
C1D8*# 
Predose 
(within 2h) 
X 
Start Holter 
recording 
 
X 
-15 min 
X 
0.5h (±5 min) 
 
 
 
 
X 
1h (±5 min) 
X 
 
 
X 
X 
1.5h (±5 min) 
 
 
 
 
X 
2h (±10 min) 
X 
 
 
X 
X 
4h (±15 min) 
X 
 
 
X 
X 
6h (±15 min) 
X 
 
 
X 
X 
8h (±15 min) 
X 
X 
Stop Holter 
recording 
 
X 
X 
C1D15& 
Predose 
(within 2h)  
X 
 
X 
X 
X 
 
C2D1& 
Predose 
(within 2h) 
X 
 
X 
X 
X 
 
2h (±10 min) 
X 
 
X 
X 
X 
 
C4D1& 
Predose 
(within 2h)  
X 
 
X 
X 
X 
 
&'
every 2 
cycles  
Predose 
(within 2h) 
X 
 
 
X 
X@ 
X@ Only C6D1 and C8D1. 
C = Cycle, D =(Study) Day, ECG = Electrocardiogram; eCRF = electronic Case Report Form; 
; 
Pd = Pharmacodynamic; PGx = Pharmacogenetic, Pk = Pharmacokinetic. 
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2 
Introduction  
M1069 is a novel, orally administered, highly selective antagonist of the A2A and A2B adenosine 
receptors that is being developed for the treatment of participants with advanced solid tumors. 
By binding adenosine receptors A2A and A2B expressed on immune cells, adenosine promotes 
immunosuppression by inhibiting activation, proliferation, and cytotoxic activity of effector 
T cells (Cekic 2016). Although initially the A2A adenosine receptor was considered to be the most 
central adenosine signaling pathway in cancer development, more recent research has revealed 
the significance of A2B receptor signaling which was shown to induce immune suppression, tumor 
proliferation, tumor angiogenesis, tumor cell invasion and metastasis (Gao 2019). A2B activation 
is known to suppress IFN-enhanced expression of major histocompatibility complex Class II 
(MHC-II) transactivator required for CD4+ T cell anti-tumor responses (Fang 2013). It has been 
suggested that high A2B receptor expression levels are generally associated with worse prognosis 
or poor survival (Mittal 2016). Moreover, multiple studies have shown the importance of several 
signaling pathways related to A2B receptor activation and the subsequent release of various 
cytokines and growth factors, which eventually led to cancer cell proliferation. 
 
 
 
 
 
 
 
Detailed information on the chemistry, pharmacology, efficacy, and safety of M1069 is in the 
Investigator’s Brochure. 
2.1 
Study Rationale  
The administration of M1069 to participants with advanced/metastatic solid tumors, for which 
no tolerated or approved/established effective treatment option exists, is justified by the 
following: 
x A2A and A2B adenosine receptors have been shown to mediate immunosuppressive and tumor-
promoting signals in the tumor microenvironment (TME). 
x
 
 
 
 
 
 
 
 
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x 
 
x Based on results from nonclinical safety pharmacology and toxicology investigations, the 
safety profile of M1069 is considered adequate for patients with advanced/metastatic solid 
tumors at the projected dose levels. Clinical experience with dual adenosine A2A/A2B 
antagonism published in the literature suggests an acceptable safety profile as monotherapy 
and no potentiating toxicities in combination with other immunotherapies. 
x Early signs of clinical activity in advanced solid tumors including colorectal cancer has been 
reported (Cecchini 2021) from a Phase Ib dose expansion study with etrumadenant, the 
A2A/A2B antagonist from Arcus Biosciences, evaluating it in combination with chemotherapy. 
2.2 
Background  
An increase in energy consumption or hypoxia in metabolically stressful conditions, including 
cancer, result in dramatic increases in extracellular concentrations of immunosuppressive 
adenosine (Cronstein 1994; Ohta 2016). Most evidence linking adenosine signaling to 
immunosuppression has been related to A2A. The A2A adenosine receptor has been recognized as 
the key receptor for adenosine driven suppression of anti-tumor CD4+ and CD8+ T cell, NK 
cell, and myeloid cell functions directly or through recruitment of other immunoregulatory cells, 
including regulatory T cells (Tregs) (Cekic 2014). However, the A2A receptor shares signaling 
with the lower affinity A2B adenosine receptor through Gs GPCR subunit activation of adenylate 
cyclase (Fredholm 2001). In this regard, the A2B receptor can compensate for inhibition of A2A 
in an adenosine rich tumor microenvironment (TME). Moreover, blocking A2B is expected to 
suppress adenosine-mediated tumor promotion by blocking of Gq subunit of GPCRs, leading to 
reduced tumor neovascularization through decreased production of VEGF by myeloid cells and 
tumor cells (Ryzhov 2008; Ryzhov 2014; Sorrentino 2015). In addition, blocking A2B is likely 
to support vascular permeability that may promote infiltration of leukocytes into tumors (Yang 
2006; Eckle 2008). Furthermore, inhibition of A2B is presumed to prevent accumulation of 
immune suppressive precursors of dendritic cells (Novitskiy 2008) and polarization of pro-
tumorigenic M2 macrophage cells (Csoka 2012). Taken together, inhibition of A2B receptors, in 
addition to inhibition of A2A receptors, is expected to provide more robust protection from 
adenosine driven tumor promotion. 
Multiple compounds targeting adenosine signaling in the TME, either by inhibiting production 
of adenosine (anti-CD39 or anti-CD73) or downstream to A2A and/or A2B receptors, are in 
development for multiple tumor types.
 
 
 
 
 
 
 
 
 
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In summary, the Sponsor has developed a potent dual A2A/A2B adenosine receptor antagonist, 
M1069, that is expected to counteract adenosine-mediated pro-tumorigenic mechanisms and to 
enhance therapeutic efficacy for other anticancer agents, including checkpoint inhibitors for solid 
tumors. 
2.3 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of M1069 may be found in the Investigator’s Brochure for M1069. 
Based on the available nonclinical data to date, the conduct of the study, as specified in this 
protocol, is considered justifiable. 
2.3.1 
Risk Assessment  
Based on preclinical data and/or data from other compounds targeting A2A and A2B adenosine 
receptors, the following potential risks (Table 3) are being considered. 
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Table 3 
Potential risks of M1069  
Potential Risks of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Study Intervention(s) 
Gastrointestinal adverse events 
For the dual A2A/A2B receptor 
antagonist AB928 mild to moderate 
abdominal pain (20%) and nausea 
(17%) have been identified as the 
most common adverse events in a 
first-in-human trial in healthy 
volunteers. (Seitz 2019). 
 
For M1069, gastrointestinal effects, 
mainly vomiting, salivation and red 
buccal mucosa, conjunctiva and 
gums were observed in repeat-
dose toxicity studies in dogs.  
Monitoring for adverse events 
during the trial and appropriate 
management as medically 
indicated. 
 
The SMC might change their 
recommendation of Study 
Intervention administration from an 
empty stomach condition to fed 
condition as deemed appropriate 
by the committee (see 
Section 5.3.1 and Section 6.6.2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
during 
the trial (see Section 1.3).  
Excitatory adverse events 
Agitation, anxiety and insomnia 
have been observed with certain 
adenosine inhibitors, such as 
Ciforadenant (Voss 2020), and 
istradefylline (USPI). Convulsions, 
dizziness, headache and tremor 
have also been observed with 
theophylline (EU SmPC). 
Monitoring for adverse events 
during the trial and appropriate 
management as medically 
indicated. 
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Potential Risks of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
 
In rats, M1069 produced an 
excitatory effect with increased 
CNS activity and respiration at 
single doses of all dose levels 
tested (30, 100 and 300 mg/kg). In 
dogs, mild to moderate increases in 
physical activity were observed at 
all dose levels tested (single doses 
of 30, 60, or 100 mg/kg). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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Potential Risks of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
 
 
 
 
 
 
 
 
 
 
 
Study Procedures 
Tumor biopsies 
Tumor biopsies are required for 
study participants as detailed in the 
Schedule of Activities. These are 
considered essential for the study`s 
scientific objectives. Biopsies carry 
a risk of adverse events including 
bleeding and infection. 
Monitoring for any risks associated 
with tumor biopsy collection and 
appropriate management as 
medically indicated. 
ECG = Electrocardiogram, EOSI = End of Study Intervention,
 SMC =Safety 
Monitoring Committee, SmPC = Summary of Product Characteristics (European Union), USPI = Prescribing 
Information (United States). 
 
2.3.2 
Benefit Assessment  
Based on preclinical experiments and available data for other compounds, therapeutic inhibition 
of adenosine signaling can potentially contribute to an anti-tumor immune response and inhibit 
growth of tumor cells. Therefore, treatment with M1069 may offer patients with advanced solid 
tumors which have failed approved therapies the chance of a treatment option by inhibiting a 
new signaling pathway that has not been targeted by their previous therapies. 
2.3.3 
Overall Benefit: Risk Conclusion  
Considering the measures taken to minimize risk to participants in this study, the potential risks 
identified in association with M1069 as monotherapy are justified by the anticipated benefits that 
may be afforded to participants with advanced solid tumors. 
3 
Objectives and Estimands  
This study is conducted in participants with metastatic or locally advanced unresectable solid 
tumors, who are intolerant or have no effective standard therapies available to them. Objectives, 
endpoints and other key estimand attributes are presented in Table 4. 
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Table 4 
Objectives, Endpoints and Other Estimand Attributes  
Objectives 
Estimand Attributes 
Primary 
To determine dose toxicity relationship and 
maximum tolerated dose (MTD, if reached) of 
M1069 as a monotherapy in participants with 
solid tumors. 
 
Endpoints: 
x 
Occurrence of DLTs. 
x 
Occurrence of AEs and treatment-related adverse 
events. 
Strategy for handling intercurrent events: 
For DLTs: 
x 
Discontinuation/interruption/delay of treatment 
(> 20% planned treatment missed during DLT 
period) to prevent a DLT: composite strategy (to be 
considered a DLT). 
For other endpoints: 
The endpoint will be analyzed regardless of whether or not 
the following intercurrent events had occurred (treatment 
policy strategy): 
x 
Treatment discontinuation 
x 
Start of subsequent anticancer therapy. 
Population: 
Patients with metastatic or locally advanced unresectable 
solid tumors, who are intolerant or have no effective 
standard therapies available to them. 
Population level summary: 
x 
DLT probabilities and associated credibility 
intervals as estimated using the BLRM model (for 
DLTs only) 
x 
Standard summary statistics.  
To determine the RDE of M1069 for further 
exploratory clinical development. 
Endpoints: 
In addition to safety, tolerability, PK, Pd (
 in ex-vivo 
stimulated blood), post-treatment changes in TME in 
available paired tumor biopsies data are considered. 
Strategy for handling intercurrent events: 
The endpoint will be analyzed regardless of whether or not 
the following intercurrent events had occurred (treatment 
policy strategy): 
x 
 Discontinuation of treatment 
x 
 Start of subsequent anticancer therapy. 
Population: Patients with metastatic or locally advanced 
unresectable solid tumors, who are intolerant or have no 
effective standard therapies available to them. 
Population level summary: 
Standard summary statistics. 
Secondary 
To characterize the PK profile of M1069. 
 
Endpoints: PK parameters (see Section 8.5) of M1069 after 
single dose administration and at steady state using non-
compartmental analysis.  
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Objectives 
Estimand Attributes 
To evaluate indicators of clinical activity of 
M1069 in terms of objective response using 
RECIST v1.1. 
Endpoint: 
Objective response using RECIST v1.1, as assessed by 
Investigator. 
Strategy for handling intercurrent events: 
• 
Discontinuation of treatment (treatment policy strategy; 
i.e. ignoring intercurrent event) 
• 
Start of subsequent anticancer therapy (treatment policy 
strategy; i.e. ignoring intercurrent event) 
• 
Progression according to RECIST v1.1 (while not 
progressed strategy). 
 
Population: Patients with metastatic or locally advanced 
unresectable solid tumors, who are intolerant or have no 
effective standard therapies available to them. 
Population level summary: Rate.  
To evaluate indicators of clinical activity of 
M1069 in terms of DoR using RECIST v1.1. 
Endpoint: 
Duration of response according to RECIST v1.1 as 
assessed by Investigator, defined as time from first 
documentation of objective response to PD or death, 
occurring within 2 scheduled tumor assessments after last 
evaluable assessment or start of treatment. 
Strategy for handling intercurrent events: 
• 
Death within 2 scheduled tumor assessments after last 
evaluable assessment or first study intervention will be 
considered as event (composite strategy). 
The endpoint will be analyzed regardless of whether or not 
the following intercurrent events had occurred (treatment 
policy strategy): 
• 
Discontinuation of treatment 
• 
Start of subsequent anticancer therapy. 
Population: Patients with metastatic or locally advanced 
unresectable solid tumors, who are intolerant or have no 
effective standard therapies available to them. 
Population level summary: Median DoR. 

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Objectives 
Estimand Attributes 
To evaluate indicators of clinical activity of 
M1069 in terms of PFS using RECIST v1.1. 
Endpoint: 
Progression-free survival as defined from date of first study 
intervention to PD according to RECIST v1.1 as assessed 
by Investigator or death. Events are considered only if 
occurring within 2 scheduled tumor assessments after last 
evaluable assessment or start of treatment. 
Strategy for handling intercurrent events: 
x 
Death within 2 scheduled tumor assessments after last 
evaluable assessment or first study intervention will be 
considered as event (composite strategy). 
The endpoint will be analyzed regardless of whether or not 
the following intercurrent events had occurred (treatment 
policy strategy): 
x 
Discontinuation of treatment 
x 
Start of subsequent anticancer therapy. 
Population: Patients with metastatic or locally advanced 
unresectable solid tumors, who are intolerant or have no 
effective standard therapies available to them. 
Population level summary: Hazard ratio. 
To assess the effect of M1069 on QT interval  
Endpoints: 
Change from baseline QTc (ǻQTc) over time. 
AE = Adverse event, BLRM = Bayesian 2-parameter logistic regression model, C = Cycle, 
 
 = (Study) Day, DLT = Dose-limiting toxicity, DoR = Duration of response, MTD = Maximum tolerated dose, 
, PD = Progressive disease, 
Pd =  Pharmacodynamic, PFS =Progression-free survival, PK = Pharmacokinetic, QT interval, corrected, 
RDE = Recommended dose for expansion, RECIST = Response Evaluation Criteria in Solid Tumors. 
 
 
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4 
Study Design  
4.1 
Overall Design  
This is a Phase I FIH dose escalation of M1069, noncontrolled, open label, multicenter clinical 
study designed to determine the safety, tolerability, PK, Pd and early signs of efficacy in 
participants with advanced solid malignancies. A Bayesian study design will be applied, using a 
Bayesian 2-parameter logistic regression model (BLRM). 
The study for a participant will include up to 28 days Screening period, a study intervention 
period consisting of consecutive 21-day cycles with twice daily oral administration of M1069, a 
DLT observation period of 21 days, End of Study Intervention Visit (within 7 days from decision 
to stop M1069 intake), and a Safety Follow-up period of 30 ± 7 days after the last M1069 intake. 
Participants who tolerate treatment without significant clinically relevant toxicities may continue 
to receive their assigned dose until progressive disease (PD) (Section 7.1.1). Participants who 
discontinue study intervention for any reason will complete the End of Study Intervention Visit. 
Screening 
Screening will be performed within 28 days prior to Day 1 of M1069 administration. If the 
participant meets all the protocol-defined inclusion and none of the exclusion criteria, the 
participant will be considered eligible for participation in the study. Screening for the next cohort 
should usually start before the SMC has taken the decision on the next dose. The eligible 
participants screened for the next cohort will, however, only be treated pending decision by the 
SMC. 
Participants who fail to meet the protocol-specified criteria or who withdraw their consent prior 
to start of treatment will be considered Screening Failures. 
Treatment Period 
The treatment period will begin at the first dose of M1069 with Cycle 1 Day 1 (C1D1) and 
consists of consecutive 21-day cycles with twice daily oral administration (BID) of M1069 or 
QD regimen determined by the SMC (see Section 6.6.2) until disease progression, unacceptable 
toxicity, withdrawal of consent, or any criterion for withdrawal from study intervention 
(Section 7.1). 
Safety Follow-up 
Safety Follow-up visit will occur 30 days (±7 days) after last dose of study drug. 
Sample Size 
The total sample size will depend on the number of cohorts to be evaluated. The planned cohort 
size is 3 participants. Data observed during the dose escalation (e.g., number of DLTs) have an 
impact on the number of cohorts. The sample size for the RDE and MTD dose levels needs to 

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be at least 6 participants. It is anticipated that 21 to 30 participants (5 projected dose levels with 
3 to 9 participants each) may be needed. 
Dose Escalation 
The first dose escalation cohort will receive M1069 as a monotherapy at the starting dose of 150 
mg BID. For further dose cohorts, the SMC will meet and review all available safety, PK and Pd 
data to provide recommendations on the dose level and regimen for the next cohort. Decision 
making of the SMC will be supported by results of a Bayesian 2-parameter logistic regression 
model. 
The term “cohort” with regards to dose escalation in this protocol is referring to a group of 
participants that are enrolled at the same dose level and evaluated by an SMC before the dosing 
decision for the next cohort is made. There may be more than one cohort on the same dose level, 
if the SMC decides that a further cohort on the same dose level is needed. 
More details on the SMC and dose escalation can be found in Section 6.6.2. The following 
predefined doses of M1069 are foreseen: 150, 300, 450, 600, and 700 mg BID. If deemed 
necessary based on obtained pharmacological data, higher dose levels than 700 mg BID with an 
increase by 15% may be recommended by the SMC. Participants will receive study intervention 
twice daily with a food restriction for 2 hours before and 1 hour after dose administration. 
Depending on the observed PK or toxicity profile the SMC may recommend QD regimen, 
different dose levels (higher or lower) or dosing conditions (fasted or fed; see Section 5.3.1). At 
each dose level, the first participant enrolled will be observed for DLTs for at least 3 days before 
further individuals are enrolled. However, the SMC may decide to shorten or prolong this 
interval based on available results. 
In principle, dose escalation in monotherapy will proceed according to SMC recommendation 
until MTD and/or until a safe RDE is determined and/or the SMC recommends ending dose 
escalation. Target DLT probability for the MTD suggested by the Bayesian model is 30%. 
A potential RDE dose level will be selected based on the data of at least 3 participants. At this 
dose level, 2 additional confirmatory cohorts with 3 participants each may be enrolled (2nd 
cohort pending SMC decision). For these additional cohorts, mandatory paired pre- and on-
treatment biopsies will be collected. 
The final RDE will be based on all available safety, tolerability, PK, 
 
 
 
 
The RDE cannot exceed the MTD. If the suggested RDE is below the MTD, dose escalation may 
continue until the MTD is reached (if applicable) or SMC recommends ending dose escalation. 
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Additional dose escalation cohorts assessing M1069 in combination with other anticancer agents 
may be added by protocol amendment. 
Dose Expansion 
Additional expansion cohorts assessing M1069 alone or in combination with other anticancer 
agents, potentially in diseases-specific settings, may be added by protocol amendment. 
4.2 
Scientific Rationale for Study Design  
Small molecule inhibitors specific to A2A as well as dual inhibitors of A2A and A2B have been 
investigated in humans previously and have demonstrated an acceptable safety profile and early 
signs of clinical activity in Phase I studies in patients with solid tumors.
 
 
 As safety, 
tolerability and also anticancer activity of M1069 have never been investigated in humans, the 
target population for initial investigation is restricted to adult participants who have 
histologically or cytologically proven locally advanced or metastatic solid malignancies and who 
are refractory to or have progressed under standard treatment and have no other treatment options 
known to confer clinical benefit. 
Escalating doses of M1069 are considered an acceptable approach to establish safety, PK, Pd 
and early signs of anti-tumor activity without putting participants at high risk of experiencing 
undue toxicity. Supervision by an SMC is necessary in order to frequently review safety and re-
assess benefit and risk. 
A Bayesian logistic regression model will be used in order to support SMC recommendations. 
Application of such a model for dose escalation will enable implementation of alternative dose 
levels not defined a priori in order to ensure participant safety and optimized definition of RDE 
and MTD as compared to a classical 3 + 3 dose escalation approach. 
4.2.1 
Participant Input into Design  
None. 
4.3 
Justification for Dose  
The proposed clinical study is a Phase I dose escalation trial aiming to explore the safety and 
tolerability of M1069 in participants with advanced cancer and limited therapeutic options. 
Therefore, ICH S9 has been considered for the determination of the FIH starting dose, (i.e., a 
dose that is expected to have pharmacologic effects and is reasonably safe to use). The selected 
starting dose of M1069 for first in human trials is 150 mg BID, and followed by dose escalation 
to 300, 450, 600, and 700 mg BID. Participants should keep at least 10 hours in between the 
2 daily doses. Participants will receive study intervention twice daily with a food restriction for 
2 hours before and 1 hour after dose administration (for fed conditions see Section 5.3.1). If 
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deemed necessary based on emerging pharmacological data, higher dose levels than 700 mg BID 
might be explored in 15% increments. The rationale is listed as below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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At 150 mg BID, the projected 
 inhibition (a proximal 
pharmacodynamic biomarker for M1069) in human at Cmin,ss is 89%, based on a mechanistic 
model developed and verified using published Phase I clinical study data from etrumadenant 
(AB928), a compound from Arcus Biosciences with the same mechanism of action (Seitz 2019). 
Doses with > 90% 
 inhibition at Cmin,ss were shown to be well tolerated in clinical studies 
ZLWK$%QR*UDGHAEs in healthy volunteers and no > Grade 3 AB928 related AEs in 
cancer patients (Powderly 2019). This further supports the selected M1069 starting dose, which 
is expected to be well tolerated in the FIH study. 
At the proposed human exposure expected at a starting dose of 150 mg BID, the projected tumor 
growth inhibition (TGI) is 77%, based on a Simeoni TGI model (Simeoni 2004) developed using 
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in vivo tumor growth data from adenosine rich (CD73high) mouse 4T1 breast tumor model that 
is refractory to checkpoint inhibitors. These analyses indicate that the proposed starting dose is 
expected to achieve exposures in humans associated with tumor growth inhibitory 
pharmacologic effects. 
Based on brain exposure studies in rats, the brain penetration of M1069 (kp,uu=0.166) at the 
proposed human starting dose of 150 mg BID is expected to be limited. 
4.4 
End of Study Definition  
A participant has completed the study if he/she has completed all study parts, including EOSI 
and the Safety follow-up Visit. 
The end of the study is defined as the date of the last participant has completed the last Safety 
follow-up Visit. 
The Sponsor may terminate the study at any time once access to study intervention for 
participants still benefitting is provided via a rollover study, expanded access, marketed product, 
or another mechanism of access, as appropriate. 
5 
Study Population  
The criteria in Sections 5.1 and 5.2 are designed to enroll only participants, who are appropriate 
for the study; thereby, ensuring the study fulfills its objectives. All relevant medical and 
nonmedical conditions should be taken into consideration when deciding whether a participant 
is suitable for this study. 
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Before performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will confirm that the participant or the participant’s legal representative 
has provided written informed consent, as indicated in Appendix 2. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Are ≥18 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participants who have histologically or cytologically proven locally advanced or metastatic 
solid malignancies and who are refractory to or have progressed under standard treatment 
or for whom standard treatment is not expected to deliver clinical benefit. 

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3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at 
Screening. 
4. Adequate hematological function as defined below: 
a. Absolute neutrophil count ≥ 1,500/mm3 or ≥ 1.5 × 109/L (Note: hematopoetic growth 
factors are not permitted in the 2 weeks before first dose). 
b. Platelet count ≥ 100,000/mm3 or ≥ 100 × 109/L (no transfusion in the past 2 weeks before 
first dose). 
c. Hemoglobin ≥ 9 g/dL (no transfusion in the past 2 weeks before first dose). 
5. Adequate hepatic function defined: by a total bilirubin level ≤ 1.5 × upper limit of normal 
(ULN), an aspartate aminotransferase (AST) level ≤ 2.5 × ULN, and an alanine 
aminotransferase (ALT) level ≤ 2.5 × ULN. 
a. Subjects with documented Gilbert disease are allowed if total bilirubin > 1.5 × ULN 
but < 3 × ULN. 
b.  Subjects with tumor involvement in their liver: AST < 3.0 × ULN, ALT < 3 × ULN, 
with normal bilirubin ≤ 1.5 × ULN and INR < 1.5 × ULN. 
6. Adequate renal function defined by an estimated creatinine clearance ≥ 60 mL/min × ULN 
according to the Cockcroft-Gault formula. 
7. Ability to swallow oral dose forms (e.g. capsules). 
8. Fresh tumor biopsies mandatory for participants at DL2 and 6 participants upon 
potential determination of RDE. Providing consent to fresh tumor biopsies taken during 
the Screening period and an on-treatment biopsy is mandatory. 
For all other dose levels: 
• Formalin-fixed paraffin-embedded block containing tumor tissue or a minimum of 
15 (preferably 25) unstained tumor slides suitable for immunohistochemistry-based 
staining of protein expression from recently obtained tumor biopsies (non-
irradiated area) ideally at or after progression on the most recent line of anticancer 
treatment required.  
• Recommended paired fresh and on-treatment biopsies, as feasible. 
• Patients for which tumor tissue is not available and a new biopsy is not 
acceptable/feasible or medically inadvisable, may be deemed eligible for study 
after consultation with “Sponsor Medic”.  
9. Life expectancy of at least 12 weeks according to Investigator judgement. 
10. Measurable disease according to RECISTv1.1. 

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
 
 
Sex 
14. Are male or female. 
Contraceptive use will be consistent with local regulations on contraception methods for those 
participating in clinical studies. 
Male participants: 
Agree to the following during the study intervention period and for at least 100 days after the 
last dose of study intervention: 
x Refrain from donating fresh unwashed semen. 
PLUS, either: 
x Abstain from intercourse with a WOCBP 
OR 
x Use a male condom: 
x When having sexual intercourse with a WOCBP, who is not currently pregnant, and 
instruct her to use a highly effective contraceptive method with a failure rate of <1% per 
year, as described in Appendix 3, since a condom may break or leak. 
Female participant: 
x Is not breastfeeding 
x Is not pregnant (i.e., has a negative pregnancy test) as required by local regulations, within 24 
hours before the first dose of study intervention. 
x Is not a WOCBP 
If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of <1% per 
year), preferably with low user dependency, as described in Appendix 3 for the following time 
periods. 
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1. 
Before the first dose of the study intervention(s), if using hormonal contraception: 
• Has completed at least one 4-week cycle of an oral contraception pill and either had or has 
begun her menses; OR, 
• Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has 
a documented negative pregnancy test using a highly sensitive assay. 
2. 
During the study intervention period: 
• Since in vitro data shows M1069 could affect metabolizing enzymes and transporters of 
hormonal contraceptives, WOCBP who are currently using hormonal contraception that 
contains estrogen and/or progestins should also use double barrier contraception. 
3. 
After the study intervention period (i.e., after the last dose of study intervention is 
administered) for at least 180 days after the last dose of study intervention and agree not to donate 
eggs (ova, oocytes) for reproduction during this period. 
The Investigator evaluates the effectiveness of the contraceptive method in relationship to the 
first dose of study intervention. 
The Investigator reviews the medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a female with an early undetected pregnancy. 
Informed Consent 
15. Capable of giving signed informed consent, as indicated in Appendix 2 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and this protocol. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Persisting toxicity related to prior therapy Grade > 1 National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, however, alopecia, sensory 
neuropathy hypothyroidism and diabetes mellitus Grade ≤ 2, despite treatment, are allowed. 
2. Prior organ transplantation including allogeneic stem cell transplantation. 
3. Participants with known brain metastases, except those meeting the following criteria: 
a. Brain metastases that have been treated locally and are clinically stable for at least 4 weeks 
prior to the start of treatment. 
b. No ongoing neurological symptoms that are related to the brain localization of the disease 
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4. Participants must be either off steroids or on a stable or decreasing dose of < 10 mg daily 
prednisone (or equivalent). 
5. Current significant cardiac conduction abnormalities, including corrected QT interval 
(QTcF, corrected with Fridericia formula) prolongation of > 470 ms or impaired 
cardiovascular function, ventricular tachycardia (including Torsades de Pointes), or a history 
of paroxysmal atrial fibrillation, serious cardiac arrhythmia and family history of sudden 
death or long QT syndrome. 
6. A history of vascular, cardiovascular or cerebrovascular disease as follows: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to 
enrollment), unstable angina, congestive heart failure (New York Heart Association 
&ODVVLILFDWLRQ&ODVV II), pulmonary thrombosis/embolism (< 3 months prior to enrollment), 
uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic 
or > 100 mm Hg diastolic despite optimal antihypertensive treatment, renal artery stenosis. 
7. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent including but not limited to inflammatory bowel diseases, autoimmune hepatitis, 
interstitial lung disease of immunologic origin, systemic lupus erythematosus, etc, with the 
following exceptions: 
a. Participants with diabetes type I, psoriasis, hypo- or hyperthyroid disease not requiring 
immunosuppressive treatment are eligible. 
8. Significant acute or chronic fungal, bacterial and/or viral infections requiring systemic 
therapy including COVID-19 
9. Known hypersensitivity to the trial treatment or to one or more of the excipients. 
 
 
 
 
 
 
Prior/Concomitant Therapy 
12. Prior treatment with another agent targeting the adenosine signaling pathway (inhibitors of 
CD39, CD73 and/or A2A or A2B receptors). 
13. Concurrent treatment with a nonpermitted drug/intervention and prohibited concomitant 
medication as listed in Section 6.5.3. 
x Strong inhibitors or inducers of CYP3A4, strong P-gp inhibitors, sensitive CYP3A4 
substrates with narrow therapeutic index, drugs associated with Torsade de Pointes should be 
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discontinued 7 days prior to treatment and avoided during treatment (see Section 6.5.3 for a 
list. The link to the website to be consulted, in case of doubt, is provided in Section 6.5.3). 
• Medications or herbal supplements known to be strong CYP3A4 inhibitors/inducers should 
be discontinued 7 days prior to treatment and avoided during treatment (see Section 6.5.3 for 
a list). The link to the website to be consulted, in case of doubt, is provided in Section 6.5.3). 
• Anticancer treatment (e.g., cytoreductive therapy, radiotherapy, immune therapy, cytokine 
therapy, monoclonal antibody, targeted small molecule therapy) or any investigational drug 
within 4 weeks or 5 half-lives, whichever is shorter prior to start of study treatment, with the 
following exceptions: 
i. 
Palliative bone-directed radiotherapy is permitted (concurrently or within 
pretreatment period, see further details under prohibited medicines, Section 
6.5.3). 
ii. 
Hormonal therapies acting on the hypothalamic pituitary gonadal axis are 
permitted (i.e., luteinizing hormone releasing hormone agonist/antagonists). No 
other hormonal anticancer therapy is permitted. 
• Major surgery (as deemed by the Investigator) for any reason, except diagnostic biopsy, 
within 4 weeks of the study treatment. 
• Participants receiving immunosuppressive agents (such as steroids), for any reason, should 
be tapered off these drugs before start of study treatment, with the following exceptions: 
i. 
Participants with adrenal insufficiency may continue corticosteroids at 
physiologic replacement dose, equivalent to < 10 mg prednisone daily. 
ii. 
Administration of steroids through a route known to result in a minimal systemic 
exposure (topical, intranasal, intro-ocular, or inhalation). 
iii. 
Previous or ongoing administration of systemic steroids for the prophylaxis or 
treatment of an acute allergic phenomenon is acceptable as long as it is anticipated 
that the administration of steroids will be completed in 14 days, or that the dose 
after 14 days will be equivalent to ≤ 10 mg prednisone daily. 
14. Known current alcohol and drug abuse as determined by the Investigator. 
15. Administration of a live vaccine within 28 days prior to study entry. 
5.3 
Lifestyle Considerations  
The following lifestyle considerations apply for participants in this study. 
5.3.1 
Meals and Dietary Restrictions  
M1069 will be administered with 240 mL (8 fluid ounces) of ambient temperature water on an 
empty stomach. All participants will abstain from all food for at least 2 hours before oral 

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administration of M1069 and for 1 hour after administration of M1069. Water can be consumed 
ad libitum. 
Dosing with food has been shown to improve GI tolerability of orally administered drugs, and 
bosutinib and ceritinib have been approved to be administered under fed condition even with 
positive food effects (Cho 2017).
 
 
 
If GI adverse events are frequently reported in a dose escalation cohort, SMC 
retains the right to start the next cohort at the same dose level under fed with low-fat meal 
condition. Pending review of PK and safety data from the empty stomach and fed cohorts at the 
same dose level, the SMC may also suggest continuing future cohorts at higher dose levels under 
fed with low-fat meal condition. The meal should be consumed within approximately 30 
minutes, and the drug should then be administered at 30 minutes after the start of the meal, with 
240 mL (8 fluid ounces) of water. 
Per the FDA guidance, a low-fat meal is defined as approximately including 400 to 500 calories 
of which 25% come from fat (i.e., 2.8 grams fat per 100 calories). A typical low-fat breakfast 
contains 8 ounces milk, one boiled egg, and one packet flavored instant oatmeal made with water 
(FDA 2019). A standard low-fat breakfast will be provided on the PK sampling days (C1D1 and 
C1D8). Considering the participants will self-administer M1069 at home most of the time, the 
low-fat meal can be extended as containing <600 calories and < 30% fat. For breakfast and 
dinner, it is encouraged for the participants to choose lower-fat and lean options of dairy, meat 
and poultry, such as skim milk, lean beef, and grilled chicken breast without the skin. Also, try 
to limit the amount of ingredients high in fat consumed, such as cheese, butter, margarine, cream, 
sausage and oils. There are no food restrictions on lunch. 
Refer to Operations Manual to obtain the written guidance and food diary. 
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 
days before the start of study intervention until after the final dose. 
5.3.2 
Caffeine, Alcohol, Tobacco, and Cannabinoid  
For visits on C1D1 and C1D8, participants will abstain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, and chocolate) for 48 hours before the start of 
dosing until after collection of the final PK and/or Pd sample. 
5.3.3 
Activity  
Participants will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities (e.g., 
watching television or reading). 
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5.4 
Screen Failures  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Rescreened participants will be assigned a new participant number. 
6 
Study Intervention(s)  
Study intervention is any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant per the study protocol. 
6.1 
Study Intervention(s) Administration  
 
ARM Name 
 
Intervention Name 
M1069 
Type  
Drug 
Dose Formulation 
M1069 filled 
. Capsule color 
is white for the doses 10 mg and 75 mg and orange for the 25 mg 
dose. 
Unit Dose Strength(s) 
10 mg, 25 mg or 75 mg per capsule 
Dose Amount 
multiple dose levels (dose escalation) 
Frequency 
twice daily (alternative: once daily if recommended by SMC) 
Route of Administration 
Oral 
Use 
Experimental 
Investigational Medicinal Product 
(IMP) and Non- Investigational 
Medicinal Product (NIMP) 
IMP 
 
Sourcing 
Sponsor 
Packaging and Labeling 
Study Intervention will be provided in a bottle. Each bottle will be 
labeled per country requirements. 
SMC = Safety Monitoring Committee. 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability  
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Upon receipt of the study intervention(s), the Investigator or designee will confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported 
and resolved before use. Also, the responsible person will check for accurate delivery. Further 
guidance and information for study intervention accountability are provided in the Operations 
Manual. 
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Only participants enrolled in the study may receive study intervention(s) and only authorized 
site staff may supply it. All study intervention(s) will be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area, per the labeled storage conditions, and 
with access limited to the Investigator and authorized site staff. 
Dispensing will be recorded on the appropriate accountability forms so that accurate records will 
be available for verification at each monitoring visit. 
Study intervention(s) accountability records at the study site will include the following: 
•     Confirmation of receipt, in good condition and in the defined temperature range. 
•     The inventory provided for the clinical study and prepared at the site. 
•     The dose(s) each participant used during the study. 
•    The disposition (including return, if applicable) of any unused study 
intervention(s). 
• Dates, quantities, batch numbers, bottle numbers, expiry dates, and the participant 
numbers. 
• The Investigator site will maintain records, which adequately documents that participants 
were provided the doses specified in this protocol, and all study intervention(s) provided 
were fully reconciled. 
• Unused study intervention(s) will not be discarded or used for any purpose other than the 
present study. No study intervention that is dispensed to a participant may be re-dispensed 
to a different participant. 
•   A Study Monitor will periodically collect the study intervention(s) accountability forms. 
• Further guidance and information for the final disposition of unused study intervention(s) 
are provided in the Operations Manual. 
• M1069 capsules should be stored in a refrigerator at or below 5°C (2°C to 8°C) until use. 
After opening, an in-use stability of 14 days is assigned, with storage at or below 25°C. 
 
6.3 
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding  
6.3.1 
Study Intervention Assignment  
Not applicable. A single study intervention will be administered in the study 
6.3.2 
Emergency Blinding  
Blinding is not applicable as the study intervention administration is open label and none of the 
assessments is blinded. 

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6.4 
Study Intervention Compliance  
On visit days, participants will receive study intervention at the investigation site. When 
participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the eCRF.  The dose of 
study intervention and study participant identification will be confirmed at the time of dosing by 
a member of the study site staff other than the person administering the study intervention. 
On non-visit days, participants will self-administer study intervention at home. Participants will 
be instructed by the Investigator/designee regarding off-site self-administration of M1069 and 
asked to record self-administration in a dosing diary.  When participants self-administer study 
intervention(s) at home, compliance with study intervention will be assessed at each visit. 
Compliance will be assessed by reviewing the dosing diary and counting returned capsules 
during the site visits and documented in the source documents and eCRF. Any deviation(s) from 
the prescribed dosage regimen are recorded in the eCRF. 
A record of the number of capsules dispensed to and taken by each participant will be maintained 
and reconciled with study intervention and compliance records.  Intervention start and stop dates, 
including dates for intervention delays and/or dose reductions will also be recorded in the eCRF. 
The Investigator will ensure that the information entered into the eCRF regarding drug 
administration is accurate for each participant. Any reason for noncompliance should be 
documented. In the situation where participants discontinue study intervention for more than 
5 days per cycle, or if ≥ 6 consecutive planned doses of M1069 are missed for reasons other than 
toxicity, re-introduction can be agreed upon after consultation with the Sponsor and the review 
of safety and efficacy (Sections 7.1). 
6.5 
Concomitant Therapy  
Record in the eCRF all concomitant therapies (e.g., medicines or nondrug interventions) used 
from the time the participant signs the informed consent until completion of the study, including 
any changes. For prescription and over-the-counter medicines, vaccines, vitamins, and herbal 
supplements, record the name, reason for use, dates administered, and dosing information. 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
6.5.1 
Rescue Medicine  
Not applicable. 
6.5.2 
Permitted Medicines  
The only permitted medications are the following: 
1. 
Hematopoietic growth factors or blood transfusions can be used if medically indicated 
according to standard of care only after the DLT period of 21 days. In case 
administration of growth factors during the DLT period is deemed necessary by the 

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Investigator to prevent serious conditions, administration will be regarded as “dose 
limiting” if considered to be related to study intervention. In such case a DLT needs to 
be documented. 
2. 
Administration of corticosteroids through a route known to result in a minimal systemic 
exposure (topical, intranasal, intra-ocular, or inhalation) and anti-infectives are 
permitted. 
Any medicines that are considered necessary to protect the participant’s welfare in emergencies 
may be given at the Investigator’s discretion, regardless if it results in a protocol deviation. 
6.5.3 
Prohibited Medicines  
Prohibited medicines at study entry are indicated in the exclusion criteria (see Section 5.2). 
During administration of study intervention and before the EOSI Visit, any other investigational 
GUXJFKHPRWKHUDS\H[WHQVLYHUDGLRWKHUDS\LQYROYLQJ 30% of bone marrow) or any other 
anticancer therapy (cytotoxic agents, biologics or other targeted therapy) are prohibited. 
The following treatments must not be administered during the study: 
x Immunotherapy including interferons, immunosuppressive drugs (eg, chemotherapy or 
systemic corticosteroids or other experimental pharmaceutical products). 
x Exception (QGRFULQH UHSODFHPHQW WKHUDS\ DW ORZ GRVH SUHGQLVRQH  10 mg daily) or 
equivalent, short term treatment of allergic reactions. Short term administration of 
systemic steroid (e.g., for treatment or prophylaxis of infusion-related reactions (IRRs) or 
prevention of hypersensitivity to concomitant medication including contrast media) or 
other immunosuppressant such as infliximab or mycophenolate (i.e., for allergic reactions) 
is allowed. Steroids with no or minimal systemic effect (topical, inhalation) are allowed. 
For participants with glioblastoma, steroid use is allowed. 
x Any live vaccine therapies for the prevention of infectious disease within 28 days prior to 
study entry and during study. Administration of mRNA vaccines and inactivated vaccines is 
allowed (e.g., inactivated influenza vaccines); COVID-19 vaccinations or booster should be 
performed at least 72 hours before and not before 72 hours after the DLT period. 
x Blood transfusions and growth factors are not allowed during the 21-day DLT observation 
period except to avoid damage to the participant. In case a blood transfusion or use of growth 
factors during the DLT observation period is necessary, participants are considered to have 
had a DLT if the underlying reason is assessed as related to the study intervention. 
x 5DGLRWKHUDS\ZLWKWKHH[FHSWLRQRISDOOLDWLYHVKRUWFRXUVHOLPLWHGILHOGLH 10 fractions 
DQGERQHPDUURZLQYROYHPHQWRUSHULQVWLWXWLRQDOVWDQGDUGUDGLRWKHUDS\ZKLFKPD\
be administered during the study. 
 
 
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days before the first administration of the study intervention and may not be administered during 
the time of study intervention administration. See Table 7 regarding drug-drug interactions. 
 
 
 Thus, 
drugs mainly metabolized by CYP3A4 with a narrow therapeutic index (NTI) should also be 
avoided during the time of study intervention administration. 
 Medications or herbal supplements known 
to be strong P-gp inhibitors must stop at least 7 days before the first administration of the study 
intervention and may not be administered during the study intervention administration. 
If the administration of a nonpermitted concomitant drug becomes necessary during the study, 
the Medical Monitor must be contacted to discuss whether the study intervention must be 
discontinued. 
Please see Table 7 for the list of strong inhibitors of CYP3A4, P-gp, strong inducer of CYP3A4, 
sensitive CYP3A4 substrate with NTI, drugs with Torsade de Pointes risk, UGT1A1 or UGT1A9 
substrate with NTI. 
For further reference, refer to the Food and Drug Administration Drug Development and Drug 
Interactions website and the University of Washington Drug Interactions Solutions website 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers, and 
https://didb.druginteractionsolutions.org/. 
Table 7 
List of Prohibited Drugs and Drugs To Be Used with Caution  
Categories 
Examples 
Action  
Strong P-gp 
inhibitor 
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, 
lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, 
ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, 
and verapamil. 
Prohibited. 
 
Strong CYP3A4 
inhibitor 
boceprevir, ceritinib, cobicistat, conivaptan, danoprevir and ritonavir, 
elvitegravir and ritonavir, grapefruit juice, idelalisib, indinavir and 
ritonavir, itraconazole, josamycin, ketoconazole, LCL161, lonafarnib, 
lopinavir and ritonavir, mibefradil, mifepristone, nefazodone, 
nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir), posaconazole, ribociclib, ritonavir, saquinavir and 
ritonavir, telaprevir, telithromycin,  tipranavir and ritonavir, 
telithromycin, troleandomycin, tucatinib, VIEKIRA PAK, 
voriconazole. 
Strong CYP3A4 
inducer 
apalutamide, avasimibe, carbamazepine, enzalutamide, ivosidenib, 
lumacraftor, mitotane, phenobarbital, phenytoin, rifampin, 
rifapentine, St. John’s wort (Hypericum perforatum). 
Sensitive 
CYP3A4 
abemaciclib, acalabrutinib, bosutinib, cobimetinib, conivaptan, 
dasatinib, dronedarone, entrectinib, everolimus, lomitapide, 
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Categories 
Examples 
Action  
substrate with 
NTI 
midostaurin, neratinib, sirolimus, tacrolimus, tolvaptan, venetoclax, 
zanubrutinib. 
Drugs 
associated with 
Torsade de 
Pointes 
amiodarone, chlorpromazine, clarithromycin, disopyramide, 
dofetilide, erythromycin, haloperidol, methadone, procainamide, 
quinidine, sotalol. 
CYP3A4 and 
UGT1A1 
substrate with 
NTI 
Irinotecan. 
UGT1A9 
substrate with 
NTI 
Not applicable 
Use with caution. 
 
 
 
 
 
 
6.5.4 
Other Interventions  
In vitro studies suggest M1069 is an inhibitor of UGT1A1 and UGT1A9, and clinical DDI risk 
may exist with their substrates at high M1069 concentrations. Thus, drugs as substrates of these 
enzymes with a narrow therapeutic index as judged by the Investigator (and after optional 
consultation with the Sponsor) should be used with caution or avoided if possible, during the 
time of study intervention administration.  
 
 
 
 
 
   
6.6 
Dose Selection and Modification  
Dose escalation, expansion or de-escalation will proceed according to the SMC 
recommendation. The SMC will provide recommendations on the next dose level based on 
safety, tolerability, and available preliminary PK and, if appropriate, Pd data. The SMC receives 
outputs of a Bayesian dose toxicity model with estimated DLT probabilities for potential next 
dose levels to support the SMC recommendation. The Bayesian model will be based on prior 
information, observed number of evaluable participants and number of participants with DLT. 
Further details on the Bayesian model are provided in Appendix 8. The SMC may also 
recommend a change in regimen to the following prespecified regimens: administration of 
M1069 QD instead of BID. 
Further details on the SMC are provided in Section 6.6.2. 
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6.6.1 
Retreatment Criteria  
Not applicable. 
6.6.2 
Safety Monitoring Committee (SMC)  
During the dose escalation part of the study, the SMC will evaluate the safety (including DLTs), 
tolerability and available PK, and available Pd data. The SMC will decide on dose escalation, 
de-escalation, additional enrolment on same dose level, dosing regimen, MTD, suspension of 
enrolment. 
In cases where enrolment of the last participant in a dosing cohort was delayed the SMC may 
decide (based on available data) upon enrolment on a dose for the next dosing cohort before all 
participants in a cohort have completed the DLT period. For this participant, the SMC will 
consider all available emerging data at a subsequent meeting. An ad-hoc meeting will be 
convened if this participant experiences a DLT. 
The SMC recommends an RDE but the determination of the RDE is made by the Sponsor. For 
RDE criteria see Section 4.1. 
The SMC can recommend modifying the schedule of administration. Based on the observed 
toxicity profile and available PK, dose level(s) that are different than, or higher or lower than the 
prespecified doses may be tested (see Section 9.4.2.1). 
The SMC can decide to change the dosing regimen and administration condition to the following: 
• Once daily 
• Administration under fed conditions 
The SMC may recommend to start a new cohort under fed with low-fat meal conditions 
depending on the nature of reported gastrointestinal and other adverse events (see Section 5.3.1 
for details). 
The usual cohort size is 3 participants, but the SMC can modify the size of cohorts. The specific 
working procedures will be described in an SMC charter, which will be established before first 
informed consent signed. 
6.6.3 
Definition of Dose-limiting Toxicity  
A DLT is defined as any of the following AEs according to the NCI-CTCAE v5.0 assessed by 
the Investigator /or the Sponsor at any dose and judged not to be related to the underlying disease 
or any previous or concomitant medication or concurrent condition occurring during the DLT 
observation period (21 days starting on the day of first administration of study intervention on 
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Study accrual will be halted, pending discussions with the SMC or the study Sponsor, if there is 
an occurrence of a Grade 5 toxicity by the NCI-CTCAE v 5.0 attributable to the treatment 
regimen or if more than 1 DLT is seen in dose level 1. 
The treatment with transfusions or growth factors (e.g., granulocyte-colony stimulating factor 
[G-CSF], erythropoetin) is not permitted during the DLT period and if it occurs will be 
considered a DLT unless the reason for use is clearly attributable to the underlying disease or 
extraneous causes (also see Sections 6.5.2 and 6.5.3). 
Participants who develop a DLT will permanently discontinue study intervention. Any DLT 
must be confirmed by the SMC. In exceptional cases, the SMC may decide on re-introduction of 
the study intervention after careful evaluation of clinical data of the individual participant. 
AEs judged as DLT will include: 
• Any Grade ≥ 3 non-hematologic AE with exception of: 
• Single laboratory value(s) abnormality that has no clinical correlate, and resolves to 
Grade ≤ 1 or to baseline within 7 days with adequate medical management or 
asymptomatic Grade ≥ 3 amylase or lipase elevation not associated with clinical 
symptoms of pancreatitis 
• Diarrhea persisting ≤ 72 hours after initiation of medical management 
• Nausea and vomiting of ≤ 72 hours duration with adequate and optimal therapy 
• Transient (≤ 72 hours) Grade 3 fatigue, local reactions, flu-like symptoms, fever, 
headache, hypertension that resolves to Grade ≤ 1 with adequate treatment 
• Grade 3 non-recurrent skin toxicity that resolves to Grade ≤ 1 in less than 7 days after 
initiation of medical management 
• Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor that resolve to Grade ≤ 2 within 6 days 
• Any autoimmune thyroid-related toxicity that clinically resolves to ≤ Grade 2 within 
7 days of initiating therapy. 
• Any death clearly due to the underlying disease or extraneous causes 
• Any Grade ≥ 4 hematologic AE, including: 
• Grade ≥3 neutropenia with clinical signs/symptoms, such as fever > 38.3 degrees C 
(e.g., for febrile neutropenia, an ANC < 1000/mm3 with single temperature of 38.3 
degrees C [101 degrees F] or a sustained temperature of ≥ 38 degrees C [100.4 degrees 
F] for more than one hour) 

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x *UDGHWKURPERF\WRSHQLDZLWKPHGLFDOO\FRQFHUQLQJEOHHGLQJ 
Exceptions: 
x Isolated Grade 4 lymphopenia without clinical correlate 
x Any Grade 4 neutropenia or thrombocytopenia of < 7 days duration not associated 
with any clinical symptoms 
Further DLTs include: 
x Hy’s law: Evidence of hepatocellular toxicity without clear alternative reason to explain the 
observed liver-UHODWHGODERUDWRU\DEQRUPDOLWLHVVXFKDVLQFUHDVHLQ$67RU$/7RI[8/1
HOHYDWLRQ DQG HOHYDWLRQ RI VHUXP WRWDO ELOLUXELQ   [ 8/1 ZLWKRXW Lnitial findings of 
cholestasis (elevated serum ALP) or other apparent clinical causality (e.g., viral hepatitis A, 
B, C or co-medication). For patients with hepatic metastases, AST or ALT > 8 x ULN or AST 
or ALT > 5 [8/1IRUGD\V 
 
 
 

 
 
 
 
  
 
  
  
 
 
  
 
x $Q\LQWHUUXSWLRQGHOD\RIVWXG\GUXJGD\VWRSUHYHQWD'/7 
Additionally, the SMC may identify as a DLT: 
x An AE (inside or outside of the DLT period), including 
 
 that in the opinion of the SMC is of potential clinical significance such that 
further dose escalation would expose participants to unacceptable risk. 
6.6.4 
Dose Modification Outside of the DLT Period  
3DUWLFLSDQWVZKRH[SHULHQFHD*UDGH 3 nonhematological AEs (for exceptions see DLT criteria) 
or Grade 4 hematological AEs, after completion of the DLT assessment period, will need to 
interrupt study treatment. However, participants may continue on study treatment of M1069 at a 
UHGXFHGGRVHSURYLGHGWKHUHDFWLRQKDVUHVROYHGWREDVHOLQHYDOXHRU*UDGH 1 within 2 weeks 
and there is no progressive disease. The dose of M1069 will be reduced by at least one dose 
level. If indicated, a further dose reduction is possible. Re-escalation of M1069 dose escalation 
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to the original level should not be considered for an individual participant once dose modification 
has been applied for safety or tolerability reasons. For dose modification for general toxicity see 
Table 8 and for ophthalmological see Table 9. 
Table 8 
Recommended Temporary Treatment Discontinuation for M1069 for 
General Toxicity (outside of DLT Period)  
Organ 
involved 
Specifics 
Toxicity 
NCI-
CTCAE 
5.0 Grade 
Management of Toxicity with permanent 
Discontinuation or Dose Interruption and 
Modification 
Renal 
Creatinine 
increased  
Grade 3 
Hold M1069 until recovery to Grade ≤ 1 or 
baseline. 
Upon recovery or returning to baseline, 
dosing may continue at same, or the previous 
lower dose level based on clinical judgment. 
Hepatic 
Increased 
AST /ALT 
Grade 3 
Isolated occurrence and not related to liver 
metastases; repeat test within 72 hours; if 
persistent or worsening, may hold off the 
M1069 until recovery to Grade ≤ 1 or 
baseline, based on Investigator’s clinical 
judgement. 
Increased 
total bilirubin 
Grade 3 
Isolated occurrence and not related to liver 
metastases; repeat test within 72 hours; if 
persistent or worsening, may hold off the 
M1069 until recovery to Grade ≤ 1 or 
baseline, based on Investigator’s clinical 
judgement. 
Other 
nonhematologi
cal toxicities 
i.e., diarrhea, 
vomiting; GI 
hemorrhage 
Grade 3 
Withhold M1069 administration until 
recovery to Grade ≤ 1, or to baseline. 
Gastrointestinal symptoms such as nausea 
and vomiting can be treated as per local 
institutional guidelines. 
Other  
Grade 3+ 
Hold M1069 based on Investigator’s clinical 
judgement. 
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; DLT = Dose-limiting toxicity; GI = Gastrointestinal, 
NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events. 
 

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6.7 
Study Intervention After the End of the Study  
The Sponsor will not provide additional care to participants after they leave the study because 
such care would not differ from what is normally expected for patients with advanced solid 
tumors. 
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7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for clinical response/tumor assessment. The SoA specifies data to be collected at the 
time of discontinuation of study intervention and follow-up and any further evaluations that need 
to be completed. Importantly, tumor assessments will be continued during the follow-up period 
until confirmed PD according to the SoA. 
Participants must be withdrawn from study interventions if any of the following occurs: 
x General important safety concerns: 
A participant's study intervention should be discontinued if the Investigator believes that 
for safety reasons (e.g., AE) it is in the participant’s best interest. 
x Occurrence of DLT during the DLT observation period: 
Participants experiencing DLTs as described in Section 6.6.3 will not receive further study 
intervention. When the resumption of treatment following the resolution of a DLT is 
deemed in the best interest for the participant, the Medical Monitor and the Sponsor 
Medical Responsible should be consulted to discuss. 
x Cardiac changes (e.g., QTc): 
If a clinically significant finding is identified (including changes from baseline in QT 
interval corrected using Fridericia’s formula [QTcF] by >60 ms or above 500 ms after start 
of treatment), the Investigator or qualified designee upon consultation with the Sponsor’s 
Medical Responsible will determine if the participant can continue in the study and if any 
change in participant management is needed. While increases in QT/QTc to > 500 ms or 
of > 60 ms over baseline are commonly used as thresholds for potential discontinuation, 
the exact criteria chosen for this study will depend on the risk-benefit level considered 
appropriate for the participant in question. This review of the ECG at the time of collection 
will be documented. Any new clinically relevant finding is reported as an AE. The final 
decision on the continuation of treatment upon the emergence of clinically significant AEs 
remains with the Investigator. 
 
 
 
 
 
 
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x 
 
  
x Pregnancy: 
See also Section 8.3.5 
x Disease progression: 
Progressive Disease (PD) as defined by RECIST v1.1 while on treatment. Participants who 
experience PD may continue treatment with study interventions under conditions 
described in Section 7.1.1 if the Investigator believes the participant will experience 
clinical benefit from the treatment and there is no unacceptable toxicity resulting from the 
treatment. Such participants will be withdrawn from the treatment if any other criteria for 
withdrawal are met or if alternative treatment options are available and indicated. 
x Clinical deterioration: 
If a patient experiences significant clinical deterioration (clinical progression), defined as 
new symptoms that are deemed by the Investigator to be clinically significant or significant 
worsening of existing symptoms or therapeutic failure requiring urgent alternative 
anticancer treatment (if available), discontinuation of the study intervention should be 
considered after discussion with the Medical Monitor. 
x Missed doses: 
A participant's study intervention can be re-introduced after a safety-related interruption 
and temporary discontinuation if the participant’s underlying disease is thought to benefit 
from re-introduction of the intervention at the discretion of the Investigator. 
x Prohibited concomitant medication: 
If the administration of a prohibited concomitant medication becomes necessary during 
the study, study intervention will be discontinued.  The Investigator may contact the 
Medical Monitor to discuss if the study intervention may be continued after application of 
a prohibited concomitant medication if patient is expected to benefit from a continuation 
of treatment. 
x Other reasons: 
The participant will be withdrawn from the study intervention if any of the following 
occurs: discontinuation of or noncompliance with the study intervention or failure to attend 
scheduled assessments that are deemed necessary for the participants’ safety or study 
integrity for more than 2 weeks in the absence of any medical reasons. 
The SoA specifies the data to collect at study intervention discontinuation and follow-up, and 
any additional evaluations that need to be completed. 
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7.1.1 
Treatment Beyond Initial Progression  
Participants will receive M1069 as study interventions as outlined in the SoA until confirmed 
disease progression. Study interventions may continue past the initial determination of disease 
progression according to RECIST v1.1 as long as the following criteria are met: 
• No new symptoms or worsening of previous symptoms (including laboratory values) 
indicating disease progression 
• Tolerance of study intervention  
• Stable ECOG PS 
• Study intervention beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (for example, central nervous system 
metastases). 
A radiographic assessment should be performed within 4 to 6 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the participant is clinically 
deteriorating and unlikely to receive any benefit from continued treatment with study 
intervention. 
7.1.2 
Treatment Beyond Confirmed Progression  
After confirmed PD, if the Investigator feels that the participant continues to achieve clinical 
benefit by continuing administration of study intervention, the participant should remain on the 
intervention and continue to receive monitoring according to the SoA. The decision to continue 
administration of study intervention beyond confirmed PD should be discussed with the Medical 
Monitor and documented in the study records. 
Participants who continue beyond confirmed progression will be followed as per the protocol 
schedule. Study interventions should be discontinued permanently upon documentation of 
further, unequivocal, disease progression unless there are no alternative therapeutic options and 
the benefit-risk assessment is favorable in consultation between the Investigator and the Medical 
Monitor and Medical Responsible. Treatment will also be discontinued once any other criteria 
for withdrawal are met. 
7.1.3 
Continuation of Study Intervention After Local Treatment 
of Disease Progression  
If disease progression is due to brain metastasis, participants may continue study interventions 
after the local treatment of the brain lesions provided that the above criteria (Section 7.1.1) are 
met in addition to the following: 
• Tumor assessment showing disease progression of brain lesion has been performed and was 
documented according to RECIST v1.1 prior to the procedure. 

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• Brain metastases have been treated locally and are clinically stable for at least 2 weeks prior 
to re-initiation of study interventions. 
• There are no ongoing neurological symptoms that are related to the brain localization of the 
disease (sequelae that are a consequence of the treatment of the brain metastases are 
acceptable). 
• Participants must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent).  
• Benefit-risk assessment to continue study intervention is favorable under consideration of any 
alternative treatment options as assessed by the Investigator. 
In addition, if disease progression is mainly due to a metastatic lesion which in the opinion of 
the Investigator may be surgically removed, participants may continue study interventions after 
the local treatment of such a lesion provided that: 
• Tumor assessment showing disease progression has been performed and was documented 
according to RECIST v1.1 prior to the procedure. 
• It has been at least 2 weeks and the participant has fully recovered from the surgery. 
• Benefit-risk assessment to continue study intervention is favorable under consideration of any 
alternative treatment options as assessed by the Investigator. 
7.1.4 
Rechallenge  
Not applicable. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
• 
A participant may withdraw from the study at any time, at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
• 
At the time of discontinuing from the study, if possible, a discontinuation visit will be 
conducted, as listed in the SoA. The SoA specifies the data to collect at study discontinuation 
and follow-up, and any additional evaluations that need to be completed. 
• 
If the participant withdraws consent for future involvement in the study, any data collected 
up to that point may still be used, but no future data can be generated, and any biological samples 
collected will be destroyed. 
• 
A participant has the right at any time to request destruction of any biological samples 
taken. The Investigator must document this in the site study records. 

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7.3 
Lost to Follow-Up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wants to or should continue in the study. 
• Before a participant is deemed “lost to follow-up”, the Investigator or designee must make 
every effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 
2) if necessary, send a certified letter (or an equivalent local method) to the participant’s last 
known mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner for information. These contact attempts should be 
documented in the participant’s medical record. 
If the participant continues to be unreachable, he/she will be deemed as “lost to follow-up”. 
8 
Study Assessments and Procedures  
Study assessments and procedures and their timing are summarized in the SoA. 
No protocol waivers or exemptions are allowed. 
Immediate safety concerns are discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations will be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened, to confirm eligibility, and if applicable, record reasons for screening 
failure. 
Prior to performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will obtain written informed consent as specified in Appendix 2. 
Procedures conducted as part of the participant’s routine medical care (e.g., blood count) and 
obtained before signing of the ICF may be used for screening or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame defined 
in the SoA. 

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8.1 
Efficacy Assessments and Procedures  
Computed tomography (CT) or magnetic resonance imaging (MRI) scans will be performed and 
collected until confirmed PD is assessed by the Investigator according to RECIST v1.1 
(Eisenhauer 2009) or until start of new anticancer therapy in case of continuation of study 
intervention beyond PD, according to the SoA (Section 1.3) and definition of local treatment of 
disease progression (Section 7.1.3). 
All images should be available for collection and potential retrospective central analysis. 
Radiographic images and physical findings (physical assessments) will be used by the 
Investigator for the local determination of PD and participant’s treatment decisions. 
For each participant, tumor response assessment will be performed by CT scan or MRI (if MRI 
is used, chest CT is mandatory) imaging of the chest/abdomen/pelvis (plus other regions as 
specifically required) and other established assessments of tumor burden if CT/MRI imaging is 
insufficient for the individual participant. All scans performed at Screening and other imaging 
performed as clinically required (other supportive imaging) need to be repeated at subsequent 
visits. In general, lesions detected at Screening need to be followed using the same imaging 
methodology and preferably the same imaging equipment at subsequent tumor evaluation visits. 
For each participant, the Investigator will designate 1 or more of the following measures of tumor 
status to follow for determining response: CT or MRI images of primary and/or metastatic tumor 
masses, physical examination findings, and the results of other assessments. All available images 
collected during the study period will be considered. The most appropriate measures to evaluate 
the tumor status of a participant should be used. The measure(s) to be chosen for sequential 
evaluation during the study must correspond to the measures used to document the progressive 
tumor status that qualifies the participant for enrolment. The tumor response assessment will be 
assessed and listed according to the SoA (Section 1.3). 
Treatment decisions will be made by the Investigator based on the Investigator’s assessment of 
disease status. Investigator’s assessment of objective tumor response to treatment will be 
performed according to RECIST v1.1 (all measurements should be recorded in metric notation, 
as described in RECIST v1.1). 
• At Baseline, tumor lesions will be categorized in target and non-target lesions as described in 
RECIST v1.1. 
• Results for these evaluations will be recorded with as much specificity as possible so that 
pretreatment and post-treatment results will provide the best opportunity for evaluating tumor 
response. 
• Any complete response (CR) or partial response (PR) should be confirmed, preferably at the 
next subsequent scheduled imaging interval, but no sooner than 6 weeks after the initial 
documentation of CR or PR. 
• The Investigator may perform scans in addition to a scheduled study scan for medical reasons 
or if the Investigator suspects PD. Participants who withdraw from the investigational 

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treatment for clinical or symptomatic deterioration before objective documentation of PD or 
who discontinue from investigational treatment for reasons other than objective PD will be 
requested to continue appropriate imaging according to the study schedule until determination 
of confirmed PD or discontinuation from the study, whichever occurs earlier. Every effort 
should be made to confirm a clinical diagnosis of PD by imaging. 
8.2 
Safety Assessments and Procedures  
The safety profile of the study intervention will be assessed through the recording, reporting and 
analysis of baseline medical conditions, adverse events (AEs), physical examination findings, 
vital signs, electrocardiograms, and laboratory tests. 
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1. 
8.2.1 
Physical Examinations  
Physical examination will be performed at the time points specified in the Schedule of Activities 
in Section 1.3. 
• A complete physical examination will include, at a minimum, assessments of the 
dermatological, pulmonary, cardiovascular, gastrointestinal, genitourinary, lymphatic, 
neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, throat, 
cognitive status and general appearance. 
• A brief physical examination will include, at a minimum, assessments of the general 
appearance, pulmonary, cardiovascular, gastrointestinal and eyes. 
• Investigators will pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2 
Vital Signs  
Vital signs will be measured at the time points specified in the Schedule of Activities 
(Section 1.3). 
• Height (at Screening only) and weight will be measured and recorded. 
• Oral temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed supine position with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• Blood pressure and pulse measurements will be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 

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intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded 
on the eCRF. 
8.2.3 
Electrocardiograms  
All types of ECGs will be recorded using the same ECG device (Holter recorder). The Holter 
recorder will be connected to a provided laptop which will allow to print out safety ECGs locally 
or upload digital ECGs for centralized reading.  
Safety ECGs 
x Triplicate 12-lead ECGs will be obtained as outlined in the SoA using an ECG machine 
(Holter recorder) that automatically calculates the heart rate and measures PR, RR, QRS, 
QT, and QTcF intervals. At the time of the ECG measurements for the QT/QTc analysis, the 
Holter recorder can be used for safety ECG and for triplicate digital ECGs. 
x The safety ECG should be performed after at least 10 minutes rest in a supine position prior 
to blood sampling and will be read locally by a physician for real time monitoring. When a 
clinically significant finding is identified, see Section 7.1 for details regarding discontinuation 
criteria. 
Holter ECG for QT/QTc Evaluation 
x Holter ECGs will be obtained as outlined in the SoA. 
x Holter ECGs should be recorded for approximately 24 hours on C1D-1, and from at least 1 
hour before until 8 hours after the first dose on C1D1 and C1D8. The participants should be 
put in a supine position at least 15 minutes prior to blood sampling, to allow 10 minutes rest 
and 5 minutes ECG extraction. Triplicate digital ECGs will be extracted from continuous 
Holter ECGs at predose (-45, -30, -15min), 1h, 2h, 4h, 6h and 8h on C1D1 and C1D8.  The 
data will be archived in digital format using a central ECG vendor and will be analyzed by a 
specialized central laboratory. 
 
  
 
 
 
 
 
 
 
 
 
 
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If the participant discontinue treatment before C3D1(+/- 7 days), 
 
 
When a clinically significant finding is identified, see Section 7.1 for details regarding 
discontinuation criteria. 
8.2.5 
Clinical Safety Laboratory Assessments  
Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 6 
at the time points listed in the SoA. All samples will be clearly identified. 
Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations. 
The tests will be performed by the local laboratory. 
The Sponsor or designee will receive a list of the local laboratory normal ranges before shipment 
of study intervention(s). Any changes to the ranges during the study will be forwarded to the 
Sponsor or designated organization. 
The Investigator will review each laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports will be filed with the source documents. 
Pregnancy testing (ȕ-HCG from serum sample at Screening and from urine or serum sample for 
all other cycles) will be conducted at the timepoints specified in the SoA. 
8.2.6 
Suicidal Ideation and Behavior Risk Monitoring  
Not applicable 
8.3 
Adverse Events and Serious Adverse Events  
The definitions of an Adverse Event (AE) and a Serious Adverse Event (SAE) are in Appendix 4. 
The Investigator and any qualified designees (e.g., Sub-Investigators) are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE. The 
Investigator remains responsible for following up AEs that are serious or that caused the 
participant to discontinue the study intervention or study, as specified in Section 8.3.3. 
Requests for follow-up will usually be made via the Study Monitor, although in exceptional 
circumstances the global patient safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 
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8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information  
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until 
the Safety Follow-up Visit at the time points specified in the SoA (Section 1.3). Beyond this 
reporting period, any new unsolicited SAEs that the Investigator spontaneously reports to the 
Sponsor will be collected and processed. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance will this exceed 24 hours, as indicated in Appendix 4. The Investigator will submit 
any updated SAE data to the Sponsor within 24 hours of it being available using the same 
procedure that was used for the initial report. 
Investigators are not obligated to actively solicit AEs or SAEs after the end of study participation. 
However, if the Investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event to be reasonably related to 
the study intervention or study participation, the Investigator will promptly notify the Sponsor. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events  
At each study visit, the participant will be queried on changes in his or her condition. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are in Appendix 4. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events  
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AEs of Special Interest (as defined in Section 8.3.8) 
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.3). Reasonable attempts to obtain this information 
will be made and documented. It is also the Investigator’s responsibility to ensure that any 
necessary additional therapeutic measures and follow-up procedures are performed. Further 
information on follow-up procedures is in Appendix 4. 

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8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events  
Prompt notification by the Investigator to the Sponsor of an SAE (particularly life-threatening 
and deaths) is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
Individual Case Safety Reports will be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators within 15 days. 
An Investigator or sub-investigator who receives an Individual Case Safety Report describing a 
SUSAR or other specific safety information (e.g., Emerging Safety Issue Report, summary or 
listing of SAEs/SUSARs) from the Sponsor will review the safety reports and confirm 
completion of this review. This information will be filed in the Investigator’s Site File, and the 
IRB/IEC will be notified, if appropriate, according to applicable local laws/regulations and site 
SOPs.  
In this global clinical multicenter study, the Sponsor is in the best position to determine an 
unanticipated problem (as defined in US Regulations 21 CFR 312.66). The Sponsor will 
immediately notify all Investigators of findings that could adversely affect the safety of 
participants, impact the conduct of the study or alter the IRB’s approval/favorable opinion to 
continue the study. An unanticipated problem is a serious adverse event that by its nature, 
incidence, severity, or outcome has not been identified in the current version of the risk analysis 
report, specified in Section 2.3. 
8.3.5 
Pregnancy  
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until 30 days after the last dose. 
If a pregnancy is reported, the Investigator will inform the Sponsor within 24 hours of learning 
of the pregnancy and will follow the procedures specified below for collection of pregnancy 
information. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant: 

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• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner, who becomes pregnant while the participant is in this study. This applies only 
to participants who receive M1069. 
• After obtaining signed consent from the pregnant female partner directly, the Investigator 
will record the pregnancy information on the appropriate form and submit it to the Sponsor 
within 24 hours of learning of the pregnancy. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and child 
will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female Participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while she is in the study. The initial information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of the pregnancy. 
• The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate, and the information 
will be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 
6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
• A spontaneous abortion (occurring at < 22 weeks gestational age) or stillbirth (occurring at 
> 22 weeks gestational age) is always considered to be an SAE and will be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as specified in Section 8.3.4. 
While the Investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
8.3.6 
Cardiovascular and Death Events  
Death and cardiovascular events (meeting the SAE definition) will be reported as per the 
reporting guidelines specified in Appendix 4. 

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8.3.7 
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as AEs or SAEs  
The following disease-related events (DREs) are common in participants with cancer and can be 
serious/life-threatening: 
x Progression of disease 
Because these events are typically associated with the disease under study, it will not be reported 
according to the standard process for expedited reporting of SAEs even though the event may 
meet the definition of a SAE. These events will be recorded on the applicable eCRF page within 
the appropriate time frame. 
However, if either of the following conditions applies, then the event will be recorded and 
reported as an SAE (instead of a DRE): 
x The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual participant. 
OR 
x The Investigator considers that there is a reasonable possibility that the event was related to 
study intervention. 
8.3.8 
Adverse Events of Special Interest  
Data from preclinical investigations in albino rats have suggested a potential for adverse retinal 
findings associated with administration of M1069. To evaluate the ophthalmological impact on 
study participants, the following ophthalmological findings are considered Adverse Events of 
Special Interest and should be reported within 24 hours to the Sponsor:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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8.4 
Treatment of Overdose  
For this study, any dose of M1069 greater than the maximum dose in the study or in the program 
that is considered safe and well tolerated within a 24-hour time period will be considered an 
overdose. 
The Sponsor does not recommend specific treatment for an overdose. 
Even if not associated with an AE or a SAE, any overdose is recorded in the eCRF and reported 
to global patient safety in an expedited manner. Overdoses are reported on a SAE and Overdose 
Report Form, following the procedure in Appendix 4, the section on Reporting SAEs. 
8.5 
Pharmacokinetics  
Whole blood samples of approximately 6 mL per collection for measurement of plasma 
concentrations of M1069. Collection times are specified in Table 2 of the SoA. 
The actual date and time (24-hour clock time) of each sample will be recorded to calculate actual 
time elapsed since the prior dose administration. In addition, the actual date and time (24-hour 
clock time) of the study intervention administration prior to sample collection should be recorded 
in the eCRF. The sampling timing may be altered with the recommendation of SMC during the 
study based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations, to add 24h post-dose sampling for QD dosing) to ensure appropriate monitoring. 
The quantification of M1069 in plasma will be performed using a validated method. 
Concentrations will be used to evaluate the PK of M1069. Remaining samples collected for 
analyses of M1069 concentration may also be used for 
 assessment of metabolites of 
M1069, or 
 and transporters, or safety or efficacy aspects related 
to concerns arising during or after the study. 
Details on processes for collection and handling of these samples are in Laboratory Flowchart. 
Retention time and possible analyses of samples after the end of study are specified in the 
respective ICF. 
The following M1069 PK parameters will be calculated, when appropriate (see Table 10). A 
non-compartmental analysis (NCA) will be performed to estimate these PK parameters for 
M1069. Other PK parameters might be added based on emerging data. Details will be included 
in the Integrated Analysis Plan. 
Considering the confounding effects from caffeine on PK-Pd relationship, caffeine intake is 
prohibited 48-hour before the dosing until after collection of the PK samples on C1D1 and C1D8. 
The daily caffeine intake information should be recorded in the diary. 
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Table 10 
Assessment of Plasma Pharmacokinetic Parameters  
Symbol 
Definition 
AUC0-tlast 
The AUC from time zero (= dosing time) to the time of the last quantifiable 
concentration (tlast). 
AUC0-tlast/Dose The dose normalized AUC0-tlast. 
AUCW 
The AUC over the dosing interval W. 
AUCW /Dose 
The dose normalized AUCW. 
AUC0-f 
The AUC from time zero (= dosing time) up to infinity with extrapolation 
of the terminal phase. 
AUC0-f/Dose 
The dose normalized AUC0- 
CL/F 
The apparent total body clearance following extravascular administration. 
Cmax 
Maximum observed concentration. 
Cmax/Dose 
The dose normalized Cmax. 
Ctrough 
The concentration observed at the end of a dosing interval immediately 
before next dosing. 
LI 
The linearity index after repeated administration. 
Racc(AUC0-8) 
The accumulation ratio of AUC0-8 after repeated administration. 
Racc(Cmax) 
The accumulation ratio of Cmax after repeated administration. 
t1/2 
The terminal half-life. 
tmax 
The time to reach the Cmax in a dosing interval. 
Vz/F 
The apparent volume of distribution during the terminal phase following 
extravascular administration. 
 
 
  
 
 
 
 
 
 
 
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8.7 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.9 
Immunogenicity Assessments  
Not applicable. 
8.10 
Health Economic  
Not applicable. 
9 
Statistical Considerations   
All analyses will be prepared by dose level and will be described in detail in the Integrated 
Analysis Plan (IAP). 
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There is no formal family-wise type I error control for this study, as such all analyses are 
considered descriptive. 
9.1 
Statistical Hypotheses  
This is an exploratory study. No formal statistical hypothesis will be tested, and all analyses are 
considered descriptive. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3 
Populations for Analyses   
The analysis populations are specified below. The final decision to exclude participants from 
any analysis population will be made during a data review meeting prior to database lock (except 
for the DLT analysis set). For the DLT analysis set the decision is taken by the SMC. 
 
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Analysis Set 
Description 
Screening (SCR)  
All participants, who provided informed consent, regardless of the 
participant’s study intervention status in the study. 
Safety (SAF) 
All participants, who were administered any dose of any study 
intervention. Analyses will consider participants as treated. 
DLT 
The DLT Set will include all participants who received at least one 
dose of study intervention and meet at least one of the following 
criteria: 
• Experienced at least one DLT during the DLT period, regardless of 
the administered number of doses of study intervention/completion 
in the DLT period. 
• Received at least 80% of the planned cumulative dose during the 
DLT period. 
• Additionally, participants who did not receive at least 80% of the 
planned total dose of study intervention, but at least 80% dosing of a 
different dose cohort and finished the DLT period, are eligible for 
the DLT analysis set to be analyzed in the highest dose cohort for 
which they received 80% of dosing. 
The final decision on evaluability for dose escalation analysis will be 
made by the SMC (e.g. considering relevant deviations from dosing 
schedule). 
PK 
All participants, who receive at least one dose of study intervention and 
provide at least one measurable post-dose concentration. Participants 
will be analyzed per the actual study intervention they received. 
Pd 
All participants, who receive at least one dose of study intervention, 
have no important events affecting Pd and provide at least one 
measurable PD endpoint post-dose. 
Participants will be analyzed per the actual study intervention they 
received. All PD analyses will be based on this analysis population. 
 
9.4 
Statistical Analyses  
In general, continuous variables will be summarized using number of participants (n); mean, 
standard deviation; median, 25th Percentile to 75th Percentile (Q1-Q3), minimum, and maximum. 
If there are less than 5 observations available only mean and the observed data will be given. 
Categorical variables will be summarized using frequency counts and percentages. 
The calculation of proportions will be based on the number of participants in the analysis set of 
interest, unless otherwise specified in the study IAP. 

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Besides the details outlined below, more details will be specified in the IAP finalized before 
database lock. 
Except for the analysis of DLTs, all analyses will be performed on the Safety Analysis 
population. 
9.4.1 
Efficacy Analyses  
Endpoint  
Category 
Statistical Analysis Methods/Further Estimand 
Attributes 
OR 
Main 
Objective response rate will be determined as the 
proportion of participants with a confirmed objective 
response of PR or CR. Confirmation of response 
according to RECIST v1.1 will be required no sooner 
than 6 weeks after the initial documentation of CR or 
PR. 
 
The 95% two-sided Confidence interval for the ORR 
will be calculated using the Clopper Pearson method. 
DoR, PFS 
Main 
Kaplan-Meier estimates (product-limit estimates) will be 
presented for the analysis of DoR and PFS together with 
a summary of associated statistics (median, survival time 
and survival rate estimates at 3, 6, 12 months and every 
6 months thereafter if applicable) including the 
corresponding 2-sided 95% CIs. 
 
DoR is defined, for participants with an objective 
response, as the time (months) from first documentation 
of objective response (CR or PR) to the date of first 
documentation of PD or death due to any cause, 
whichever occurs first. The censoring rules for DoR are 
as described below for PFS. 
PFS is defined as the time (in months) from date of first 
administration of study intervention to the date of the 
first documentation of PD or death due to any cause, 
whichever occurs first. PFS data will be censored on the 
date of the last non-missing tumor assessment for 
participants who do not have an event (PD or death) or 
for participants for which the event is reported after 2 or 
more missed subsequent scheduled tumor assessments. 
Participants who do not have a baseline tumor 
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Endpoint  
Category 
Statistical Analysis Methods/Further Estimand 
Attributes 
assessments will be censored at the date of the start of 
study intervention. 
 
 
 
 
CI = Confidence interval, CR = Complete response, DoR = Duration of response; 
PD = Pharmacodynamic, PFS = Progression-free survival, PR = Partial response; OR = 
Objective response; ORR = Objective response rate, RECIST = Response Evaluation Criteria 
in Solid Tumors. 
 
9.4.2 
Safety Analyses  
Except for the analysis of DLTs (a primary endpoint), all safety analyses will be performed on 
the Safety Analysis population. 
Endpoint 
Category 
Statistical Analysis Methods/Further Estimand 
Attributes 
DLT 
 
Main 
Bayesian logistic regression analysis as described in 
Appendix 8. 
At end of dose escalation analysis and main analysis, the 
number and proportion of participants experiencing DLTs 
will be reported by dose level, based on observations 
during the first study intervention cycle. Posterior 
probabilities (2.5%, 25%, 50%, 75%, 95% and 97.5% 
quantiles) for DLT probabilities at selected doses will be 
estimated from the Bayesian logistic regression model. 
DLT 
 
Sensitivity 2 parameter frequentist modeling (without prior). 
AEs, Treatment-
Related Adverse 
Event 
Main 
TEAEs are defined as AEs emerging or worsening after 
start of treatment until 30 days after end of treatment. 
Adverse events will be coded according to the latest 
available version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Severity of AEs will be 
graded by the Investigator using the NCI-CTCAE 
(Version 5) toxicity grades. Treatment-related AEs will be 
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defined as any AE considered as related to M1069 
according to Investigator. Incidence of TEAEs and 
treatment-related AEs summarized by SOC and PT. 
Deaths 
 
Main 
Counts and percentages. 
Changes in 
laboratory 
measurements and 
vital signs 
 
Main 
Summary statistics and line plots. 
Laboratory results will also be classified by Grade 
according to NCI-CTCAE. Worst on-treatment grades as 
well as shifts to worst on-treatment grades will be 
summarized. Measurements without NCI-CTCAE grading 
will be summarized by above, within and below normal 
limits. 
 
 
 
AE = Adverse event, DLT = Dose-limiting toxicity, IAP = Integrated analysis plan, MedDRA = Medical Dictionary for 
Regulatory Activities, NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events, 
PT = Preferred Term, SOC = System Organ Class, TEAE = Treatment-emergent adverse event.  
9.4.2.1 
Dose Escalation  
Analyses to decide on dose escalation will be performed on the DLT set and will be based on 
concentration available safety, preliminary PK and available Pd data.  To support the decision 
on dose escalation, the SMC will receive results of a Bayesian dose toxicity model, including 
the recommendation of the next dose level. This Bayesian two-parameter logistic regression 
model (Neuenschwander 2008) is further specified in Appendix 8. For each SMC meeting, the 
model will be updated with the number of DLTs and evaluable participants per dose level. The 
following dose levels are foreseen: 150, 300, 450, 600, and 700 mg BID. If deemed necessary 
based on obtained pharmacological data, higher dose levels than 700 mg BID with an increase 
by 15% may be recommended by the SMC. Participants will receive study intervention twice 
daily with a food restriction for 2 hours before and 1 hour after dose administration. However, 
the SMC may decide to investigate different doses, dosing regimen and dosing conditions (see 
Section 6.6.2). 
The dose suggested by the model for the next cohort will be based on minimizing the Bayesian 
Risk. 
The SMC may choose a different dose than suggested by the Bayesian escalation approach. Also, 
the SMC may decide to change dosing of M1069 to once daily instead of twice daily. In such a 
case the dose toxicity model will be extended, or a separate model will be set up. 
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The MTD will be defined by the SMC. The target DLT probability for the MTD suggested by 
the Bayesian model is 30%. The prerequisites for the MTD suggestion from the model are
described in the Appendix 8. 
Analyses for the Bayesian dose escalation will be performed on the DLT set. Usually, decisions 
on dose escalation are taken once all participants of the most recent cohort have completed the 
DLT period or dropped out. In exceptional cases, however, the SMC may decide on the next 
cohort earlier, i.e., before the last participant of a cohort has finished the DLT period (considering 
the model recommendation). Per definition of the DLT set, participants who have not completed 
the DLT period are not included for update of the model, unless they experienced a DLT. 
However, data of such participants will be included at next SMC (if criteria for the Dose 
escalation set are fulfilled).
Details on analyses for SMCs will be described in the SMC IAP.
Before first dosing, the assumed relationship between dose level and toxicity is specified through 
the prior distribution. The prior distribution chosen for this trial corresponds to the following: 
Probability for DLT
150 mg
300 mg
450 mg
600 mg
700 mg
Prior mean
Prior median
DLT = Dose-limiting toxicity.
Details of the model, including the prior distribution are described in Appendix 8. 
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9.4.3.1 
Pharmacokinetic Profile  
Estimation of Individual PK Parameters: 
x Pharmacokinetic parameters will be calculated using standard non-compartmental methods 
and the actual administered dose. 
x Non-compartmental computation of PK parameters will be performed using the computer 
program Phoenix® WinNonlin® version 6.3, or higher (Certara, L.P., 1699 S Hanley Road, 
St Louis, MO 63144, USA). 
x The statistical software SAS® (Statistical Analysis System, SAS-Institute, Cary NC, USA, 
windows version 9.1 or higher) may be used to produce tables, listings and figures and in the 
calculation of PK Parameters if appropriate. 
Pharmacokinetic analyses will be specified in the IAP finalized before database lock. More 
details on the PK parameters planned to be analyzed are described in Section 8.5. 
 
  
 
 
  
 
 
 
 
9.4.4 
Sequence of Analyses  
The SMC will review available data during study conduct. The cutoff for dose escalation 
assessments by the SMC will usually be triggered by the completion of the DLT period (or 
dropout) of the last participant in the respective dose escalation cohort of usually 3 participants. 
When enrolment of the last participant in a dosing cohort is delayed, the SMC may decide (based 
on available data) upon enrolment and dose for the next dosing cohort before all participants in 
a cohort have completed Cycle 1. The Bayesian model will then be updated with the available 
data, and the data from the participant not having completed the DLT period at time of SMC will 
be considered in the next SMC. In these cases, cutoff can be earlier (after the DLT period of the 
first 2 participants are finished or they experienced a DLT). 
Primary Analysis: The cutoff for the primary analysis will be LSLV or 13 weeks after LSFD, 
whichever comes first. 
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Follow-up analyses to report further efficacy and safety data will be done once the End of Study 
has been reached. 
Additional analysis during the study might be conducted, e.g., for publication or decision making 
purposes. 
More details will be described in the IAP. 
10 
References  
Bové DS, Yeung WY, Palermo G, et al. Model-based dose escalation designs in R with crmPack. 
J Stat Softw. 2019; 89(10):1-22.  
Cekic C, Day YJ, Sag D, et al. Myeloid expression of adenosine A2A receptor suppresses T and 
NK cell responses in the solid tumor microenvironment. Cancer Res. 2014;74(24):7250-9.  
Cekic C, Linden J. Purinergic regulation of the immune system. Nat Rev Immunol. 
2016;16(3):177-92.  
Cecchini M, Quah C, Liu S, et al. ARC-3: Updated results of etrumadenant (AB928) + 
mFOLFOX-6 in patients with metastatic colorectal cancer. American Association for Cancer 
Research (AACR) Virtual Annual Meeting. 2021. Poster # CT129.  
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lymphoma kinase (ALK)-rearranged metastatic non–small cell lung cancer (NSCLC). Journal of 
Thoracic Oncology 12.9 (2017):1357-67.  
Csoka B, Selmeczy Z, Koscso B, et al. Adenosine promotes alternative macrophage activation 
via A2A and A2B receptors. FASEB, 2012;26:376-86.  
Cronstei BN. Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol, 1994;76(1):5-
13.  
Eckle T, Faigle M, Grenz A, et al. A2B adenosine receptor dampens hypoxia-induced vascular 
leak. Blood. 2008;111(4): 2024-35.  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (Version 1.1). Eur J Cancer. 2009;45:228-47.  
Fang M, Xia J, Wu X; et al. Adenosine signaling inhibits CIITA-mediated MHC Class II 
transactivation in lung fibroblast cells. Eur. J. Immunol. 2013:43:2162-73.  
Food and Drug Administration. Guidance for Industry Estimating the Maximum Safe Starting 
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in INDS and NDAs- Clinical Pharmacology Considerations. Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) February 2019.  
Fredholm BB, Ijzerman AP, Jacobson KA, et al. International union of pharmacology. XXV. 
Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001;53(4):527-52.  

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Gao ZG, Jacobson KA. 2B Adenosine Receptor and Cancer. Int J Mol Sci. 2019;20:5139.  
Mittal D, Sinha D, Barkauskas D, et al. Adenosine 2B receptor expression on cancer cells 
promotes metastasis. Cancer Res. 2016;76:4372-82.  
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase 
I cancer trials. Stat Med. 2008;27(13):2420-39.  
Novitskiy SV, Ryzhov S, Zaynagetdinov R, et al. Adenosine receptors in regulation of dendritic 
cell differentiation and function. Blood, 2008;112(5):1822-31.  
Ohta A. A metabolic immune checkpoint: adenosine in tumor microenvironment. Front 
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Powderly J, Spira A, Gutierrez R, et al. Phase 1 Evaluation of AB928, a novel dual adenosine 
receptor antagonist, combined with chemotherapy or AB122(anti-PD-1) in patients with 
advanced malignancies. ESMO 2019. poster 1206P.  
Ryzhov S, Novitiskiy SV, Zaynagetdinov, R. et al. Host A2B adenosine receptors promote 
carcinoma growth. Neoplasia, 2008;10(9): 987-95.  
Ryzhov S, Biktasova A, Goldstein AE, et al. Role of JunB in adenosine A2B receptor-mediated 
vascular endothelial growth factor production. Mol Pharmacol. 2014;85: 62-73.  
Seitz L, Jin L, Leleti M, et al. Safety, tolerability, and pharmacology of AB928, a novel dual 
adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers. Invest New 
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Simeoni M, Magni P, Cammia C, et al. Predictive pharmacokinetic-pharmacodynamic modeling 
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Sorrentino C, Miele L, Porta A, et al. Myeloid-derived suppressor cells contribute to A2B 
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Voss M, Hotson A, Willingham S, et al. CD68+Tumor-associated myeloid cells as the target of 
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11 
Appendices  
Appendix 1 
Abbreviations  
 
A2A/2B 
Adenosine Receptor 2A/2B 
ADL 
Activity of daily living 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
 
 
BID  
Twice daily 
BLRM 
Bayesian 2-parameter logistic regression model 
C 
Cycle 
CIOMS 
Council for International Organizations of Medical Sciences 
CR 
Complete Response 
CREB 
cAMP response element-binding protein, 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT  
Computed tomography 
CYP 
Cytochrome P450 
D 
(Study) Day 
DDI 
Drug-drug interatction 
DL 
Dose level 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DRE 
Disease-related event 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
CCI

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EOSI  
End of Study Intervention 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EZ-line 
Ellipsoid line 
FDA 
U.S. Food and Drug Administration 
FFPE 
Formalin-fixed Paraffin-embedded 
FIH 
First in Human 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
GI 
Gastrointestinal 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest Non-severely Toxic Dose 
HRT 
Hormonal replacement therapy 
IAP 
Integrated Analysis Plan 
IMP 
Investigational Medicinal Product 
IRT 
Interactive response technology 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone releasing system 
GCP 
Good Clinical Practice 
hCG 
human chorionic gonadotropin 
IAP 
Integrated Analysis Plan 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 

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LAM 
lactational amenorrhoea method 
LSFD 
Last Subject First Dose 
LSLV 
Last Subject Last Visit 
MD 
Mean Deviation 
MedRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
MRI 
Magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events  
NOAEL 
No observed adverse effect level 
NTI 
Narrow therapeutic index 
 
 
OR 
Objective response 
ORR 
Objective response rate 
 
 
PD 
Progressive disease 
Pd 
Pharmacodynamic 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
P-gp 
P-glycoprotein 
PGx 
Pharmacogenetic 
PR 
Partial Response 
PT 
Preferred Term 
QD 
Once daily 
QSP 
Quantitative system pharmacology 
QTcF 
QT interval in the ECG, corrected by Fridericia formula 
RDE 
Recommended Dose for Expansion 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
 
 
SMC 
Safety Monitoring Committee 
CCI
CCI
CCI

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SmPC 
Summary of Product Characteristics (European Union) 
SoA 
Schedule of Activities 
SoC 
System Organ Class 
STD 
Severely toxic dose 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse events. 
TME 
Tumor microenvironment 
Tregs 
Regulatory T-cells 
USPI 
Prescribing Information (United States) 
VEGF 
Vascular endothelial growth factor 
ULN 
Upper Limit of Normal 
WOCBP 
Woman of Childbearing Potential 

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Appendix 2 
Study Governance  
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with enough, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions on the study. 
Participants will be informed that their participation is voluntary. 
Participants or their legally-authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50; the Japanese ministerial ordinance 
on GCP local regulations; ICH guidelines; Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable; and the IRB/IEC or study center. 
The medical record will include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent will also sign the ICF. 
If the ICF is updated during their participation in the study, participants will be re-consented to 
the most current, approved version. 
A copy of the ICF(s) will be provided to the participant or the participant’s legally authorized 
representative. 
The original signed and dated consent will remain at the Investigator’s site and will be safely 
archived so that it can be retrieved at any time for monitoring, auditing and inspection purposes. 
Participants who are rescreened are required to sign a new ICF. 
Data Protection 
The Sponsor will assign a unique identifier to participants after obtaining their informed consent. 
Rescreened participants will be assigned a new participant number. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any identifiable information will not be transferred. 
The Sponsor will inform participants that their personal study-related data will be used per local 
data protection and privacy laws. The level of disclosure will also be explained to the participant 

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and pregnant partners (if applicable), who will be required to give consent for their data to be 
used, as specified in the informed consent. 
The participant will be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate 
IRB/IEC members, and by regulatory authority inspectors.  All such persons will strictly 
maintain participants’ confidentiality. 
Study Administrative 
The study will be conducted at approximately 3 study sites in North America, including 
approximately 2 study sites in the US. The Coordinating Investigator listed on the title page 
represents all Investigators for decisions and discussions on this study, per ICH GCP. The 
Coordinating Investigator will provide expert medical input and advice on the study design 
and execution and is responsible for the review and signoff of the clinical study report. 
The study will appear in the following clinical studies registries: ClinicalTrials.gov. 
Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) will be formed in this study. The SMC consists of 
Sponsor representatives (including, but not limited to the Medical Responsible, the Patient 
Safety Strategy Lead, the Biostatistician, and the PK expert) and Investigators. The Medical 
Monitor from the Contract Research Organization will be a SMC member. The SMC may 
modify the frequency of meetings as deemed appropriate during the study. See Section 6.6 
for more details. 
The Clinical Research Organization, IQVIA, will be responsible for the following activities: 
o IQVIA central laboratory services (Q2S) 
o Clinical data management study design and programming 
o Clinical ancillary supplies services 
o Clinical data management 
o Clinical operations 
o Feasibility 
o Global site services 
o Medical monitoring 
o Operational planning 
o Pharmacovigilance and Drug safety services 
o Project financial analysts 
o Project management 
o Project vendor management. 

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• Catalent is responsible for drug supply and distribution responsibilities (e.g., use of regional 
distribution centers). 
• The IRT (interactive response technology) will be used to trigger supply/re-supply of IMP to 
sites, assign unique participant numbers, allocate participants to study intervention group at 
enrollment visit, and to provide study intervention to participants at each study intervention 
visit. 
• ERT (eResearchTechnology, Inc) (ECG) monitoring will be performed as specified in the 
SoA for end of study central QTc analysis. 
• The Sponsor is responsible for supply and manufacture of M1069 and for study oversight. 
• Details of structures and associated procedures will be defined in a separate Project 
Management Plan. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and the following: 
• Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
The Investigator will submit the protocol, protocol amendments (if applicable), ICF, Investigator 
Brochure, and other relevant documents (e.g., advertisements) to an IRB/IEC and the IRB/IEC 
will review and approve them before the study is initiated. 
Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures. 
• Notifying the IRB/IEC of SAEs or other significant safety findings, as required by IRB/IEC 
procedures 
• Providing oversight of the study conduct at the site and adherence to requirements of 21 CFR, 
ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site. 

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Emergency Medical Support 
The Sponsor or designee will provide Emergency Medical Support cards to participants for use 
during the study. These provide the means for participants to identify themselves as participating 
in a clinical study. Also, these give health care providers access to any information about this 
participation that may be needed to determine the course of medical treatment for the participant. 
The information on the Emergency Medical Support card may include the process for emergency 
unblinding (if applicable). 
The first point of contact for all emergencies will be the clinical study Investigator caring for the 
participant.  Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard process 
established for Investigators. 
When the Investigator is not available, the Sponsor provides the appropriate means to contact a 
Sponsor (or designee) physician. This includes provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor (or 
designee) physician to assist with the medical questions. 
Clinical Study Insurance and Compensation to Participants 
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions will meet good local standards, as applicable. 
Clinical Study Report 
After study completion, the Sponsor will write a clinical study report in consultation with the 
Coordinating Investigator, 
Publication 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows Merck to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a Coordinating 
Investigator will be designated by agreement. 
Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 

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Dissemination of Clinical Study Data 
After completion of the study, a CSR will be written by the Sponsor in consultation with the 
Coordinating Investigator following the guidance in ICH Topic E3 and will be submitted in 
accordance with local regulations. 
Any and all scientific, commercial, and technical information disclosed by the Sponsor in this 
protocol or elsewhere should be considered the confidential and proprietary property of the 
Sponsor. The Investigator shall hold such information in confidence and shall not disclose the 
information to any third party except to such of the Investigator’s employees and staff who had 
been made aware that the information is confidential and who are bound to treat it as such and 
to whom disclosure is necessary to evaluate that information. The Investigator shall not use such 
information for any purpose other than for determining mutual interest in performing the study 
and, if the parties decide to proceed with the study, for the purpose of conducting the study. 
The Investigator understands that the information developed from this clinical study will be used 
by the Sponsor in connection with the development of the study intervention and therefore may 
be disclosed as required to other clinical Investigators, to the US Food and Drug Administration, 
and to other government agencies. The Investigator also understands that, to allow for the use of 
the information derived from the clinical study, the Investigator has the obligation to provide the 
Sponsor with complete test results and all data developed in the study. No publication or 
disclosure of study results will be permitted except under the terms and conditions of a separate 
written agreement. 
Data Quality Assurance 
All participant study data will be recorded on printed or electronic eCRFs or transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are complete, accurate, legible, and timely by physically or 
electronically signing the eCRF. Details for managing eCRFs are in the Data Management Plan. 
The Investigator will maintain accurate documentation (source data) that supports the 
information in the eCRF. 
The Investigator will permit study-related monitoring, quality assurance audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to the study file and source data. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan. 
The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once quality 
control and quality assurance procedures have been completed. Details will be outlined in Data 
Management documents and procedures. 

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Study Monitors will perform ongoing source data verification to confirm that data in the eCRF 
are accurate, complete, and verifiable; that the safety and rights of participants are being 
protected; and that the study is being conducted per the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study for 15 years after study completion, unless local regulations, institutional 
policies, or the Sponsor requires a longer retention. No records may be destroyed during the 
retention period without the Sponsor’s written approval. No records may be transferred to 
another location or party without the Sponsor’s written notification. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 
The Investigator will keep a paper or electronic file (medical file and original medical records) 
at the site for each study participant. The file will identify each participant, contain the following 
demographic and medical information for the participant, and will be as complete as possible: 
• Participant’s full name, date of birth, sex, height, and weight 
• Medical history and concomitant diseases 
• Prior and concomitant therapies (including changes during the study) 
• Study identifier (i.e., the Sponsor’s study number) and participant’s study number. 
• Dates of entry into the study (i.e., signature date on the informed consent) and each visit to 
the site 
• Any medical examinations and clinical findings predefined in the protocol 
• All AEs 
• Date that the participant left the study, including any reason for early withdrawal from the 
study or study intervention, if applicable. 
All source data will be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory 
results). Each document will have the participant number and the procedure date; ideally, printed 
by the instrument used for the procedure. As necessary, medical evaluation of these records will 
be performed, documented, signed and dated by the Investigator. 
Data recorded on printed or electronic eCRFs that are transcribed from source documents will 
be consistent with the source documents or the discrepancies will be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records will be available. 
The Study Monitors will use printouts of electronic files for source data verification. These 
printouts will be signed and dated by the Investigator and kept in the study file. Printing the files 

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will not be necessary if the Study Monitor is permitted to access and review electronic participant 
files or other electronic study records at Investigator sites, provided that they are given their own 
unique access and is “Read Only”. 
Source documents are stored at the site for the longest possible time permitted by the applicable 
regulations, and/or as per ICH GCP guidelines, whichever is longer. The Investigator ensures 
that no destruction of medical records is performed without the Sponsor’s written approval. 
Definition of what constitutes source data is found in Monitoring Plan. 
Study and Site Start and Closure 
First Act of Recruitment 
• The study start date is the date when the clinical study will be open for recruitment. 
• The first act of recruitment is when the first site is opened and will be the study start date. 
Study Closure and Site Termination 
• The Sponsor reserves the right to close the study site or terminate the study at any time and 
for any reason. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a site closure 
visit has been completed. 
• The Investigator may initiate site closure at any time, provided there is reasonable cause and 
enough notice is given in advance of the intended termination. 
• Reasons for the early closure of a study site by the Sponsor or Investigator may include: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local Health Authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further development of the Sponsor’s compound 
• If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any Contract Research 
Organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator will promptly inform the participants 
and assure appropriate participant therapy and/or follow-up. 

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Appendix 3 
Contraception  
Definitions: 
WOCBP: 
A woman is of childbearing potential (fertile) following menarche and until becoming 
postmenopausal unless permanently sterile, as specified below. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, consider additional evaluation. 
Postmenopause: 
Postmenopause is defined as no menses for 12 months without an alternative medical cause. 
• A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in a female not using hormonal contraception or HRT. However, 
in the absence of 12 months of amenorrhea, confirmation with more than 1 FSH 
measurement (> 40 IU/L or mIU/mL) is required. 
• A female on HRT and whose menopausal status are in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if she wishes to 
continue her HRT during the study. Otherwise, she must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Permanent sterilization: 
For this study, permanent sterilization includes: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Documentation can come from the site personnel’s review of the individual’s medical records, 
medical examination, or medical history interview. 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion applies to determine 
study entry. 

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Contraception Guidance: 
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods That Have Low User Dependency 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
IUD 
IUS 
Bilateral tubal occlusion 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly effective method 
of contraception. The spermatogenesis cycle is approximately 90 days. 
Documentation can come from the site personnel’s review of the individual’s medical records, medical 
examination, or medical history interview. 
Highly Effective Methods That Are User Dependent 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
Oral 
Intravaginal 
Transdermal 
Injectable 
Progestogen-only hormone contraception associated with inhibition of ovulation 
Oral 
Injectable 
Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire period 
of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant. 
Barrier Methods (to be used in addition to a highly effective method) 
Male or female condom with or without spermicide 
Cap, diaphragm, or sponge with spermicide] 
Notes: 
• 
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive 
methods for clinical study participants. 
• 
Highly effective methods are those with a failure rate of <1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly. 
• 
“Hormonal contraception may be susceptible to interaction with the study intervention(s), which may reduce 
the efficacy of the contraceptive method. As such, 1) barrier methods (male or female condom with or without 
spermicide; cap, diaphragm, or sponge with spermicide) in addition to hormonal contraception or 2) a non-
hormonal intrauterine device must be used”. 
• 
If locally required, in accordance with CTFG guidelines, acceptable contraceptive methods are limited to 
those which inhibit ovulation as the primary mode of action. 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM are not acceptable methods of contraception for this study. Male condom and female 
condom cannot be used together (due to risk of failure from friction). 

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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether considered related to the study intervention or not. 
• 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention.  
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered as the 
AE rather than the procedure itself. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may have 
been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or 
a SAE.  However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as an AE or a SAE if they fulfill the definition of an AE or SAE. 
Events NOT Meeting the AE Definition 
• 
Unless judged by the Investigator to be more severe than expected for the participant’s condition, any 
clinically significant abnormal laboratory findings, other abnormal safety assessments that are associated with 
the underlying disease, the disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 

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AE/SAEs Observed in Association with Disease Progression 
Progression of the disease/disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) will not be reported as AEs/SAEs, unless the participant’s general 
condition is more severe than expected for his/her condition and/or unless the outcome is fatal 
within the AE reporting period, as defined in Section 8.3.1. 
Other Adverse Events to be Reported Using a Specialized Procedure or Form: 
• Any case of overdose, whether or not associated with an AE (serious or non-serious), 
must be recorded in the eCRF and reported to the Sponsor in an expedited manner using 
the SAE and Overdose Report Form. 
• Pregnancies and their outcomes must be reported to the Sponsor using the Pregnancy 
Report Form. In case of an abnormal outcome, the SAE report form (when the subject 
sustains an event) and the Parent-Child/Fetus Adverse Event Report Form (when the 
child/fetus sustains an event) must be transmitted to the Sponsor. 
SAE Definition 
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) 
Results in death 
b) 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if 
it were more severe. 
c) 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE will be 
considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
• However, all events leading to unplanned hospitalizations or unplanned prolongation of an elective 
hospitalization (i.e., undesirable effects of any administered treatment) must be documented and reported 
as SAEs. 

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d) Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
e) 
Is a congenital anomaly/birth defect 
f) 
Other situations: 
• Medical or scientific judgment will be exercised in deciding whether SAE reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events are usually considered as 
serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
Any suspected transmission of an infectious agent via a study intervention is also considered 
an SAE for reporting purposes, as specified below for reporting SAEs or DLTs. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (e.g., 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
As needed, the Sponsor may ask for copies of certain medical records (e.g., autopsy reports, 
supplemental lab reports, documents on medical history/concomitant medications, discharge letters), as 
supporting source documentation. All participant identifiers, except the participant number, will be 
redacted on these copies before submission to the Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
• 
If an AE constitutes a DLT this is documented accordingly. 
• 
Specific guidance is in the eCRF Completion and Monitoring Conventions. 

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Assessment of Intensity 
The Investigator will assess the intensity of each AE and SAE reported during the study and assign it to 1 of 
the following categories: 
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering 
with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities.  Do not confuse an AE that is assessed as 
severe with a SAE. Severe is a category used to rate the intensity of an event; both AEs and SAEs can be 
assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined criteria specified in the definition of 
an SAE, NOT when it is rated as severe. 
Investigators will reference the National Cancer Institute - Common Terminology Criteria for AEs (CTCAE), 
version 5.0 (publication date: 27 November 2017), a descriptive terminology that can be used for AE 
reporting. 
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the beginning of 
the above referenced document, and specific event grades are also provided. 
If the severity for an AE is not specifically graded by NCI-CTCAE, the Investigator is to use the general NCI-
CTCAE definitions of Grade 1 through Grade 5, using his or her best medical judgment. 
The 5 general grades are: 
• 
Grade 1 or Mild 
• 
Grade 2 or Moderate 
• 
Grade 3 or Severe 
• 
Grade 4 or Life-threatening 
• 
Grade 5 or Death 
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE. However, a laboratory 
abnormality of Grade 4, such as anemia or neutropenia, is considered serious only if the condition meets one 
of the serious criteria specified below. 
If death occurs, the primary cause of death or event leading to death will be recorded and reported as an 
SAE. “Fatal” will be recorded as the outcome of this specific event and death will not be recorded as separate 
event. Only, if no cause of death can be reported (e.g., sudden death, unexplained death), the death per se 
might then be reported as an SAE. 
 
Assessment of Causality 
• 
The Investigator will assess the relationship between study intervention and each AE/SAE occurrence: 
• Unrelated: Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention. A reasonable alternative 
explanation will be available. 
• 
Related: Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study intervention administration will be considered and 
investigated. 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for marketed 
products, in his/her assessment. 

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• 
For each AE/SAE, the Investigator will document in the medical notes that he/she has reviewed the 
AE/SAE and assessed causality. 
• 
There may be situations when an SAE has occurred, and the Investigator has minimal information to 
include in the initial report to the Sponsor or its designee.  To meet the reporting timeline, the causality 
assessment is not required for the initial report. 
• 
The Investigator may change his/her causality assessment after considering follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 
• 
The Investigator will perform or arrange for the conduct of supplemental measurements and/or 
evaluations, as medically indicated or as requested by the Sponsor/designee to elucidate the nature 
and/or causality of the AE or SAE, as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide Sponsor/designee with a copy of any post-mortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor/designee within 24 hours of receipt of 
the information. 
Reporting of SAEs 
SAE Reporting by an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to the Sponsor or its designee will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool, specified 
below, to report the event within 24 hours. 
• 
The site will enter into the electronic system the SAE data within 24 hours after becoming aware of the 
event. It is expected that the investigator/sub-investigator signs off this data in the system and any 
relevant associated data (e.g., additional laboratory tests, medical records, diagnostic reports, 
histopathological examinations, or consultation with other health care professionals) will be entered as 
soon as it becomes available.  
• 
After the study is completed at a site, the electronic data collection tool will be taken off-line to prevent the 
entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken off-line, then the site can report this 
information on a paper SAE form or to the Sponsor’s safety department. 
• 
By exception, an SAE (or follow-up information) may be reported by telephone.  The site will complete the 
electronic SAE data entry immediately thereafter. 
SAE Reporting by a Paper Form 
• 
SAE reporting on a paper report form is used as a back-up method for an Electronic Data Capture system 
failure. The form includes completion instructions for the Investigator, names, addresses, and telephone 
and fax numbers. All information from the paper form will be transcribed into the electronic form as soon 
as the system becomes available. 
• 
Facsimile transmission (fax to mail) of the paper form or any follow-up information is the preferred method 
for transmission and will be done within 24 hours to the Sponsor or its designee. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is acceptable 
with a copy of the form sent by overnight mail or courier service. 

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• 
Initial notification via telephone does not replace the need for the Investigator to complete and sign the 
form within 24 hours after becoming aware of the event. 
• 
Additional documents (e.g. laboratory reports, autopsy report, hospital discharge letter) and relevant 
pages from the eCRF may be required in addition (e.g. medical history, concomitant medication). The 
data provided will be consistent with the information in the eCRF. 
Recording and Reporting of DLTs 
• 
Each event that meets the DLT criteria, as specified in Section 6.6.3, will be recorded in the eCRF within 
24 hours after awareness of the event. 
• 
Serious DLTs will be reported in an expedited manner, using the SAE reporting process, as specified 
above. 
• 
Notification of each DLT related event (non-serious and serious) will be reported to the Sponsor or its 
designee within 24 hours from the date of awareness. 
Reporting of AESIs 
• 
For a non-serious AESI, the site will complete the specific AESI report form and notify the Sponsor 
immediately (within 24 hours), using the same process for reporting SAEs, as specified above. 
• 
For a serious AESI, the site will complete an SAE report form, using the SAE reporting process, specified 
above. 
Reporting of Pregnancies 
• 
Pregnancy will be reported whether related to the study intervention using the applicable paper form. 
• 
The applicable form will be used to report if an abnormal outcome of the pregnancy occurs and the 
child/fetus sustains an event. 
• 
Facsimile transmission (fax to mail) of the paper form or any follow-up information is the preferred method 
for transmission and will be done within 24 hours to the Sponsor or its designee. 

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Appendix 5 
Liver Safety: Suggested Actions and Follow-up Assessments  
See Section 6.6.3 and Section 6.6.4 for management of liver toxicities. 

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Appendix 6 
Clinical Laboratory Tests  
The protocol-required clinical laboratory test are in the following table. All safety-required 
clinical laboratory tests will be performed by a local laboratory. 
 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
Mean corpuscular volume 
(MCV) 
White Blood Cell 
Count with Differential: 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Hemoglobin 
Mean corpuscular hemoglobin 
(MCH) 
Hematocrit 
Erythrocytes 
Reticulocytes  
Biochemistry 
Blood Urea 
Nitrogen/total 
urea 
Potassium 
Aspartate aminotransferase 
Total bilirubin/indirect 
bilirubin 
 
Creatinine 
Sodium 
Alanine aminotransferase 
Total protein 
 
Glucose 
Calcium 
Alkaline phosphatase 
CRP 
 
Albumin 
Amylase 
Lactate dehydrogenase 
Ferritin 
 
Lipase 
Magnesium 
Uric acid 
Creatinine Clearance 
Coagulation 
aPTT (sec) 
PT (sec) 
INR 
 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes by 
dipstick 
• 
Microscopic examination (if blood or protein is abnormal).  
Other Screening 
Tests 
• 
FSH 
• 
Serum (at Screening) and highly sensitive urine (during M1069 treatment) hCG 
pregnancy test (as needed for a WOCBP). 
• 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody). 
 
 

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Appendix 8 
Model for Bayesian Dose Escalation  
The Bayesian model results are based on the number of DLTs and evaluable participants per 
dose level. The SMC will receive results of a Bayesian [two-parameter logistic regression] model 
updated with the observed DLT data (Neuenschwander 2008), including a recommendation for 
the next dose. For a dose level dj, the relationship between dose and probability of toxicity P 
(DLT) is defined by: 
ܲ൫ܦܮܶห݀௝, ߙ, ߚ൯=
ୣ୶୮ቆఈାୣ୶୮(ఉ)כ୪୭୥ቆ
೏ೕ
೏ೝ೐೑ቇቇ
ଵାୣ୶୮ቆఈାୣ୶୮(ఉ)כ୪୭୥ቆ
೏ೕ
೏ೝ೐೑ቇቇ
, 
ZLWKELYDULDWHQRUPDOO\GLVWULEXWHGSDUDPHWHUVĮȕusing the following parameterization: 
x Pre-selected dose level dj İ^150 mg, 300 mg, 450 mg, 600 mg, 700 mg} 
 
 
 
 
 
 
The following toxicity regions will be defined: 
 
Probability of 
DLT 
Loss term 
(weight in loss function)  
Under-Dosing 
(0.0, 0.20] 
[1] 
Target toxicity 
(0.20, 0.35] 
[0] 
Excessive toxicity 
(0.35, 0.60] 
[1] 
Unacceptable toxicity 
(0.60, 1.00] 
[2] 
The model-based recommendation for the next dose level is the dose level that minimizes the 
loss function. The loss function is defined as the sum of products of the probability to lie within 
each of the toxicity regions, and the associated loss term: 
x 1 × P (Under-Dosing) + 0 × P (targeted toxicity) + 1 × P (excessive toxicity) + 2 × P 
(unacceptable toxicity). 
The model will be provided with the following dose levels: 150, 300, 450, 600, and 700 mg BID. 
The set of doses can be changed any time by the SMC. 
The target DLT probability for the MTD suggested by the Bayesian model is 30%. 
C
C
I

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The SMC will be notified of a potential MTD once the estimate for DLT probability of a potential 
MTD reaches sufficient precision, i.e.: 
• 
 
 
 
 
In case information arises from other studies that changes current knowledge on the dose toxicity 
relationship, the prior distribution will be updated prior to the first participant being treated in 
this study. This change will be documented in the SMC charter. If changes are needed due to a 
change in regimen or change from fasted to fed condition, these will also be documented in the 
SMC charter prior to the first SMC with patients with the new regimen / fasting status. 
Posterior distribution and the recommended next dose level suggested by the model will be 
calculated using SAS v 9.4 or higher, EAST version 6.5 or higher, or R version 3.5.1 or higher 
with library package bcrm (Sweeting 2013) or package crmPack (Bové 2019). 
 
 
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Appendix 9 
Protocol Amendment History  
The information for the current amendment is on the title page. 
 

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Appendix 10 
Sponsor Signature Page  
 
Study Title: 
First-in-Human Study to Investigate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics and 
Clinical Activity of M1069 in Participants with 
Metastatic or Locally Advanced Unresectable Solid 
Tumors. 
Regulatory Agency Identifying 
Numbers: 
 
Clinical Study Protocol Version: 11 November 2021 / Version 2.0 
I approve the design of the clinical study: 
 
____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Name, academic degree: 
 
Function/Title: 
 
Institution: 
Merck Healthcare KGaA 
 
Address: 
Merck Healthcare KGaA 
Global Clinical Development Immuno-Oncology 
Frankfurter Str. 250 – F135 
64293 Darmstadt 
Germany 
 
Telephone number: 
 
 
 
Fax number: 
Not Applicable 
E-mail address: 
 
PPD
PPD
PPD
CCI
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Appendix 11 
Coordinating Investigator Signature Page  
 
Study Title: 
First-in-Human Study to Investigate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics and 
Clinical Activity of M1069 in Participants with 
Metastatic or Locally Advanced Unresectable Solid 
Tumors. 
Regulatory Agency Identifying 
Numbers: 
IND 
 
Clinical Study Protocol Version: 11 November 2021 / Version 2.0 
Site Number: 
 
I approve the design of the clinical study, am responsible for the conduct of the study at this site 
and understand and will conduct it per the clinical study protocol, any approved protocol 
amendments, International Council on Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws. 
 
____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Name, academic degree: 
 
Function/Title: 
 
Institution: 
 
Address: 
 
 
 
 
Telephone number: 
 
Fax number: 
 
E-mail address: 
 
 
PPD
PPD
PPD
PPD
CCI
PPD
PPD
PPD

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Appendix 12 
Principal Investigator Signature Page  
 
Study Title: 
First-in-Human Study to Investigate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics and 
Clinical Activity of M1069 in Participants with 
Metastatic or Locally Advanced Unresectable Solid 
Tumors 
Regulatory Agency Identifying 
Numbers: 
IND 
 
Clinical Study Protocol Version: 11 November 2021 / Version 2.0 
Site Number: 
 
I am responsible for the conduct of the study at this site and understand and will conduct it per 
the clinical study protocol, any approved protocol amendments, International Council on 
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws. 
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain 
and supply details about ownership interests in the Sponsor or Investigational Medicinal Product 
and any other financial ties with the Sponsor. The Sponsor will use any such information solely 
for complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with 
any necessary information regarding ownership interest and financial ties including those of my 
spouse and dependent children, and to provide updates as necessary to meet Health Authority 
requirements. 
 
____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Name, 
academic 
degree: 
[Insert Name and highest degree or 
for a single center study, insert from 
Title Page] 
 
Function/Title: 
 
 
Institution: 
[Insert Name of Institution or for a 
single center study, insert from Title 
Page] 
 
Address: 
[Insert Full Mailing Address (e.g., 
Street, 
City, 
postal 
code, 
and 
Country] 
 
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Telephone number: 
[Insert 
Full 
number, 
including 
country code] 
 
Fax number: 
[Insert 
Full 
number, 
including 
country code or “Not Applicable”] 
 
E-mail address: