Clinical trial NCT03306420
Conditions: Metastatic or Locally Advanced Unresectable Solid Tumors
Keywords: MS201408-0005A MS201408-0005B MS201408-0005C First-in-Human Advanced solid tumors
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2017-10-03; Completion date: 2019-01-14
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase I, open-label study to determine the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD), and preliminary antitumor activity of MS201408-0005A as single agent (Part IA only) and in combination with MS201408-0005C or MS201408-0005B (Part IB, Part IC).

Detailed description:

Arms: arm 1: Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months). arm 2: Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months). arm 3: Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months). arm 4: Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months). arm 5: Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Interventions: intervention 1: M4112
Intervention descriptions: intervention 1: All participants who received M4112 100,200,400,600 and 800 mg twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).

Protocol documents:
Prot_001.pdf: 
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Clinical Study Protocol
Clinical Study Protocol Number
MS201408-0005
Title
Phase 
I, 
First-in-Human, 
Open-Label, 
Multiple-Ascending Dose Study to Investigate the 
Safety, 
Tolerability, 
Pharmacokinetics, 
Pharmacodynamics and Clinical Activity of M4112 
an IDO1/TDO2 Inhibitor as Single Agent 
 
 
 in Subjects with Metastatic or 
Locally Advanced Unresectable Solid Tumors
Phase
I
IND Number
EudraCT Number
To be determined
Coordinating Investigator
 
Phone: 
Fax: 
Email:
Sponsor
Countries outside US: Merck KGaA Darmstadt, 
Germany.
US and Canada: EMD Serono Research & 
Development Institute, Inc., Billerica, MA, US.
Medical Responsible: 
Merck KGaA
Frankfurter Strasse 250, 
64293 Darmstadt, Germany
Phone: 
Mobile: 
Email: 
Sponsor Legal Representative in the 
European Union 
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt, Germany
Clinical Study Protocol Version
08 September 2017 / Version 2.0
Replaces Version
28 July 2017 / Version 1.0
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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 © 2017 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved.
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Table of Contents
Table of Contents
..............................................................................................................3
Table of In-Text Tables .......................................................................................................8
Table of In-Text Figures......................................................................................................8
List of Abbreviations ...........................................................................................................9
1
Synopsis..............................................................................................13
2
Sponsor, Investigators and Study Administrative Structure...............44
2.1
Safety Monitoring Committee............................................................45
3
Background Information.....................................................................45
3.1
M4112.................................................................................................47
3.4
Rationale for the Current Clinical Study and Overall Benefit and 
Risk Considerations............................................................................54
3.4.1
Rationale for the Current Clinical Study ............................................54
3.4.2
Overall Risk-Benefit Assessment.......................................................56
4
Study Objectives.................................................................................61
4.1
Primary Objectives .............................................................................61
4.2
Secondary Objectives .........................................................................61
4.3
Exploratory Objectives .......................................................................61
5
Investigational Plan ............................................................................63
5.1
Overall Study Design and Plan...........................................................63
5.2
Discussion of Study Design................................................................69
5.2.1
Inclusion of Special Populations ........................................................69
5.2.2
Scientific Rationale for Study Design ................................................69
5.2.3
Justification for Dose..........................................................................70
5.2.4
Rationale for Endpoints......................................................................73
5.3
Selection of Study Population ............................................................73
5.3.1
Inclusion Criteria ................................................................................73
5.3.2
Exclusion Criteria...............................................................................75
5.4
Criteria for Initiation of Study Treatment...........................................77
5.5
Criteria for Subject Withdrawal..........................................................78
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5.5.1
Withdrawal from Study Treatment.....................................................78
5.5.2
Withdrawal from the Study ................................................................79
5.6
Premature Termination of the Study...................................................79
5.7
Definition of End of Study .................................................................80
6
Investigational Medicinal Product and Other Drugs Used in the 
Study...................................................................................................80
6.1
Description of Investigational Medicinal Products ............................80
6.2
Dosage and Administration ................................................................81
6.2.1
Dose Escalation Cohort (Part I)..........................................................81
6.2.3
Specific Rules for Treatment Modifications.......................................82
6.2.4
Dose Limiting Toxicities....................................................................84
6.3
Assignment to Treatment Groups.......................................................86
6.4
Noninvestigational Medicinal Products to be Used............................86
6.5
Concomitant Medications and Therapies ...........................................87
6.5.1
Permitted Medicines...........................................................................87
6.5.2
Prohibited Medicines..........................................................................88
6.5.3
Other Interventions.............................................................................89
6.5.4
Special Precautions.............................................................................89
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................90
6.6
Packaging and Labeling of the Investigational Medicinal Product..101
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product.............................................................................101
6.8
Investigational Medicinal Product Accountability...........................103
6.9
Assessment of Investigational Medicinal Product Compliance .......104
6.10
Blinding ............................................................................................104
6.11
Emergency Unblinding.....................................................................104
6.12
Treatment of Overdose .....................................................................104
6.13
Medical Care of Subjects after End of Study ...................................105
7
Study Procedures and Assessments..................................................105
7.1
Schedule of Assessments..................................................................105
7.1.1
Screening and Baseline Procedures and Assessments......................105
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7.1.2
Treatment Period ..............................................................................106
7.1.3
End of Treatment ..............................................................................107
7.2
Demographic and Other Baseline Characteristics ............................108
7.2.1
Demographic Data............................................................................108
7.2.2
Diagnosis of Tumor..........................................................................109
7.2.3
Medical History ................................................................................109
7.2.4
Vital Signs and Physical Examination..............................................109
7.2.5
Computed Tomography or Magnetic Resonance Imaging Scans 
for Tumor Assessment at Baseline ...................................................110
7.2.6
Cardiac Assessments ........................................................................110
7.2.7
Clinical Laboratory Tests .................................................................111
7.3
Efficacy Assessments .......................................................................111
7.4
Assessment of Safety........................................................................112
7.4.1
Adverse Events .................................................................................113
7.4.2
Pregnancy and In Utero Drug Exposure...........................................118
7.4.3
Clinical Laboratory Safety Assessments ..........................................119
7.4.4
Vital Signs, Physical Examinations, and Other Assessments...........121
7.5
Pharmacokinetics..............................................................................121
7.5.1
Body Fluid(s)....................................................................................122
7.5.2
Pharmacokinetic Calculations ..........................................................122
7.7
Other Assessments............................................................................126
7.7.1
Anti-Drug Antibody..........................................................................126
8
Statistics............................................................................................127
8.1
Sample Size ......................................................................................127
8.2
Randomization..................................................................................127
8.3
Endpoints..........................................................................................127
8.3.1
Primary Endpoints ............................................................................127
8.3.2
Secondary Endpoints ........................................................................128
8.3.3
Other Endpoints................................................................................129
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8.4
Analysis Sets.....................................................................................130
8.5
Description of Statistical Analysis....................................................131
8.5.1
General Considerations.....................................................................131
8.5.2
Analysis of Primary Endpoints.........................................................132
8.5.3
Analysis of Secondary Endpoints.....................................................133
8.5.4
Pharmacokinetic Calculations ..........................................................135
8.5.5
Concentration-QTc analysis .............................................................135
8.5.6
Analysis of Safety and Other Endpoints...........................................135
8.6
Interim and Additional Planned Analyses ........................................137
9
Ethical and Regulatory Aspects........................................................137
9.1
Responsibilities of the Investigator ..................................................137
9.2
Subject Information and Informed Consent .....................................137
9.3
Subject Identification and Privacy....................................................138
9.4
Emergency Medical Support and Subject Card................................139
9.5
Clinical Study Insurance and Compensation to Subjects .................139
9.6
Independent Ethics Committee or Institutional Review Board........139
9.7
Health Authorities.............................................................................140
10
Study Management ...........................................................................140
10.1
Case Report Form Handling.............................................................140
10.2
Source Data and Subject Files..........................................................140
10.3
Investigator Site File and Archiving.................................................141
10.4
Monitoring, Quality Assurance, and Inspection by Health 
Authorities ........................................................................................141
10.5
Changes to the Clinical Study Protocol............................................142
10.6
Clinical Study Report and Publication Policy ..................................142
10.6.1
Clinical Study Report .......................................................................142
10.6.2
Publication........................................................................................142
11
References Cited in the Text.............................................................143
12
Appendices .......................................................................................146
Appendix I:
Contraceptive Guidance and Woman of Childbearing 
Potential...........................................................................................147
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Appendix II:
Strong Inhibitors and Inducers of CYP3A4 or Substrates with 
a Narrow Therapeutic Range and Drugs Causing QTc 
Prolongation ....................................................................................149
Appendix III:
Response Evaluation Criteria in Solid Tumors (RECIST 1.1)...150
Appendix IV:
Immune-Related Response Criteria..............................................155
Appendix V:
Operating Characteristics of Bayesian Dose Escalation 2-
Parameter Logistic Regression Model with Selected Prior and 
Overdose Control Boundary at 35% ............................................156
Appendix VI:
Signature Pages and Responsible Persons for the Study ............159
Signature Page – Coordinating Investigator...............................................................161
Signature Page – Principal Investigator ......................................................................162
Sponsor Responsible Persons not Named on the Cover Page....................................163
Appendix VII:
Protocol Amendments and List of Changes.................................164
Amendment 1, 08 September 2017, Global
Amendment........................................165
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Table of In-Text Tables
Table 1
Schedule of Assessments – Part IA (Dose Escalation – M4112 as 
Single Agent)......................................................................................24
 
 
Table 4
Schedule of Assessments – Pharmacokinetic, Pharmacodynamic, 
and Electrocardiogram Schedule – Part IA (Dose Escalation –
M4112 as Single Agent) – Cycle 1 and Day 1 of Cycle 2..................38
 
 
 
Table 7
Anticipated Human Exposure of M4112 in the Prespecified Dose 
Escalation Range in Comparison with Parameters in the Dog...........67
Management of Immune-Related Adverse Events of 
 
, and M4112 as Single Agent 
....................94
Table 10
Clinical Laboratory Safety Assessments ..........................................120
Table 11
Pharmacokinetic Parameters for M4112 ..........................................123
Table 13
Analysis Sets.....................................................................................131
Table 14
Subject Characterization Based on ADA Results.............................134
Table of In-Text Figures
Figure 1
First-in-Human Study Design for Single Agent and Combination 
Dose Escalation of M4112..................................................................64
Figure 2
Assessment and Initial Management of Tumor Lysis Syndrome.......93
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List of Abbreviations
7+n×3
After treatment Cycle 7 subjects will be assessed at the start of every 
third cycle
ADA
Anti-drug antibody
ADR
Adverse drug reaction
AE(s)
Adverse event(s)
AESI(s)
Adverse event(s) of special interest
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the drug concentration-time curve
AUC0-8
Area under the drug concentration-time curve from 0 to 8 h 
postdosing
βHCG
β-human chorionic gonadotropin
BID
Twice daily
BOR
Best overall response
CD
Cluster of differentiation
CI
Confidence interval
Cmax
Maximum plasma concentration observed postdose
Cmin
Minimum observed postdose (trough) plasma concentration
CR
Complete response
CRO
Contract Research Organization
CT 
Computed tomography 
CTCAE 4.03
Common Terminology Criteria for Adverse Events Version 4.03
cQTc
Concentration-QTc
CYP
Cytochrome P450
DCR
Disease control rate
DLT
Dose-limiting toxicities
DOR
Duration of response
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic case report form
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Emax
Maximum effect
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
H1
Histamine H1
HBcAb
Hepatitis B core antibody
HBsAb
Antibody to hepatitis B surface antigen
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCVAb
Hepatitis C virus antibody
HED
Human equivalent dose
HIV
Human immunodeficiency virus
HNSTD
Highest non-severely toxic dose
iAP
Integrated analysis plan
IB
Investigator’s Brochure
IC50
Half maximal effective concentration
ICF
Informed Consent Form
ICH
International Council for Harmonization
IDO1
Indoleamine-2,3-dioxygenase 1
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL
Interleukin
IMP(s)
Investigational Medicinal Product(s)
INF
Interferon
irAE
Immune-related adverse event
IRB
Institutional Review Board
irPD
Immune-related progressive disease
irPR
Immune-related partial response
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
iv
Intravenous
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MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute 
NE
Not evaluable
NK
Natural killer
NOAEL
No-observed-adverse-effect-level
NSAID
Nonsteroidal anti-inflammatory drug
OBD
Optimal biological dose
PBMC
Peripheral blood mononuclear cell
PD
Pharmacodynamics
PFS
Progression-free survival
 
PK
Pharmacokinetic(s)
PPI
Proton pump inhibitor
PR
Partial response
Q 2 weeks
Once every 2 weeks
Q 4 weeks
Once every 4 weeks
Q 8 weeks
Once every 8 weeks
Q 12 weeks
Once every 12 weeks
QD
Once daily
QTc
Corrected QT interval
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RP2D
Recommended Phase II dose
SAE
Serious adverse event
SCC
Squamous cell carcinoma
SD
Standard deviation
SMC
Safety Monitoring Committee
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T4
Thyroxine
TDO2
Tryptophan-2,3-dioxygenase 2
TEAE
Treatment-emergent adverse event
TLS
Tumor lysis syndrome
tmax
Time to reach maximum concentration
TMTB
Total measured tumor burden
TNF
Tumor necrosis factor
TRAE
Treatment-related adverse event
Tregs
Regulatory T cells
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
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1
Synopsis
Clinical Study Protocol Number
MS201408-0005
Title
Phase 
I, 
First-in-Human, 
Open-Label, 
Multiple-Ascending Dose Study to Investigate 
the 
Safety, 
Tolerability, 
Pharmacokinetics, 
Pharmacodynamics and Clinical Activity of 
M4112 an IDO1/TDO2 Inhibitor as Single Agent 
 
 
 
 
 
 in Subjects 
with 
Metastatic 
or 
Locally 
Advanced 
Unresectable Solid Tumors
Phase
I
IND Number
FDA covered study
Yes
EudraCT Number
To be determined
Coordinating Investigator
 
Phone: 
Fax: 
Email:
Sponsor
Countries outside US: Merck KGaA Darmstadt, 
Germany.
US and Canada: EMD Serono Research & 
Development Institute, Inc., Billerica, MA, US.
Medical Responsible: 
Merck KGaA
Frankfurter Strasse 250, 
64293 Darmstadt, Germany
Phone: 
Mobile: 
Email: 
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Sponsor Legal Representative in the 
European Union
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt, Germany
Study centers/countries
Approximately 3 to 5 sites in the US for the dose 
escalation part (Part I).
Planned study period
(first subject in-last subject out)
October 2017 to April 2020
Trial Registry
ClinicalTrials.gov and other applicable registries
Objectives: 
Primary Objectives
Part IA (Dose Escalation – M4112 as Single Agent)
! To determine safety and tolerability or, if observed, the maximum tolerated dose (MTD), 
and to define the recommended Phase II dose (RP2D) of M4112 as single agent in subjects 
with solid tumors.
 
 
Secondary Objectives
Part IA (Dose Escalation – M4112 as Single Agent)
! To characterize the PK parameters of M4112 as single agent 
! To assess QT prolongation potential by central tendency, outlier analysis and the slope of 
exposure-QTc analysis 
! To evaluate preliminary clinical activity parameters using RECIST 1.1.
 
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Methodology: 
This study is a Phase I, open-label study designed to determine the safety, tolerability, PK, 
PD, and preliminary antitumor activity of M4112 as single agent (Part IA only) 
 
 The target population for Part I 
(Dose Escalation) comprises of subjects with advanced or metastatic solid malignancies for 
whom no effective standard therapy exists or has failed or subjects who are intolerant to 
established therapy known to provide clinical benefit for their condition. 
The study for an individual subject will include up to 21 + 7 days screening period, a 
treatment period consisting of 28-day cycles of M4112 either as single agent 
 
, End of Treatment Visit, and a 
Safety Follow-up period including a visit at 30 ± 3 days 
 
 after the last M4112 intake 
 
if applicable. M4112 will be administered orally twice daily (BID; or regimen 
determined by the Safety Monitoring Committee [SMC]). Subjects who tolerate M4112 
without significant clinically relevant toxicities may continue to receive their assigned dose 
as long as there is no evidence of confirmed disease progression. Subjects who discontinue 
treatment for any reason will complete the Safety Follow-up Visits. 
Screening Period:
Screening will be performed within 21 + 7 days prior to Day 1 of M4112 administration. If,
at Screening, the subject meets all the protocol-defined inclusion and none of the exclusion 
criteria, the subject will be considered as eligible and will be enrolled into the study. Subjects 
who fail to meet the protocol-specified criteria or who withdraw their consent will be 
considered screening failures. 
Treatment Period:
The treatment period will begin at the first dose of M4112 in Cycle 1 Day 1 and consist of 
consecutive 28-day cycles of continuous M4112 treatment (BID or other regimen determined 
by the SMC) either as monotherapy 
 
 Subjects will be instructed to take M4112 at 
least 1 h prior to a meal and at least 2 h after a meal.
Subjects who tolerate study treatment without clinically relevant toxicities may continue to 
receive their assigned dose as long as there is no evidence of confirmed disease progression.
Part IA to Part IC: Dose Escalation
A broad dose range in monotherapy will be investigated to determine the safety profile, 
tolerability, PK, and PD markers and to explore signs of antitumor activity in subjects with 
advanced solid tumors.
Subjects will receive M4112 at the starting dose of 100 mg BID (100 mg BID which equals 
to 200 mg total daily dose) at least 1 h prior to a meal and at least 2 h after a meal. Cohorts 
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will consist of 3 subjects each, if not decided differently by the SMC. The first subject of 
each dose level will be observed for at least 5 days before the second subject can be treated. 
Subsequent subjects may receive first dosing at no less than 48 h intervals between subjects
for the first 2 cohorts of mono 
. If the safety profile is acceptable and 
agreed by the SMC, the 48 h observation after Subject 2 may be removed). The safety and 
tolerability data and available PK and PD data (as minimum Day 1 and Day 15 PK and PD 
data from previous cohort and all available PK and PD data from the current cohort) will be 
reviewed by the SMC at the end of each cohort. In cases where enrollment of last subject in a 
dosing cohort is delayed, the SMC may decide (based on available data) upon enrollment and 
dose for the next dosing cohort before all subjects in a cohort have completed Cycle 1. The
SMC will be assisted in their dosing and regimen (administration schedule) decisions by PK, 
PD, and a Bayesian 2-parameter logistic regression model modeling dose-limiting toxicity 
(DLT) rate with overdose control. The model incorporates nonclinical toxicity data in the 
prior and DLTs observed until the SMC to provide a recommended dose for the next cohort. 
During the dose escalation part of the study, the SMC will advise, primarily based on safety 
(DLTs) and additional data relevant for the treatment, on dose escalation, dose de-escalation, 
dose level expansion or regimen change, or it may recommend suspension of enrollment, 
with the final decision being a Sponsor decision. The SMC may also recommend a cohort 
size different from 3 subjects as the Bayesian design allows dose recommendation based on 
less or more than 3 subjects.
Prespecified ascending doses of 100, 200, 400, 600, 800, and 900 mg BID (means 
respectively, 100 mg BID for 200 mg total daily dose, 200 mg BID for 400 mg total daily 
dose, 400 mg BID for 800 mg total daily dose, 600 mg BID for 1,200 mg total daily dose, 
800 mg BID for 1,600 mg total daily dose, 900 mg BID for 1,800 mg total daily dose) as 
single agent in 28-day cycles are foreseen. Dose escalation decisions will be driven primarily 
by DLT, safety, and tolerability. 
 
 
 
A BID dosing regimen will be followed, based on PK modelling, to achieve the target Cmin
over the dosing interval at a lower total daily dose and thereby reducing Cmax and AUC over 
the day to potentially improve safety and tolerability when compared to once daily (QD)
dosing. Based on PK data from subjects, the SMC will evaluate whether this regimen can be 
sustained or needs to be changed. 
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In principle, dose escalation of single agent M4112 (Part IA) will proceed according to the 
recommendation of the SMC to at least the upper end of the above given dose range, unless 
the MTD has been reached or there is excess of PK nonlinearity, or the SMC recommends to 
end dose escalation following review of safety, tolerability, PK and PD results. Depending on 
the observed toxicity profile and available PK and PD, a dose regimen different to or dose(s) 
higher/lower than the prespecified doses may be tested. 
 
!
 
 
 
!
 
 
 
 
 
 
 
 
 
 
 
The starting dose of M4112 
will be dependent on 
the observed safety, tolerability, and PK/PD profile during dose escalation in the single agent 
cohort (Part IA) and will lag at least 1 dose level behind the last completed safe dose level of 
M4112 as single agent, which was confirmed as safe by the SMC. 
 
 
 
 
 
 
 
 
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!
 
 
 
!
 
 
 
.
DLT Definition
DLTs will be used to determine dose escalation, dose de-escalation, and the MTD (if 
reached), using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events Version 4.03 (CTCAE 4.03). DLTs are defined in the clinical study protocol.
All subjects treated in dose escalation cohorts who miss > 5 planned total daily doses of 
M4112 
 in the first cycle (first 28 days) of the dose 
escalation part for other than safety reasons are not eligible for DLT assessment, will not be 
considered in the Bayesian model and will not formally be replaced. If no evaluable subject 
from a cohort is left, the SMC will still convene to decide upon the continuation of the study 
and the number of subjects for the next cohort.
Subjects with nausea and vomiting will maintain normal schedule without re-dosing. 
The MTD is defined by the SMC. An MTD is suggested from the Bayesian logistic 
regression model with target toxicity of 30%. 
Subjects who tolerate M4112
 without significant clinically 
relevant toxicities will continue to receive their assigned dose until discontinuation criteria 
are met, withdrawal of consent or the study ends, whatever occurs first.
Follow-up Period:
The Safety Follow-up Visit is scheduled 30 ± 3 days and 90 ± 6 days (for Part IB and Part IC; 
as a phone call) after the last dose of M4112,
 
 until resolution of AEs to Grade 1, before start of any new anticancer therapy, whatever 
comes first.
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Subjects who discontinue treatment must be followed on study until resolution of toxicity or 
until confirmed disease progression.
Planned number of subjects: 
Part I (A to C; Dose Escalation): Monotherapy escalation A: Approximately 24 subjects, 
.
Primary endpoints: 
Part IA (Dose Escalation – M4112 as Single Agent)
! Occurrence of DLTs in subjects receiving M4112 as single agent during the first 4 weeks 
(Day 1 to Day 28 of Cycle 1) of treatment
! Occurrence of treatment-emergent adverse events (TEAEs) and TRAEs according to 
NCI-CTCAE 4.03 (including deaths) in subjects receiving M4112 as single agent from 
start of treatment up to the last Safety Follow-up Visit
! Treatment-emergent changes from baseline in clinical laboratory measures, vital signs, 
Eastern Cooperative Oncology Group Performance Status (ECOG PS), and physical 
examination findings in subjects receiving M4112 as single agent up to the last Safety 
Follow-up Visit.
 
 
 
 
 
 
 
 
 
 
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Secondary endpoints:
Part IA (Dose Escalation – M4112 as Single Agent)
! Plasma PK parameters for M4112: AUC0-8, Cmax, tmax, AUC0-8/dose, Cmax/dose, (Days 1 and 
15), Racc(AUC0-8) and Racc(Cmax) (Day 15), Cmin, and Cmin/dose (Days 8 and 15 of Cycle 1 and 
Day 1 of Cycle 2)
! Slope of concentration-QTc (cQTc) regression based on time-matched electrocardiogram 
(ECG) readings (3 or more replicates) and PK samples during Cycle 1 at Day 1 and Day 
15, central tendency and outlier analyses for absolute QTcF, and delta QTc
! BOR, DOR, DCR, time to tumor response, and PFS using RECIST 1.1, up to confirmed 
tumor progression.
 
 
 
 
 
 
 
 
 
 
Concentration-QTc and safety ECG:
Time-matched ECG readings (3 or more replicates) will be collected at -45, -30, and -15 min 
predose and at 0.5, 1, 2, 3, 4, 6, and 8 h postdose, just prior to PK sample collections during 
Cycle 1 at Day 1 and Day 15 during Part IA (M4112 monotherapy). 
Safety ECG: Time-matched triplicate digital ECG will be collected (upload for central read) 
at Day 1 and Day 15 (time points) predose, and 2, 3, 4, and 8h postdose, just prior PK 
collections in Part IB and IC.
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Pharmacokinetics:
! Pharmacokinetic parameters for M4112 will be based on plasma concentrations collected 
predose and at 0.5, 1, 2, 3, 4, 6 and 8 h postdosing on Days 1 and 15 of Cycle 1. Predose 
concentrations on Day 8, Cycle 1 and predose and 2 h postdose on Day 1, Cycle 2 will be 
assessed.
!
 
 
 
 
 
 
 
Efficacy assessments:
In addition to a baseline assessment prior to start of treatment, during treatment, computed 
tomography (CT) scans will be done for tumor assessments within 7 days prior to Day 1 of 
Cycles 3, 5, and 7 and thereafter every 3 cycles until progressive disease. These assessment 
can also be done by magnetic resonance imaging (MRI; if MRI is used, CT of chest is 
mandatory), using the same method at all subsequent assessment time points. Follow-up 
assessments will be performed at time points indicated in the Schedule of Assessments.
The clinical endpoints to be assessed for efficacy evaluation include time to tumor response, 
objective response, BOR, DCR, DOR, and progression-free survival per Investigator 
according to RECIST 1.1.
Safety assessments: 
The safety profile of M4112 will be assessed through the recording, reporting and analysis of 
baseline medical conditions, adverse events (AEs), adverse events of special interest (AESIs), 
DLTs in Cycle 1 and any treatment-emergent immune-related AE observed in subsequent 
cycle (Cycle 2) that in the opinion of the SMC needs to be taken into account for safety and 
proposal of dose escalation, physical examination findings including vital signs, laboratory 
tests (chemistry, hematology, and coagulation), ECOG PS, and a 12-lead ECG in triplicate 
from the date of signature of first informed consent until the either until the 30 ± 3 days 
Safety Follow-up Visit, or until the 90 ± 6 days Safety Follow-up Visit (Part IB and Part IC 
only; as a phone call), or before the start of any anticancer therapy, whatever comes first.
 
 
 
 
 
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Diagnosis and key inclusion and exclusion criteria: 
Key inclusion criteria for Part IA, 
Male or female subjects ≥18 years of age with histologically or cytologically proven 
advanced or metastatic solid malignancies for whom no effective standard therapy exists or 
has failed or subjects who are intolerant to established therapy known to provide clinical 
benefit for their condition (dose escalation cohorts; Part I) An ECOG PS of 0 to 1 at 
Screening and adequate hematological, renal and hepatic function as defined by protocol 
specified criteria.
Key exclusion criteria for Part IA, 
Intolerance to immune checkpoint inhibitor therapy as defined by the occurrence of an 
adverse drug reaction requiring drug discontinuation (dose escalation cohorts), concurrent 
anticancer treatment or immunosuppressive agents.
Prior organ transplantation including allogeneic stem cell transplantation, brain metastases 
(except those meeting certain protocol specified criteria which are acceptable), significant 
acute or chronic infections, a history of cardiovascular/cerebrovascular disease or current 
significant cardiac conduction abnormalities and hypokalemia as specified in the protocol.
Warfarin or other Vitamin K antagonists treatment, strong inhibitors or inducers of 
cytochrome P450 (CYP)3A4, and drugs with a narrow therapeutic index, which are 
predominantly metabolized by CYP3A4 and drugs known to have a high risk to prolong QTc 
as per label.
Pregnancy or lactation. 
Severe hypersensitivity reactions to monoclonal antibodies, known hypersensitivity to the 
IMPs or to one or more of the excipients of M4112, 
, autoimmune 
diseases (inflammatory bowel diseases, interstitial lung disease, or pulmonary fibrosis), and 
live vaccines within 28 days prior to study entry.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule: 
Part I (A 
):
M4112: Subjects will be administered an oral dose of M4112 BID (or a regimen determined 
by the SMC) at least 1 h prior to a meal and at least 2 h after a meal in 28-day cycles. 
 
.
 
 
 
 
 
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Reference therapy: dose/mode of administration/dosing schedule: Not applicable
Planned study and treatment duration per subject: 
The study for an individual subject will include up to 21 + 7 days screening period, a 
treatment period consisting of 28-day cycles of M4112 either as single agent
 
 End of Treatment Visit, and a 
Safety Follow-up period including a visit at 30 ± 3 days and a visit at 90 ± 6 days (Part IB 
and Part IC only; as a phone call) after the last M4112 intake
 
 Subjects who tolerate M4112 without significant clinically relevant toxicities may 
continue to receive their assigned dose as long as there is no evidence of confirmed disease 
progression.
Statistical methods: 
Analyses will be prepared by cohort and dose level. There is no formal significance level for 
this study and all analyses are considered descriptive. Dose escalation will be aided by a 
Bayesian 2-parameter logistic regression model. The SMCs dedicated to dose escalation 
decisions will receive results of a Bayesian 2-parameter logistic model with overdose control 
updated with the observed DLT data. Recommendation will be based on a loss function.
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Table 1
Schedule of Assessments – Part IA (Dose Escalation – M4112 as Single Agent)
Duration (Days)
28
28
28
28
28
28
28
nx28
Assessment
Screeningb
Treatment Period
End of 
Treatment
Safety 
Follow-up
Treatment Cycle
(28-day cycles)
1 
(DLT 
observation 
period)
2
3
4
5
6
7
7+n×3 
Until Progression
Within 7 Days 
of Decision to 
Discontinuec,d
30 ± 
3 Days
Visit Daya
21 + 7
1
8
15 22
1
15
1
15
1
15
1
15
1
15
1
1
Written informed consent
X
Review of inclusion/exclusion 
criteria
X
Xe
Demographic data
X
Medical history including 
malignant disease and 
malignant disease drug 
therapy or radiotherapy or 
surgery
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q 4 weeks
X
X
Physical examinationf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q 4 weeks
X
X
Height/weight/vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q 4 weeks
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
Q 4 weeks
X
X
Chest X-ray
X
Triplicate digital 12-lead 
electrocardiogramh
X
X
X
X
X
X
X
Q 8 weeks 
X
X
Hematologyi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q 4 weeks
X
X
Coagulationj
X
X
X
X
X
X
X
Q 8 weeks
X
X
Serum chemistryk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q 4 weeks
X
X
Troponin–Tk
X
X
X
X
X
X
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Duration (Days)
28
28
28
28
28
28
28
nx28
Assessment
Screeningb
Treatment Period
End of 
Treatment
Safety 
Follow-up
Treatment Cycle
(28-day cycles)
1 
(DLT 
observation 
period)
2
3
4
5
6
7
7+n×3 
Until Progression
Within 7 Days 
of Decision to 
Discontinuec,d
30 ± 
3 Days
Visit Daya
21 + 7
1
8
15 22
1
15
1
15
1
15
1
15
1
15
1
1
Free T4, TSH
X
X
X
X
X
Q 8 weeks 
X
Hepatitis B and Cm
X
Serum, urine pregnancy test 
(if applicable)n
X
X
X
X
X
X
X
X
Q 4 weeks
X
Urinalysiso
X
X
X
X
X
Q 8 weeks
X
X
M4112 dispensation 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q 4 weeks
M4112 administration
Continuous administrationp
M4112 compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q 4 weeks
X
Adverse events assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q 4 weeks
X
X
PK blood sample for M4112 
as single agentr
X
X
X
X
4β-hydroxycholesterol and 
cholesterolt
X
X
X
CT (chest, abdomen, pelvis) 
or MRIu
X
X
X
X
Q 12 weeks
Tumor evaluation, stagingu,v
X
X
X
X
Q 12 weeks
Treatment cycles: 28 days; after treatment Cycle 7 (on Day 1 only) subjects will be assessed at the start of every third cycle (7+n×3). 
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aPTT = activated partial thromboplastin time; CD = cluster of differentiation; CT = computed tomography; ECG = electrocardiogram; DLT = dose-limiting toxicities; 
ECOG PS = Eastern Cooperative Oncology Group Performance Status; βHCG = β-human chorionic gonadotropin; HBcAb = hepatitis B core antibody; 
HBsAb = antibody to hepatitis B surface antigen; HBsAg = hepatitis B surface antigen; HCVAb = hepatitis C virus antibody; 
; 
Ig = immunoglobulin; IL = interleukin; INF = interferon; 
; MRI = magnetic resonance imaging; NK = natural killer; PBMC = peripheral blood 
mononuclear cell; PD = pharmacodynamic; 
 PK = pharmacokinetic; TNF = tumor necrosis factor; 
; TSH = 
thyroid-stimulating hormone; QTc = corrected QT interval.
a
Time window of assessment visits: Cycle 1 and 2: ± 1 day; every cycle thereafter: ± 3 days.
b
Screening tests must be performed within 21 + 7 days before the first administration of M4112, unless indicated otherwise.
c
All subjects should undergo an End of Treatment Visit after M4112 is discontinued for any reason. This visit should be performed within 7 days after the 
decision to discontinue study treatment but before any new antineoplastic therapy is started (if possible), whichever occurs earlier. 
d
All subjects who discontinue M4112 treatment must undergo the End of Treatment Visit (within 7 days) and Safety Follow-up Visit (within 30 ± 3 days) for full 
safety evaluation. 
e
Inclusion/exclusion criteria should be reviewed before Cycle 1 Day 1 before the subject’s enrollment, which needs to be confirmed by the Sponsor (see 
Section 5.3).
f
The physical examination at Screening will including, general appearance, skin, pulmonary, cardiovascular, gastrointestinal, external genitourinary only as 
medically relevant, lymphatic, neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, throat, and cognitive status. 
g
On Day 1 and Day 15 of every cycle, vital signs (blood pressure, pulse, respiratory rate, temperature) will be assessed predose (within 15 min of oral dosing
after the subject has rested in the semi-recumbent position for 3 to 5 min), and then every 15 min from dosing of M4112 for an additional 2 h. Observation 
can be extended per investigator’s discretion. Height and weight at Screening only.
h
For ECG time points of safety monitoring: Standard triplicate (within 2 min) digital 12-lead ECG will be obtained after the subject has been rested in semi-
recumbent position for at least 5 min at Screening, predose and 2, 3, 4 and 8 h postdose on Days 1 and 15 of Cycle 1, predose on Day 8 of Cycle 1, and on 
Day 1 Cycle 2 (and + 2 h postdose), Day 1 Cycle 4, Day 1 Cycle 6 and then every second cycle thereafter at predose and at least 60 min postdose on these 
visits. ECGs will be also performed during the End of Treatment and Safety Follow-up Visit (30 ± 3 days). Triplicate ECGs will be read locally. The calculated 
QTc average of the three 12-lead ECGs must be ≤450 ms for continued eligibility. Subjects, in which the calculated QTc average increases to > 500 ms or 
> 60 ms change over baseline during treatment with M4112, have to interrupt study treatment until further clinical evaluation of QT prolongation. 
During single agent dose escalation (Part IA), replicate digital 12-lead ECGs within 2 min after a minimum of 5 min rest in semi-recumbent position will also 
be collected on Days 1 and 15 of Cycle 1 for concentration-QTc analysis, for time points, see Table 4.
For Part 1A only, replicate ECGs (Holter) will also be collected on Days 1 and 15 of Cycle 1 for exposure-QTc analysis.
i
Hematology includes complete blood count with differential and platelet counts. Blood samples for hematology will be obtained prior to administration of study 
drug (see Table 10).
j
Coagulation with aPTT and prothrombin time. Blood samples will be collected prior to administration of study drug (see Table 10).
k
Blood samples for serum chemistry profile will be obtained prior to the administration of the study drug (see Table 10). Full serum chemistry will be performed 
at Screening and in Cycle 1 on Day 1 and Day 15; core chemistry in Cycle 1 on Day 8 and Day 22. In Cycle 2 to 6 thereafter, full chemistry will be performed 
on Day 1 and core chemistry on Day 15. From Cycle 7 onwards, full chemistry will be performed on Day 1 of every cycle and at the End of Treatment and 
Safety Follow-up Visits. Troponin-T will be measured at Day 1 and 15, predose every 2 weeks for the first 3 cycles.
l
 
 
m
Hepatitis B screening: HBsAg, HBsAb, HBcAb IgG and IgM; hepatitis C screening: HCVAb with reflex to HCV RNA.
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n
βHCG must be determined from serum at Screening and from serum or urine thereafter in women of childbearing potential. Appropriate menopausal status of 
women can be confirmed by testing for increased FSH levels at Screening. A negative pregnancy test must be available on Day 1 of each cycle, prior to 
M4112 administration. Results of the most recent pregnancy test (within last 28 days) must be available prior to next administration of the study drug. Women 
who have undergone hysterectomy or bilateral oophorectomy and postmenopausal women are exempt from pregnancy testing.
o
A full urinalysis is required at Screening, the End of Treatment Visit and at Safety-follow-up Visit and includes pH, ketones, specific gravity, bilirubin, protein, 
blood, and glucose and a basic urinalysis (protein content only) on Day 1 of Cycles 1, 3, 5, 7 and every second cycle thereafter prior to administration of 
M4112. If urinalysis (full or basic) is positive for protein, sediment will be evaluated.
p
On study site visit days, the morning dose of M4112 will be administered at the study site. M4112 will be administered at least 1 h prior to a meal and
at least 2 h after a meal. Meal times should be collected on the appropriate eCRF.
t
Used as endogenous metabolite and substrate to assess metabolism by cytochrome P450 3A4.
u
During treatment, CT or MRI scans will be done for tumor assessments within 7 days prior to Day 1 of Cycles 3, 5 and 7 and thereafter every 3 cycles until 
progressive disease or use of an alternative anticancer therapy. Of note: The method used for baseline assessment must be used for all subsequent 
assessments. A CT or MRI scan is mandatory to confirm a complete response, partial response and progressive disease at least 4 weeks later. 
v
Pretreatment tumor assessment should be performed within 21 + 7 days before the first dose of M4112. A chest X-ray should be performed before a CT or 
MRI scan to exclude prohibitive entry criteria. CT scans (with contrast media, unless contraindicated) of the chest, abdomen, and pelvis and any other 
disease sites (eg, neck) should be performed. Alternatively, tumor assessment at Screening can be done by MRI, using the same method at all subsequent 
assessment time points. Tumor assessment should be continued until confirmed disease progression or stop of study.
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.
 
 
. 
 
 
 
t
Post corresponds to end of infusion.
 
 
 
.
.
 
 
 
 
 
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l
 
 
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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 4
Schedule of Assessments – Pharmacokinetic, Pharmacodynamic, and Electrocardiogram Schedule –
Part IA (Dose Escalation – M4112 as Single Agent) – Cycle 1 and Day 1 of Cycle 2
Cycle/Day 
Time points 
(h postdose)
of M4112
PK sampling 
(blood)a,b
Triplicate digital 
ECGc
PK volume 
for M4112a
(mL)
Time 
window 
(± minb)
Cycle 1 Day:
1
Predose
X
Xe (within 45 min)
4
- 45
1
0.5
X
Xc
4
± 5
1
1
X
Xc
4
± 5
1
2
X
Xc,f
4
± 10
1
3
X
Xc,f
4
± 10
1
4
X
Xc,f
4
± 10
1
6
X
Xc
4
± 10
1
8
X
Xc,f
4
± 10
8
Predosed
X
Xf (within 30 min) 
4
- 30
15
Predosed
X
Xe (within 45 min)
4
- 45
15
0.5
X
Xc
4
± 5
15
1
X
Xc
4
± 5
15
2
X
Xc,f
4
± 10
15
3
X
Xc,f
4
± 10
15
4
X
Xc,f
4
± 10
15
6
X
Xc
4
± 10
15
8
X
Xc,f
4
± 10
Cycle 2 Day:
1
Predosed
X
Xf (within 30 min)
4
- 30
1
2
X
Xf
4
± 10
Total
76
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ECG = Electrocardiogram; eCRF = electronic case report form; 
; 
; PBMC = peripheral blood mononuclear 
cell; PD = pharmacodynamics; PK = pharmacokinetics; QTc = corrected QT interval; 
.
a 
Including optional metabolite analysis from samples. For all study medication administration, a physician must be present at the site or immediately 
available to respond to emergencies during all administrations. Critical care and resuscitation facilities should be available immediately.
b
Actual collection times should be collected in the eCRF along with the times of the last dose administration.
c
For subjects in single M4112 dose escalation:
QTc monitoring: In addition to the ECGs collected for safety monitoring, subjects will undergo replicate (at least 3) digital 12-lead ECGs after a minimum of 
5 min rest in the semi-recumbent position on Cycle 1 at Day 1 and Day 15 at -45, -30 and -15 min predose and at 0.5, 1, 2, 3, 4, 6 and 8 postdose. ECG 
recordings must be performed before PK sampling time points. Time points may change if Cmax is not as predicted. 
d 
Predose = approximately 12 (± 4) h post the last evening dose.
e 
Predose replicate readings will be collected -45, -30 and -15 min predose; a triplicate digital 12-lead ECG will also be collected predose (within 30 min) for 
local reading.
f
In addition, standard digital triplicate (within 2 min) 12-lead safety ECGs are to be collected predose and at 2, 3, 4 and 8 h postdose on Days 1 and 15 and 
predose on Day 8 during Cycle 1, and predose and + 2 h postdose on Day 1 Cycle 2. Safety ECGs will be read locally and all ECGs should be assessed 
on the day of collection to determined continued eligibility. The calculated QTc average of the triplicate 12-lead ECGs must be ≤450 ms for eligibility. 
Subjects, in which the calculated QTc average increases to > 500 ms or > 60 ms change over baseline during treatment with M4112, have to interrupt study 
treatment until further clinical evaluation.
ECGs should be repeated if QTc is outside the range until resolution. To assess the safety and tolerability of the IMP, an ECG can be repeated at the 
Investigator’s discretion at unscheduled visits. Start of resting time, ECG time, and PK sampling time will be recorded in the eCRF. Day 1 and Day 15 
triplicate digital ECGs will be also be uploaded for summary statistics, outlier and exposure-QTc analyses.
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2
Sponsor, Investigators and Study Administrative Structure
The Sponsor of this clinical study is EMD Serono Research & Development Institute, Inc., 
Billerica, MA, in the US and Canada and Merck KGaA, Darmstadt, Germany, in the rest of the 
world.
The study will be conducted at approximately 3 to 5 sites in the US for the dose escalation part 
(Part 1).
A contract research organization (CRO), 
 will undertake the 
operational aspects of this study. Details of such structures and associated procedures will be 
defined in a separate Integrated Project Management Plan maintained by 
. The 
Integrated Project Management Plan will be prepared by the 
 Clinical Project 
Manager in cooperation with other 
 operational team leads.
The Sponsor will coordinate the study and will utilize the support of the CRO for the 
management of most activities of the study. Sponsor will perform oversight of the activities 
performed by the CRO.
The study will appear in the following clinical study registry: ClinicalTrials.gov and other 
applicable registries.
The Coordinating Investigator represents all Investigators for decisions and discussions 
regarding this study, consistent with the International Council for Harmonization (ICH) Topic E6 
Good Clinical Practice (GCP). The Coordinating Investigator will provide expert medical input 
and advice relating to study design and execution and is responsible for the review and signoff of 
the clinical study report.
Signature pages for the Protocol Lead and the Coordinating Investigator as well as a list of 
Sponsor responsible persons are provided in Appendix VI.
The Clinical Study Supplies department of the Sponsor will supply the study medication of 
 M4112, and 
to the sites. 
Safety laboratory assessments will be performed locally. Results from these local laboratories 
will be recorded according to the electronic case report form (eCRF) completion guidelines.
Pharmacokinetic (PK), 
 (central laboratory), and 
 
assessments will be performed under the responsibility and/or supervision of the Sponsor. 
The Drug Safety department, Merck KGaA, Darmstadt, Germany, or their designated 
representatives will supervise drug safety and the timely reporting of adverse events (AEs) and 
serious adverse events (SAEs).
Monitoring and data management will be performed by 
, and the Sponsor will be 
responsible for regulatory submission. 
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Quality assurance of the study conduct will be performed by the Development Quality Assurance 
Department, Merck KGaA, Darmstadt, Germany.
 will write the study statistical analysis plan, perform the statistical analyses, and 
will provide the outputs from the statistical analyses. The Sponsor’s department of Global 
Biostatistics will supervise the statistical analyses.
2.1
Safety Monitoring Committee
A Safety Monitoring Committee (SMC) will review the safety data on a regular basis. The SMC 
consists of members of the Sponsor (Drug Safety Product Leader, Medical Responsible, Clinical 
Pharmacologist and Biostatistician), the CRO (Medical Responsible) and the Coordinating 
Investigator. Ad hoc members may be invited as needed. During the dose-escalation part of the 
study, the SMC will evaluate the safety, tolerability, pharmacokinetics (PK) and available 
 
 
Based primarily 
on dose-limiting toxicities (DLTs), the SMC will advise on dose escalation, dose de-escalation, 
dose expansion, change in administration schedule/regimen (change for example from twice 
daily [BID] to once daily [QD]), or recommend suspension of enrollment, with the final 
adjudication being a Sponsor decision. The SMC will recommend the starting dose for M4112  
based on the observed safety, tolerability, available PK and PD markers 
of M4112 as single agent 
 The SMC will 
decide, by consensus, on continuation of the study, or recommend modification or suspension of 
the study, with the final adjudication being a Sponsor decision. During the course of the study, 
the SMC may modify the frequency of its meetings as deemed appropriate. In cases where 
enrollment of the last subject in a dosing cohort was delayed, the SMC may decide (based on 
available data) upon enrollment and dose for the next dosing cohort before all subjects in a 
cohort have completed Cycle 1. Subjects will be assigned sequentially to cohorts of either 
M4112 as a single agent, 
 
The specific working procedures will be described in an SMC charter, which will 
be established prior to the start of recruitment.
3
Background Information
Immunotherapy has shown encouraging response rates in different solid tumors, however, the 
majority of subjects will not receive significant benefit from these agents, suggesting the 
existence of additional immunoregulatory pathways. 
 
 
 
 
 
 
 
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3.1
M4112
M4112 Pharmacology in Animal Models
M4112 (also known as MSC2579448) is an orally available small molecule inhibitor of the 
immunoregulatory metabolic enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 
2,3-dioxygenase (TDO2) (41). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.
 
 
 
 
 
 
 
 
 
!
 
 
 
 
 
 
 
 
 
 
 
!
 
 
 
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3.4
Rationale for the Current Clinical Study and Overall Benefit 
and Risk Considerations
Refer to the IB for further information about the nonclinical and clinical programs and guidance 
for the Investigator.
This clinical study will be conducted in compliance with the clinical study protocol, ICH GCP,
and any additional applicable regulatory requirements.
Based on the available nonclinical and clinical data to date, the conduct of the study specified in 
this protocol is considered justifiable.
3.4.1
Rationale for the Current Clinical Study
The purpose of this study is to evaluate the safety, tolerability, PK, PD, and preliminary efficacy 
of M4112 as single agent,
 2 immune 
checkpoint inhibitors with distinct modes of action, in subjects with proven advanced or 
metastatic solid malignancies for whom no effective standard therapy exists or has failed or 
subjects who are intolerant to established therapy known to provide clinical benefit for their 
condition. The dose escalation part of the study will establish the RP2D of M4112 as single 
agent 
. 
The administration of M4112 to subjects with advanced solid tumors for whom no 
approved/established effective treatment option exists is justified by the following:
! M4112 is a dual IDO1/TDO2 inhibitor able to inhibit immune suppression in vitro when 
administered as a monotherapy and with enhanced efficacy 
 with immune 
check point inhibitors in animal models
 
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Together, these findings suggest that M4112, 
 
, may have the potential to be an effective anticancer therapy and thus support its 
clinical development.
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3.4.2
Overall Risk-Benefit Assessment
The administration of M4112 to subjects with advanced solid tumors for whom no 
approved/established effective treatment option exists is justified by the following:
! M4112 is a dual IDO1/TDO2 inhibitor able to inhibit immune suppression in vitro when 
administered as a monotherapy and with enhanced efficacy in preclinical models 
 
! Clinical experience with IDO1 inhibitor agents described in the literature demonstrate an 
acceptable safety profile as single agent
 
 and encouraging clinical antitumor activity in solid tumors in Phase I studies.
!
 
 
 
 
 
 
 
 
 
IDO1/TDO2 are key regulators of adaptive and innate immunity. 
 
 
 
 
 
 
 
 
This clinical study will be conducted in compliance with the regulations of ICH GCP, and any 
additional applicable regulatory requirements.
The safety monitoring and reporting as well as risk management and mitigation measures 
inherent to early phase clinical studies in oncology patients are considered adequate for this
study.
3.4.2.1
Risk-Benefit Ratio of M4112
The risk-benefit ratio of M4112 has been determined based on the following:
!
 
 
 
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!
 
 
 
 
 
 
 
.
!
 
 
 
 
!
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following potential risks of M4112 are
1. Gastrointestinal intolerance including ulceration, bleeding with anemia and inflammation of 
gastric mucosa.
2. Liver toxicity either due to liver hypertrophy or direct liver lesions.
3. QT/QTc prolongation.
4. Inhibition/autoinduction of CYP3A4.
5. irAEs/autoimmune disorders.
Gastro-intolerance including ulceration and inflammation of gastric mucosa is a potential risk for 
M4112. The symptoms of gastrointestinal intolerance (nausea, vomiting, and diarrhea etc.) will 
be closely monitored, reported, and investigated. Discontinuation/interruption of treatment will 
be recommended for higher grade (Grade ≥3) events. 
Liver toxicity is the clinically significant potential risk and relates to findings in animal toxicity 
studies. Subjects must be screened for potential impaired liver function or liver disease prior to 
treatment with a detailed medical history and clinical examination. All subjects enrolled in the 
clinical study should be counseled for early recognition and reporting of drug-related liver 
disease, and should be closely monitored in case of increased liver function tests and bilirubin 
(see Section 6.2.3). 
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QT/QTc prolongation is another important potential risk for M4112. A detailed medical history 
and medical examination to rule out a pre-existing heart disease and history of QT/QTc 
prolongation must be conducted (see Section 5.3.2). Subject inclusion and exclusion criteria and 
withdrawal criteria will exclude subjects deemed to be at risk for increase of QT. Time-matched 
triplicate digital ECG will be collected at Screening and at multiple time points (predose and 
postdose [Cmax]) in Cycle 1 and subsequent follow-up ECGs through all cycles. In M4112 
monotherapy cohorts only (Part IA only), replicate ECGs (Holter) will also be collected on 
Days 1 and 15 of Cycle 1 for exposure-QTc analysis. Treatment modification guidance is 
described in Section 6.2.3.
M4112 is a sensitive substrate to CYP3A4 and it cannot be excluded that it inhibits or induces 
CYP3A4 to a clinically relevant extent. Strong inhibitors or inducers of CYP3A4 and drugs with 
a narrow therapeutic index, which are predominantly metabolized by CYP3A4, should be 
discontinued 7 days prior to treatment and avoided during treatment. 
Subjects treated with M4112 should also be monitored for potential irAEs, which may first 
manifest after weeks of treatment. Such events may consist of persistent rash, diarrhea and 
colitis, autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy or uveitis and other 
inflammatory eye conditions. Risk management guidance is provided in Section 6.5.5.3. 
No embryo-fetal toxicity study have been performed to date, therefore effects on pregnancy 
cannot be excluded, pregnancy and lactation are excluded from the study. Highly effective 
contraception must be used for men and women of childbearing potential (Section 5.3.1 and 
Section 5.3.2). 
Liver toxicity and irAEs will be considered AESIs for M4112 requiring expedited reporting 
from the Investigator to the Sponsor within 24 h of learning of its occurrence.
 
 
 
 
 
 
 
 
 
 
 
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Instructions for treatment interruption/discontinuation or modification of infusion-related 
reactions/hypersensitivity will be provided to investigators as well as guidance for medical 
management (Table 8). 
. Inclusion criteria for the 
study will require adequate entry hemoglobin value. Respective hematological parameters will 
be monitored every week during the 1st cycle of dose escalation phase. Treatment modification, 
interruption, and discontinuation rules, depending on severity, will be provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4
Study Objectives
4.1
Primary Objectives
Part IA (Dose Escalation – M4112 as Single Agent)
! To determine safety and tolerability or, if observed, the MTD, and to define the RP2D of 
M4112 as single agent in subjects with solid tumors.
 
 
4.2
Secondary Objectives
Part IA (Dose Escalation – M4112 as Single Agent)
! To characterize the PK parameters of M4112 as single agent
! To assess QT prolongation potential by central tendency, outlier analysis and the slope of
exposure-QTc analysis to evaluate preliminary clinical activity parameters using RECIST 1.1.
! To evaluate preliminary clinical activity parameters using RECIST 1.1.
 
 
4.3
Exploratory Objectives
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5
Investigational Plan
5.1
Overall Study Design and Plan
This study is a Phase I, open-label study designed to determine the safety, tolerability, PK, PD, 
and preliminary antitumor activity of M4112 as single agent (Part IA only) 
 
 (see Figure 1). The target population for Part I (Dose 
Escalation) comprises of subjects with advanced or metastatic solid malignancies for whom no 
effective standard therapy exists or has failed or subjects who are intolerant to established 
therapy known to provide clinical benefit for their condition. 
The study for an individual subject will include up to 21 + 7 days screening period, a treatment 
period consisting of 28-day cycles of M4112 either as single agent 
 
 End of Treatment Visit (within 7 days), and a Safety 
Follow-up period including a visit at 30 ± 3 days and a visit at 90 ± 6 days (as a phone call) after 
the last M4112 intake 
 M4112 will be 
administered orally daily BID (or regimen determined by SMC) (see Section 6.2). Subjects who 
tolerate M4112 without significant clinically relevant toxicities may continue to receive their 
assigned dose as long as there is no evidence of confirmed disease progression (see 
Section 5.5.1). Subjects who discontinue treatment for any reason will complete the End of 
Treatment and Safety Follow-up Visits. 
The study design schematic is presented in Figure 1.
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Figure 1
First-in-Human Study Design for Single Agent 
Dose 
Escalation of M4112
DL = Dose level; DLT = dose-limiting toxicity; OBD = optimal biological dose; MTD = maximum tolerated dose; 
RP2D= recommended Phase II dose; SMC = Safety Monitoring Committee; SoC = standard of care.
In addition, any treatment-emergent immune related adverse event observed in subsequent cycle (Cycle 2) that in the 
opinion of the SMC needs to be taken into account for the overall evaluation of the safety and proposal of dose 
escalation will be considered.
Screening Period:
Screening will be performed within 21 + 7 days prior to Day 1 of M4112 administration. If, at 
Screening, the subject meets all the protocol-defined inclusion and none of the exclusion criteria, 
the subject will be considered as eligible and will be enrolled into the study. Subjects who fail to 
meet the protocol-specified criteria or who withdraw their consent will be considered screening 
failures. 
Treatment Period:
The treatment period will begin at the first dose of M4112 in Cycle 1 Day 1 and consist of 
consecutive 28-day cycles of continuous M4112 (BID or other regimen determined by the SMC), 
either as monotherapy 
 
 Subjects will be instructed to take M4112 at least 1 h prior to a meal and 
at least 2 h after a meal. Meal times should be collected on the appropriate eCRF.
Eligible subjects will initiate therapy at the dose level appropriate at the time of enrollment. The 
Sponsor’s Medical Responsible, or designee, must confirm enrollment and dose level (during 
dose escalation only) after receipt of the appropriate information relating to study entry.
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Subjects who tolerate study treatment without significant clinically relevant toxicities may 
continue to receive their assigned dose as long as there is no evidence of confirmed disease 
progression.
Part IA to Part IC: Dose Escalation
A broad dose range in monotherapy is planned to be investigated to determine the safety profile, 
tolerability, PK, and PD markers and to explore signs of antitumor activity in subjects with 
advanced solid tumors.
Subjects will receive M4112 at the starting dose of 100 mg BID (100 mg BID which equals to 
200 mg total daily dose) at least 1 h prior to a meal and at least 2 h after a meal. Cohorts will 
consist of 3 subjects each, if not decided differently by the SMC. Cohorts will consist of 
3 subjects each, if not decided differently by the SMC. The first subject of each dose level will 
be observed for at least 5 days before the second subject can be treated. Subsequent subjects may 
receive first dosing at no less than 48 h intervals between subjects for the first 2 cohorts of mono 
 If the safety profile is acceptable and agreed by the SMC, the 48 h 
observation after Subject 2 may be removed. The safety and tolerability data and available PK 
and PD data (as minimum Day 1 and Day 15 PK and PD data from previous cohort and all 
available PK and PD data from the current cohort) will be reviewed by the SMC at the end of 
each cohort. In cases where enrollment of last subject in a dosing cohort was delayed, the SMC 
may decide (based on available data) upon enrollment and dose for the next dosing cohort before 
all subjects in a cohort have completed Cycle 1. The SMC will be assisted in their dosing and 
regimen (administration schedule) decisions by PK, PD, and a Bayesian 2-parameter logistic 
regression model modeling DLT rate with overdose control. The model incorporates nonclinical 
toxicity data in the prior and DLTs observed until the SMC meeting to provide a recommended 
dose for the next cohort. The SMC can choose a dose different from the one recommended by 
the model. During the dose escalation part of the study, the SMC will advise, primarily based on 
safety (DLTs) during the first cycle, and any TEAE observed in subsequent cycle that in the 
opinion of the SMC needs to be taken into account (additional DLT criteria, see Section 6.2.4), 
for the overall evaluation of the safety and proposal of dose escalation dose, dose de-escalation, 
dose level expansion or regimen change, or it may recommend suspension of enrollment, with
the final adjudication being a Sponsor decision. A Bayesian 2-parameter logistic regression 
model will incorporate observed DLTs from all previously completed cohorts to provide a 
recommended dose for the next cohort. The SMC may also recommend a cohort size different 
from 3 subjects as the Bayesian design allows dose recommendation based on less or more than 
3 subjects.
Based on the absence of clinical signs or other adverse findings, the 30 mg/kg/day in the dog was 
considered the NOAEL in this study. The subsequent dose, 100 mg/kg/day, was considered not 
tolerated due to the adverse findings in an early sacrificed (Day 15) male dog administered 
100 mg/kg/day. No HNSTD was defined in dogs in the 4-week toxicity study. The dose of 
30 mg/kg/day was defined as the NOAEL and the starting dose in Phase I takes into 
consideration the HNSTD according to the guideline ICH S9 as well as margins relative to the 
NOAEL in the dog the most sensitive animal species (described further in Section 5.2.3) and 
translates to a human equivalent dose (HED) of approximately 16.7 mg/kg/day; the starting dose 
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is approximately 1/6 of the HED at 2.8 mg/kg/day or approximately 100 mg for a 70 kg human 
administered BID.
Prespecified ascending doses of 100, 200, 400, 600, 800, and 900 mg BID (means respectively, 
100 mg BID for 200 mg total daily dose, 200 BID for 400 mg total daily dose, 400 mg BID for 
800 mg total daily dose, 600 mg BID for 1,200 mg total daily dose, 800 BID for 1,600 mg total 
daily dose, 900 mg BID for 1,800 mg total daily dose) as single agent in 28-day cycles are 
foreseen. Dose escalation decisions will be driven primarily by DLT, safety, and tolerability. The 
MTD may not be reached in the anticipated PD active dose range of M4112, therefore, the 
assessment of PD effects may be used to explore the optimal biological dose (OBD) and to 
inform on the RP2D. 
A BID dosing regimen will be followed based on PK modelling to achieve the target Cmin over 
the dosing interval at a lower total daily dose and thereby reducing Cmax and AUC over the day 
to potentially improve safety and tolerability when compared to QD dosing. Based on PK data 
from subjects, the SMC will evaluate whether this regimen should be continued or a different 
regimen explored.
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In principle, dose escalation of single agent M4112 will proceed according to the 
recommendation of the SMC to the upper end of the above given dose range, unless the MTD 
has been reached or there is excess of PK nonlinearity, or the SMC recommends to end dose 
escalation following review of safety, tolerability, PK and PD results. Depending on the 
observed toxicity profile and available measured PK and PD, or dose regimen different or higher 
than the prespecified doses may be tested. 
 
!
 
 
 
!
 
 
This dose level will then be studied in ≤6 evaluable subjects to establish safety, tolerability, PK 
and PD and will be defined as RP2D of M4112 as single agent. 
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Consecutively, the following groups of dose escalations
 
 are foreseen, starting while monotherapy dose 
escalation is still ongoing: 
! M4112 administered orally BID 
 
in subjects with advanced and 
metastatic solid tumors 
! M4112 administered orally BID 
 
in subjects with advanced and metastatic solid 
tumors.
The starting dose of M4112 
 will be dependent on the 
observed safety, tolerability, and PK/PD profile during dose escalation in the single agent cohort 
(Part IA) and will lag at least 1 dose level behind the last completed safe dose level of M4112 as 
single agent, which was confirmed as safe by the SMC. For selection of the starting dose, 
predictions based on an updated PK/PD, 
 
 
 
.
Dose escalation will proceed until the OBD of M4112 
 
 dose escalation ends due 
to occurrence of DLTs establishing an MTD, or the SMC recommends to end dose escalation 
following review of safety, tolerability, PK and PD results, whatever occurs first. The maximum 
dose of M4112 
 in 
monotherapy determined in Part I of the study. 
 
!
 
 
 
 
 
 
 
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DLT Definition
DLTs will be used to determine dose escalation, dose de-escalation, and the MTD (if reached), 
using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
Version 4.03 (CTCAE 4.03). DLTs are defined in Section 6.2.4.
All subjects treated in dose escalation cohorts who miss > 5 planned total daily doses of M4112 
 in the first cycle (first 28 days) of the dose escalation part 
for other than safety reasons are not eligible for DLT assessment, will not be considered in the 
Bayesian model and will not formally be replaced. If no evaluable subject from a cohort is left, 
the SMC will still convene to decide upon the continuation of the study and the number of 
subjects for the next cohort.
Subjects with nausea and vomiting will maintain normal schedule without re-dosing. 
The MTD is defined by the SMC. An MTD is suggested from the Bayesian logistic regression 
model with DLT target rate of 30%. 
Subjects who tolerate M4112 
 without significant clinically 
relevant toxicities will continue to receive their assigned dose until discontinuation criteria are 
met, withdrawal of consent or the study ends, whatever occurs first (see Section 5.5.1 for 
exceptions). 
Follow-up Period
The Safety Follow-up Visit is scheduled 30 ± 3 days and 90 ± 6 days (as a phone call) after the 
last dose of M4112, 
 or until 
resolution to Grade 1, before start of any new anticancer therapy, whatever comes first (see 
Section 5.5.1).
Subjects who discontinue treatment must be followed on study until resolution of toxicity or until 
confirmed disease progression.
5.2
Discussion of Study Design
5.2.1
Inclusion of Special Populations
Not applicable
5.2.2
Scientific Rationale for Study Design
 
 
 
 
 
 
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5.2.3
Justification for Dose
5.2.3.1
Single Agent M4112 (Part IA)
The starting dose for the First-in-Human study of M4112 was determined based on the ICH 
Guideline S9 “Nonclinical Evaluation for Anticancer Pharmaceuticals” (2009):
! Considering the severely toxic dose and HNSTD according to guideline ICH S9
! Considering PK/PD modeling of the predicted pharmacological active dose range in humans. 
Two pivotal 4-week toxicity studies in rats and dogs have adequately defined the safety and risk 
profile of M4112 to support multiple dosing in humans. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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!
 
 
!
 
!
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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!
 
 
 
!
 
!
 
!
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.2.4
Rationale for Endpoints
The study objectives and endpoints are standard Phase I objectives and endpoints, namely to 
define the safety, tolerability, PK, and PD of M4112 as single agent 
 
 in humans, and to explore its preliminary antitumor activity in subjects with 
advanced disease.
The subject population and the key endpoints are well selected to address the primary objectives 
and key secondary objectives of this study.
5.3
Selection of Study Population
Only individuals who fulfill all inclusion criteria without matching any exclusion criteria may be 
enrolled into the study as subjects. Prior to performing any study assessments not part of the 
subject’s routine medical care, the investigator will ensure that the subject or the subject’s legal 
representative has provided written informed consent following the procedure described in 
Section 9.2.
5.3.1
Inclusion Criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
1. Signed written informed consent form (ICF) before any study-related procedure is 
undertaken that is not part of the standard subject management.
2. Male or female subjects ≥18 years of age. 
3. Subject population
In the dose escalation cohorts (Part IA
): Histologically or cytologically proven 
advanced or metastatic solid malignancies for whom no effective standard therapy exists or 
has failed or subjects who are intolerant to established therapy known to provide clinical 
benefit for their condition
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening.
5. Subjects who have been treated previously with a checkpoint inhibitor may enroll.
6. Adequate hematological function as defined below: 
a. Absolute neutrophil count ≥1,500/mm3 or ≥1.5 × 109/L
b. Platelet count ≥100,000/mm3 or ≥100 × 109/L
c. Hemoglobin ≥9 g/dL.
7. Adequate hepatic function defined: by a total bilirubin level ≤1.5 × upper limit of 
normal (ULN), an AST level ≤2.5 × ULN, and an ALT level ≤2.5 × ULN
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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 < 3.0 × ULN, with normal bilirubin ≤1.5 × ULN and INR < 1.5. 
8. Adequate renal function defined by an estimated glomerular filtration rate > 50 mL/min 
according to the Cockcroft-Gault formula or normal creatinine laboratory values
(Glomerular filtration rate [mL/min/1.73 m2] = 175 × serum creatinine (Scr)-1.154 × age -
0.203 × 1.212 [if African American] × 0.742 [if female])
9. Male participants must agree to use and to have their female partners use a highly effective 
contraception (i.e., methods with a failure rate of less than 1 % per year) as detailed in 
Appendix I of this protocol 30 days before first dose of study treatment (as appropriate), 
during the treatment period and for at least 60 days after the last dose of study treatment of 
M4112 as single agent 
 
d must refrain from donating sperm during this period.
10. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix I), not 
breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix I
OR
b. A WOCBP who agrees to use a highly effective contraception (i.e., methods with a
failure rate of less than 1 % per year) as detailed in Appendix I of this protocol 
30 days before start of first dose of study treatment (as appropriate), during the 
treatment period and for at least 60 days after the last dose of study treatment of 
M4112 as single agent 
 
Since the effect of potential of M4112 to induce/inhibit CYP3A4 is unknown at this time, 
WOCBP that are currently using hormonal contraception that is a substrate for CYP3A4 
should also use double barrier contraception.
11. Women of childbearing potential must have a negative plasma pregnancy test at the 
Screening Visit and a negative urine pregnancy test on Day 1 before enrollment and dosing. 
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5.3.2
Exclusion Criteria
Subjects are not eligible for this study if they fulfill any of the following exclusion criteria:
1. Prior therapy with: 
 
 Intolerance to immune checkpoint inhibitor therapy as defined by the occurrence 
of an adverse drug reaction (ADR) requiring drug discontinuation.
2. Persisting toxicity related to prior therapy Grade > 1 NCI-CTCAE 4.03, however sensory 
neuropathy Grade ≤2 is acceptable and alopecia is acceptable.
3. Prior organ transplantation including allogeneic stem cell transplantation.
4. All subjects 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 (sequelae that are a consequence of the treatment of the brain metastases 
are acceptable).
c.
Subjects must be either off steroids or on a stable or decreasing dose of < 10 mg 
daily prednisone (or equivalent).
5. Concurrent treatment with a nonpermitted drug/intervention:
a.
Strong inhibitors or inducers of CYP3A4, and drugs with a narrow therapeutic 
index, which are predominantly metabolized by CYP3A4 should be discontinued 
7 days prior to treatment and avoided during treatment (see Appendix II for a list. 
The link to the website to be consulted, in case of doubt, is provided in 
Section 6.5).
b. Drugs known to have a high risk of prolonging QTc as per label (see Appendix II
for a list and Section 6.5.1 for exceptions to nonpermitted drugs).
c.
Drugs that are known to increase gastric pH should be stopped at least 1 week 
before the start of study treatment
d. Anticancer treatment (eg, cytoreductive therapy, radiotherapy, immune therapy, 
cytokine therapy, monoclonal antibody, targeted small molecule therapy) or any 
investigational drug within 4 weeks prior to start of study treatment, or not 
recovered from AE related to such therapies, with the following exceptions: 
i. Palliative bone-directed radiotherapy is permitted (concurrently or within 
pretreatment period).
ii. Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis are 
permitted (ie, luteinizing hormone-releasing hormone agonist/antagonists). 
No other hormonal anticancer therapy is permitted.
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e.
Major surgery (as deemed by the Investigator) for any reason, except diagnostic 
biopsy, within 4 weeks of the study treatment and/or if the subject has not fully 
recovered from the surgery within 4 weeks of the study treatment.
f.
Subjects 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. Subjects 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 
management 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.
g. Warfarin or other Vitamin K antagonists.
6. Current significant cardiac conduction abnormalities, including corrected QT interval (QTc) 
prolongation of > 450 ms or impaired cardiovascular function, ventricular tachycardia, 
hypokalemia or a history of paroxysmal atrial fibrillation, serious cardiac arrhythmia and 
family history of sudden death or long QT syndrome.
7. A history of cardiovascular/cerebrovascular disease as follows: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to 
enrollment), unstable angina or congestive heart failure (New York Heart Association 
Classification Class ≥II).
8. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent:
a.
Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not 
requiring immunosuppressive treatment are eligible.
b. Autoimmune diseases: eg, inflammatory bowel diseases, interstitial lung disease 
or pulmonary fibrosis 
9. Pneumonitis and history of pneumonitis.
10. A history of difficulty of swallowing, gastric or small bowel surgery with history of 
malabsorption or other chronic gastro-intestinal disease or conditions that may hamper 
compliance and/or absorption of the M4112. 
11. Any psychiatric condition that would prohibit the understanding or rendering of Informed 
Consent, or interfere with compliance to study requirements and procedures in the opinion of 
Investigator and/or Sponsor. 
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12. Known current alcohol and drug abuse as determined by the Investigator. 
13. Hepatocellular carcinoma
14. Legal incapacity or limited legal capacity if no consent by legal representative.
15. Significant acute or chronic infections requiring systemic therapy including, among others:
a.
History of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome.
b. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as, HBV 
surface antigen positive and HBV core antibody positive with reflex to positive 
HBV DNA or HBV core antibody positive alone with reflex to positive HBV 
DNA or positive HCV antibody with reflex to positive HCV RNA). Subjects with 
a history of infection must have polymerase chain reaction documentation that 
infection has cleared.
c.
Active tuberculosis (history of exposure or history of positive TB test with 
presence of clinical symptoms, physical, or radiographic findings). 
16. Known hypersensitivity to the IMPs or to one or more of the excipients of M4112, 
 
17. Known 
severe 
hypersensitivity 
reactions 
to 
monoclonal 
antibodies 
(Grade ≥3 
NCI-CTCAE 4.03), or uncontrolled asthma (ie, 3 or more features of partially controlled 
asthma).
18. Pregnancy or lactation.
19. Administration of a live vaccine within 28 days prior to study entry.
5.4
Criteria for Initiation of Study Treatment
The inclusion and exclusion criteria will be checked at the Screening Visit. This is an open-label 
study without randomization. Eligible subjects who have provided written informed consent will 
be enrolled after verification of fulfilling all inclusion criteria without matching any exclusion 
criteria.
The Sponsor’s Medical Responsible, or designee, must confirm enrollment and dose level during 
dose escalation after receipt of the appropriate information relating to entry. 
Individuals who do not meet the criteria for initiating treatment (screen failure) may be 
rescreened once.
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5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from Study Treatment
A subject must be withdrawn from study treatment if any of the following occurs: 
! Subject withdrew consent
! Subject lost to follow-up
! Participation in another clinical study
! Any events that unacceptably endanger the safety of the subject
! Occurrence of an exclusion criterion which is clinically relevant and affects the subject’s 
safety, if discontinuation is considered necessary by the Investigator and/or Sponsor
! Occurrence of AEs, for which discontinuation is desired or considered necessary by the 
Investigator and/or the subject (if applicable)
! Any DLT during the DLT observation period (applicable for Part I): Subjects experiencing 
DLTs as described in Section 6.2.4 will not receive further protocol therapy. Subjects who 
discontinue treatment must be followed on study until resolution of toxicity or until disease 
progression
! Disease progression: In case of disease progression per RECIST 1.1 (Appendix III), the 
subject should be withdrawn from study treatment. However, treatment may continue past the 
initial determination of disease progression per RECIST 1.1 (Appendix III) as long as the 
following criteria are met: 
o
No new symptoms or worsening of previous symptoms (including laboratory 
values) indicating disease progression
o
Tolerance of treatment either as single agent 
o
Stable ECOG PS
o
Treatment beyond progression will not delay an imminent intervention to 
prevent serious complications of disease progression (for example, central 
nervous system metastases).
! The decision to continue treatment should be discussed with the Medical Monitor and 
documented in the study records.
! Subjects should be discontinued from treatment if there is further evidence of progressive 
disease (further progression is defined as an additional 10% increase in tumor burden volume 
from time of initial progressive disease) at the control ≥ 4 weeks and < 6 weeks from the 
initial scan documenting disease progression; however, continued treatment is possible in 
consultation with the Medical Monitor. The assessment of clinical benefit should be balanced 
by clinical judgment as to whether the subject is clinically deteriorating and unlikely to 
receive any benefit from continued treatment. If the Investigator feels that the subject 
continues to achieve clinical benefit by continuing treatment, the subject should remain on the 
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study and continue to be monitored according to the Schedule of Assessments (Table 1, 
Table 2, and Table 3).
! If the administration of a prohibited concomitant medication (see Section 6.5.2) becomes 
necessary during the study, the subject will be withdrawn from study treatment (the Sponsor 
may be contacted to confirm whether study treatment must be discontinued prior to doing so)
! Occurrence of pregnancy
! Noncompliance that is deemed by the Investigator or the Sponsor to compromise subject 
safety or study integrity (see Section 6.9).
! Occurrence of any Grade ≥3 AEs and irAEs as defined in Section 6.2.4 or deemed necessary 
by Investigator or the Sponsor for subject safety.
All subjects who discontinue M4112 treatment 
 
should undergo the End of Treatment Visit (within 
7 days), Safety Follow-up Visit (within 30 ± 3 days), and a second Safety Follow-up Visit 
) as indicated in the Schedule of 
Assessments (Table 1, Table 2, and Table 3) for full safety evaluation. Subjects who discontinue 
treatment must be followed on study until resolution of toxicity or until confirmed disease 
progression.
5.5.2
Withdrawal from the Study
Subjects may withdraw from the study at any time without giving a reason. Withdrawal of 
consent will be considered withdrawal from the study. In case of withdrawal, subjects will be 
asked to continue Safety Follow-up Visits. 
A subject must be withdrawn from the study if any of the following occur during the study:
! Withdrawal of the subject’s consent
! Participation in any other interventional study during the treatment duration of this study
! Subject lost to follow-up.
In case of withdrawal from the study, the assessments scheduled for the End of Treatment Visit 
should be performed (see Section 7.1.3), if possible, with focus on the most relevant 
assessments. In any case, the appropriate eCRF section must be completed.
If a subject fails to attend scheduled study assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible.
Subjects who do not complete the DLT period for reasons other than a DLT/AE will not be 
replaced.
5.6
Premature Termination of the Study
The clinical study may be terminated prematurely or suspended at the request of Health 
Authorities or if new safety or efficacy information leads to an unfavorable benefit-risk 
assessment for any IMP. The Sponsor may discontinue the study if it becomes unjustifiable for 
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medical or ethical reasons, for poor enrollment, or because of discontinuation of clinical 
development of an IMP or withdrawal of an IMP or comparator from the market for safety 
reasons.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs) will be informed about the discontinuation of the study in accordance with applicable 
regulations. The study may be terminated or suspended upon request of the Health Authorities.
In the situation of a premature termination of the study, subjects on treatment who are having a 
clinical benefit may continue to receive the IMP based on the Investigator’s request and in 
consultation and agreement with the Sponsor.
5.7
Definition of End of Study
The end of study is defined as the last subject having completed the last Safety Follow-up Visit, 
and/or stopped due to unacceptable toxicity, disease progression, Investigator/subject decision, 
withdrawn consent, lost to follow-up or has died, whichever comes first.
6
Investigational Medicinal Product and Other Drugs Used in 
the Study
The term “Investigational Medicinal Product” refers to an active substance or a placebo being 
tested or used as a reference therapy in a clinical study, including products that have a marketing 
authorization but are formulated, packaged, or administered differently from the authorized form, 
used for an unauthorized indication, or used to gain further information about the authorized 
form. In this study, the IMPs are M4112, 
.
6.1
Description of Investigational Medicinal Products
 
 
 
 
 
 
. 
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6.2
Dosage and Administration
Subjects will be administered an oral dose of M4112 BID (or a regimen determined by the SMC) 
at least 1 h prior to a meal and at least 2 h after a meal in 28-day cycles. The SMC may need to 
make changes on the dosing and regimen (eg, BID to QD) of M4112. Meal times should be 
collected on the appropriate eCRF.
6.2.1
Dose Escalation Cohort (Part I)
6.2.1.1
Subjects Receiving M4112 as Single Agent
Administration of M4112:
BID continuous administration of M4112 as single agent at doses recommended by the SMC is 
foreseen. On study site visit days, the morning dose of M4112 will be taken at the study site.
Administration of M4112:
BID continuous administration of M4112 as single agent at doses recommended by the SMC is 
foreseen. On infusion day visits, M4112 will be administered after premedication (within 
30 min) 
 
 
 
 
 
 
 
 
 
 
 
 
 
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! Subjects in Part I of the study who experience a Grade ≥3 nonhematological AEs (for 
exceptions see DLT criteria) or Grade 4 hematological ADR, after completion of the DLT 
assessment period (ie, first 28 days of treatment with M4112), need to interrupt study 
treatment; however, subjects may continue on study treatment of M4112 at a reduced dose 
provided the reaction has resolved to baseline value or Grade ≤1 within 2 weeks and there is 
no progressive disease. The dose of M4112 will be reduced to a dose defined by the SMC. If 
indicated, a further dose reduction is possible. 
! At evidence of hepatocellular injury attributable to study drug, such as increase in AST or 
ALT ≥5-fold ULN or ≥3 x ULN elevation of ALT or AST and elevation of serum total 
bilirubin to ≥2 x ULN, without initial findings of cholestasis (elevated serum alkaline 
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phosphatase) or other apparent clinical causality (eg, viral hepatitis A, -B, or -C, alcohol abuse 
or co-medication (ie, paracetamol [acetaminophen]), subjects should interrupt study treatment 
and undergo close observation. This should include monitoring for symptoms (clinical signs 
of hepatitis, or hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal 
pain, jaundice, fever, or rash) and hepatic function (AST, ALT, alkaline phosphatase [ALP]) 
and fractionated bilirubin) at least every 3 days, until symptoms and/or hepatic function 
abnormalities resolve, stabilize or return to baseline values. This event should be reported to 
the Sponsor within 24 h of learning of its occurrence. Re-exposure of the subject to the study 
drug and possible dose level reduction will be determined by the SMC.
! Once the dose of M4112 has been reduced in an individual subject, it must not be escalated 
again
! If more than 2 dose reductions of M4112 are indicated, the subject will be permanently 
discontinued from study treatment
! M4112 must also be permanently discontinued in case study treatment delays exceed 2 weeks, 
regardless of the reason for delay
! Subjects who experience an increase in QT: Subjects in which the calculated QTc average 
(using the Fridericia correction calculation) increases to > 500 ms on any triplicate reading or 
≥60 ms change over baseline during treatment with M4112 have to interrupt study treatment 
until further clinical evaluation.
6.2.4
Dose Limiting Toxicities
DLTs will be used to determine dose escalation, dose de-escalation, and the MTD (if reached), 
using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events
Version 4.03 (CTCAE 4.03). 
DLTs are defined as any Grade ≥3 AEs and irAEs, during treatment of either M4112 as single 
agent 
 by the Investigator and/or the Sponsor, 
during Cycle 1 at any dose level: 
! Any Grade ≥3 nonhematological AE or irAE assessed by the Investigator or Sponsor during 
the first Cycle (first 28 days) of study treatment except:
a.
Diarrhea of ≤6 days duration following adequate and optimal therapy that resolves to 
Grade ≤1
b. Grade 3 skin toxicity that resolves to Grade 1 or less with supportive measures within 
7 days
c.
Nausea and vomiting of ≤72 h duration with adequate and optimal therapy
d. Single laboratory values out of the normal range that have no clinical correlate, and 
resolve to Grade ≤2 within 6 days with adequate medical management (except 
Grade ≥3 liver function test increase without any clinical correlate)
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e.
Grade 3 infusion-related reactions resolving within 6 h from the end of infusion and 
controlled with medical management
f.
Transient (≤72 h) Grade 3 fatigue, local reactions, flu-like symptoms, fever, 
headache that resolves to Grade ≤1 with adequate treatment 
g. Keratoacanthoma and SCC of the skin. Any suspicious skin lesion that is local and 
should be resected with negative resection margin
h. Symptomatic thyroid dysfunction which is manageable with adequate treatment and 
resolves to Grade 2 within 6 days 
i.
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 
j.
Asymptomatic Grade ≥3 lipase or amylase elevation not associated with clinical 
manifestations of pancreatitis. 
! Any TEAE observed in subsequent cycle that in the opinion of the SMC needs to be taken 
into account for the overall evaluation of the safety and proposal of dose escalation 
! Any Grade 4 neutropenia of > 5 days duration, Grade ≥3 febrile neutropenia
! Grade 3 hemoglobin decrease (< 8.0 g/dL) despite blood transfusion or erythroid growth 
factor 
! Grade 4 hemoglobin decrease assessed as related to study drug
! Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding 
! Any Grade ≥ 3 clinical signs and symptoms related to increased QTc
! Evidence of hepatocellular toxicity attributable to study drug, such as increase in AST or 
ALT ≥5-fold ULN for at least or ≥3 x ULN elevation of ALT or AST and elevation of serum 
total bilirubin to ≥ 2 x ULN, without initial findings of cholestasis (elevated serum ALP) or 
other apparent clinical causality (eg, viral hepatitis A, B, C, or co-medication). 
If the above criteria are met, subjects should undergo close observation, including monitoring for 
symptoms (clinical signs of hepatitis, hypersensitivity, fatigue, decreased appetite, nausea, 
vomiting, abdominal pain, jaundice, fever, or rash) and hepatic function (AST, ALT, ALP and 
fractionated bilirubin) at least every 3 days, until symptoms and/or hepatic function 
abnormalities resolve, stabilize or return to baseline values. This event should be reported to the 
Sponsor within 24 h of learning of its occurrence.
Subjects experiencing DLTs during the DLT observation period (applicable for Part I only) as 
described in Section 6.2.4 will not receive further protocol therapy. Subjects with nausea and 
vomiting will maintain normal schedule without re-dosing.
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In addition, any immune-related toxicity event observed in the next cycle will be reviewed and 
taken into account by the SMC for the overall evaluation of the safety and proposal of dose 
escalation of M4112 
.
All subjects treated in dose escalation cohorts who miss > 5 planned total daily doses of M4112 
 in the first cycle (first 28 days) of the dose escalation part 
for other than safety reasons are not eligible for DLT assessment, will not be considered in the 
Bayesian model, and will not formally be replaced.
The MTD is defined by the SMC. An MTD is suggested from the Bayesian logistic regression 
model with target toxicity of 30%. 
6.3
Assignment to Treatment Groups
Once the subject has provided a signed ICF and meets all inclusion criteria and does not meet 
any exclusion criterion, subjects will be assigned to receive open-label M4112 as a single agent, 
Subjects will be assigned sequentially to cohorts of either M4112 as a single agent, 
 
. During 
dose-escalation, the SMC may decide (based on available data) upon enrollment and dose for the 
next dosing cohort before all subjects in a cohort have completed Cycle 1.
Subject identifiers will comprise 17 digits, the first 10 digits representing the study number, the 
following 3 digits representing the site number, and the last 4 digits representing the subject 
number, which is allocated sequentially starting with 
.
6.4
Noninvestigational Medicinal Products to be Used
Storage, handling, preparation, and disposal of commercially sourced non IMPs should occur 
according to the package insert specifications and local institutional guidelines.
The investigator is responsible for ensuring accountability for non IMPs, including reconciliation 
of drugs and maintenance of drug records in the same manner as described for IMPs in 
Section 6.8.
Immediate access to an intensive care unit or equivalent environment and appropriate medical 
therapy (including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and 
oxygen) must be available for use in the treatment of infusion-related reactions
 
 
 
As with all monoclonal antibody therapies, there is a risk of hypersensitivity reaction. Patients
should be monitored for signs/symptoms  of infusion reactions including but not limited to
pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and 
urticaria. Interruption or slow the rate of infusion for mild or moderate infusion-related reactions. 
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If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. Guidelines for management of infusion-related reactions and severe 
hypersensitivity and flu-like symptoms according to the NCI are found in Sections 6.5.5.1 and 
6.5.5.2, respectively. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf. Subjects should be instructed to report any delayed 
reactions to the Investigator immediately.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.5
Concomitant Medications and Therapies
All concomitant medications taken by the subject during the study, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, 
dose, duration and indication of each drug. Nondrug interventions and any changes to a 
concomitant medication or other intervention should also be recorded in the eCRF.
6.5.1
Permitted Medicines
Any medications, therapies or procedures (other than those excluded by the clinical study 
protocol) that are considered necessary for the subjects’ welfare according to local standard of 
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care and will not interfere with 
 
 may be given at the Investigator’s discretion.
Other drugs to be used for prophylaxis, treatment of hypersensitivity reactions, and treatment of 
fever or flu-like symptoms are described in Section 6.5.5.2.
Hematopoietic growth factors can be used if medically indicated according to standard of care 
only after the DLT period of 28 days.
Erythropoietin and darbepoetin-alpha are permitted outside the DLT window. Hormonal 
therapies acting on the hypothalamic-pituitary-gonadal axis are permitted (ie, luteinizing 
hormone-releasing hormone agonist/antagonists). No other hormonal anticancer therapy is 
permitted.
Rescue medications may be administered due to anticipated adverse reactions or anticipated 
emergency situations.
Administration of corticosteroids through a route known to result in a minimal systemic 
exposure (topical, intranasal, intra-ocular, or inhalation) and anti-infectious drugs are permitted.
6.5.2
Prohibited Medicines
Prohibited medicines are indicated in the exclusion criteria (see Section 5.3.2).
During the study, any other investigational drug, chemotherapy, extensive radiotherapy 
(involving ≥30% of bone marrow) or any other anticancer therapy (cytotoxics, biologics or other 
targeted therapy) are prohibited.
In vitro assessments indicate that M4112 is a sensitive substrate to CYP3A4 and cannot exclude 
that it can inhibit or induce CYP3A4 at a clinically relevant extent. Strong inhibitors or inducers 
of CYP3A4, and drugs with a narrow therapeutic index, which are predominantly metabolized 
by CYP3A4 should be discontinued 7 days prior to treatment and avoided during treatment. 
 
 An 
updated list of nonpermitted drugs can be accessed via the following link:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664
Drugs known to have a high risk to prolong QTc as per label or Credible Meds web site 
(formerly AZCert) are prohibited. For antihistamines only drugs with high risk of QTc 
prolongation (in the label) or risk mentioned in the label are prohibited (Diphenhydramine is 
considered of low risk and can be used)
Corticosteroids and immunesuppressants given systemically at therapeutic doses are not 
permitted throughout treatment other than for treatment of immune-related adverse events and 
for endocrine replacement therapy (equivalent to < 10 mg prednisone daily). 
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Concomitant use of warfarin or other Vitamin K antagonists is also prohibited.
The solubility of M4112 is pH dependent; therefore, co-administration of antacid drugs, 
H2-blocker and proton pump inhibitors (PPIs) are likely to decrease the absorption of M4112. 
H2-blockers or PPIs should be stopped 5 days prior to the first treatment, and avoided during the 
entire treatment period with IMP. Antacid drugs should not be taken 1 h before IMP 
administration until 2 h after IMP administration.
The following treatments must not be administered during the study:
! Immunotherapy including interferon, immunosuppressive drugs (eg, chemotherapy or 
systemic corticosteroids except for short term treatment of allergic reactions, endocrine 
replacement therapy at low dose prednisone [≤10 mg daily] or equivalent, or for the treatment 
of irAEs or other appropriate short term steroid use), or other experimental pharmaceutical 
products. Short term administration of systemic steroid or other immunosuppressant such as 
infliximab or mycophenolate (ie, for allergic reactions or the management of irAEs) is 
allowed. Steroids with no or minimal systemic effect (topical, inhalation) are allowed. 
Note: for subjects with glioblastoma, steroid use is allowed
! Adefovir
! Prophylactic use of corticosteroids for infusion related reactions is prohibited
! Any live vaccine therapies for the prevention of infectious disease within 28 days prior to 
study entry and during study. Administration of inactivated vaccines is allowed (eg, 
inactivated influenza vaccines)
! Blood transfusions and erythroid growth factors are not allowed during the 28-day DLT 
window during the escalation phase. These subjects are considered to have had a DLT if the 
drop in hemoglobin is rated as drug related, or subjects are regarded as not evaluable, if the 
event is not related to study medication. 
If the administration of a nonpermitted concomitant drug becomes necessary during the study, 
the subject will be withdrawn from study treatment (the Medical Monitor should be contacted to 
discuss whether the IMP must be discontinued).
6.5.3
Other Interventions
Interventions as indicated in the eligibility criteria in Section 5.3 are applicable.
6.5.4
Special Precautions
Special precautions on Day 1 and Day 15 of every cycle, vital signs (blood pressure, pulse, 
respiratory rate, temperature,) will be assessed predose (within 15 min of oral dosing and 
infusion), and then every 15 min 
 during 
infusion and for an additional 2 h post-infusion. If vital signs are not stable after 2 h (either blood 
pressure > 140/> 90 mmHg or < 90/< 60 mmHg compared to normal blood pressure at start or 
changes of > 20 reading points between measurements, for heart rate and respiration rate changes 
of ≥20% compared to start) then continue monitoring every 15 min until stable on 2 consecutive 
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repeated measurements. If vital signs are stable after 2 h, subjects will be monitored for vital 
signs every 60 min up to 8 h post-infusion on Days 1 and 15 of Cycle 1 only. These monitoring 
will be performed in an area with resuscitation equipment and emergency agents In addition 
monitor subjects for signs/symptoms of infusion reactions including but not limited to pyrexia, 
chills, flushing, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow 
the rate of infusion for mild or moderate infusion-related reactions. 
 
 
 
 
 
 
 
 
 
Due to possible food effects on the PK of M4112, M4112 should be administered at least 1 h 
prior to a meal and at least 2 h after a meal.
Subjects will be instructed to avoid any intake of grapefruit, grapefruit juice, Seville oranges, 
Seville orange marmalade, or other products containing grapefruit or Seville oranges and 
cranberries within 7 days prior to Day 1 of M4112 administration and during M4112 
administration. The same applies to herbal supplements which induce or inhibits CYP3A, 
including but not limited to St. John’s wort. For further details, see the Drug Development and 
Drug Interactions website mentioned in Section 6.5.2. 
The treatment recommendations for infusion-related reactions and severe hypersensitivity 
reactions according to the NCI are as outlined in Sections 6.5.5.1 and 6.5.5.2, respectively.
Investigators should also monitor subjects closely for potential irAEs, which may become 
manifest earliest after weeks of treatment. Such events may consist of persistent rash, diarrhea 
and colitis, autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and 
other inflammatory eye conditions. The spectrum of hypothetical irAEs also includes formation 
of auto-antibodies like anti-nuclear antibodies (ANAs) or anti-neutrophil cytoplasmic antibodies 
(ANCAs). See Section 6.5.5.3 for details on the management of irAEs.
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
Any Grade 4 ADRs require treatment discontinuation except for single laboratory values out of 
normal range that are unlikely related to study treatment as assessed by the Investigator, do not 
have any clinical correlate, and resolve within 7 days with adequate medical management.
Any Grade ≥ 3 AEs and irAEs require treatment discontinuation with exception of any of ADRs 
mentioned in Section 6.2.3 and 6.2.4 in the DLT criteria.
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6.5.5.1
Infusion-Related Reactions
 
 
 
 
 
6.5.5.2
Severe Hypersensitivity Reactions and Flu-Like Symptoms
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf (UK Resuscitation Council). Subjects should be 
instructed to report any delayed reactions to the investigator immediately.
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A. Symptoms
! Impaired airway
! Decreased oxygen saturation (< 92%)
! Confusion
! Lethargy
! Hypotension
! Pale/clammy skin
! Cyanosis.
B. Management
! Epinephrine injection and dexamethasone infusion
! Subject should be placed on monitor immediately
! Alert intensive care unit for possible transfer if required
 
 
 
 
 
 
 
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Figure 2
Assessment and Initial Management of Tumor Lysis Syndrome 
TLS = tumor lysis syndrome.
Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium-size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell-lysis potential
Assess cell-lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6-8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4-6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinol or ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia
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6.5.5.3
Immune-Related Adverse Events
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur. Treatment of irAEs 
is mainly dependent upon severity (NCI-CTCAE grade):
! Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent monitoring
! Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4)
! Grade 3 to 4: treat with high dose corticosteroids.
Treatment of irAEs should follow guidelines set forth in Table 9.
Table 9
Management of Immune-Related Adverse Events of 
 
 M4112 as Single Agent 
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE 4.03)
Initial Management
Follow-up Management
Grade 1
Diarrhea: < 4 stools/day over 
Baseline
Colitis: asymptomatic 
 
M4112 therapy
Symptomatic treatment (eg, 
loperamide)
Close monitoring for worsening symptoms
Educate subject to report worsening 
immediately
If worsens:
Treat as Grade 2, 3, or 4 
Grade 2
Diarrhea: 4 to 6 stools per day over 
Baseline; iv fluids indicated < 24 h; 
not interfering with ADL
Colitis: abdominal pain; blood in 
stool 
Delay 
, or 
M4112 therapy
Symptomatic treatment
If improves to Grade 1: 
Resume 
 or M4112 
therapy
If persists > 5 to 7 days or recurs:
Treat as Grade 3 to 4
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per 
day over Baseline; incontinence; iv 
fluids ≥24 h; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention 
indicated, peritoneal signs
Grade 4: life-threatening, 
perforation
Withhold 
 
 M4112 therapy for 
Grade 3
Permanently discontinue 
 M4112 
therapy for Grade 4 or 
recurrent Grade 3. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade 1, then taper 
over at least 1 month, resume 
 
 therapy following steroids taper (for 
initial Grade 3).
If worsens, persists > 3 to 5 days, or recurs 
after improvement: 
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab should not 
be used in cases of perforation or sepsis
Permanently discontinue IMP 
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Dermatological irAEs
Grade of Rash
(NCI-CTCAE 4.03)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering ≤30% body surface area 
Continue 
 
 M4112 therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids) 
If persists > 1 to 2 weeks or recurs: 
Withhold 
 M4112 
therapy
Consider skin biopsy 
 
 
 
 
 
If worsens: 
Treat as Grade 3 to 4 
Grade 3 to 4
Covering > 30% body surface area; 
life threatening consequences 
Withhold 
 
 M4112 therapy for 
Grade 3.
Permanently discontinue for 
Grade 4 or recurrent Grade 3
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
If improves to Grade 1: 
Taper steroids over at least 1 month and 
add prophylactic antibiotics for opportunistic 
infections 
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE 4.03)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding 
, or M4112 
therapy
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4 
Grade 2
Mild to moderate new symptoms 
Withhold 
 
M4112 therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily, 
consider hospitalization 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Consider bronchoscopy, lung 
biopsy 
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to near Baseline, 
taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and then resume 
 M4112 therapy 
following steroids taper 
If not improving after 2 weeks or worsening: 
Treat as Grade 3 to 4 
Grade 3 to 4
Grade 3: Severe new symptoms; 
Permanently discontinue 
r M4112 
therapy
If improves to Baseline: 
Taper steroids over at least 6 weeks 
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Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE 4.03)
Initial Management
Follow-up Management
New/worsening hypoxia; 
Grade 4: life-threatening 
Hospitalize 
Pulmonary and Infectious 
Disease consults
1.0 to 2.0 mg/kg/day 
prednisone equivalent 
Add prophylactic antibiotics 
for opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If not improving after 48 h or worsening: 
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, iv 
immunoglobulin, or mycophenolate mofetil) 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE 4.03)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 
3.0 x ULN and/or total bilirubin 
> ULN to 1.5 x ULN 
Continue 
, 
 M4112 therapy
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4 
Grade 2
AST or ALT > 3.0 to ≤5 x ULN 
and/or total bilirubin > 1.5 to 
≤3 x ULN 
Withhold 
, 
 M4112 therapy
Increase frequency of 
monitoring to every 1 to 
2 days 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections 
Consult gastroenterologist/ 
hepatologist
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted
If returns to Baseline: 
Taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
 M4112 therapy 
following steroids taper.
If worsens: Treat as Grade 3-4.
Grade 3 to 4
AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN 
Discontinue 
 
 M4112 therapy 
Increase frequency of 
monitoring to every 1 to 
2 days 
1.0 to 2.0 mg/kg/day 
methylprednisolone iv or iv 
equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consult gastroenterologist
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted (for 
If returns to Grade 2: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram (g) twice 
daily 
If no response within an additional 3 to 
5 days, consider other immunosuppressants 
per local guidelines
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Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE 4.03)
Initial Management
Follow-up Management
study sites in Germany, only 
MRI is to be used)
Renal irAEs
Grade of Creatinine Increased
(NCI-CTCAE 4.03)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 
1.5 x ULN
Continue 
 
M4112 therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4
Grade 2 
Creatinine increased > 1.5 to 
6 x ULN
Withhold 
 
M4112 therapy
Increase frequency of 
monitoring to every 3 days
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections
Consider renal biopsy
If returns to Baseline:
Taper steroids over at least 1 month, and 
resume 
 M4112 
therapy following steroids taper.
If worsens: 
Treat as Grade 4.
Grade 3 to 4
Creatinine increased > 6 x ULN
Permanently discontinue 
 M4112 
therapy
Monitor creatinine daily
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections
Consider renal biopsy
Nephrology consult
If returns to baseline:
Taper steroids over at least 1 month, 
Cardiac irAES
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and/or new laboratory 
 
or cardiac 
imaging abnormalities suggestive 
of myocarditis.
Withhold 
, 
 M4112 therapy
Hospitalize 
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced 
heart failure and arrhythmia 
management
Cardiology consult to 
If symptoms improve and immune-mediated 
etiology is ruled out, re-start 
 
 
 M4112 therapy.
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-
mediated etiology is suspected or confirmed 
following cardiology consult, manage as 
immune-mediated myocarditis.
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Cardiac irAES
Myocarditis
Initial Management
Follow-up Management
establish etiology and rule-
out immune-mediated 
myocarditis. 
Guideline based supportive 
treatment as per cardiology 
consult.*
Consider myocardial biopsy if 
recommended per cardiology 
consult.
Immune-mediated myocarditis
Permanently discontinue 
 M4112 
therapy.
Guideline based supportive 
treatment as appropriate as 
per cardiology consult.*
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Once improving, taper steroids over at least 
1 month and add prophylactic antibiotics for 
opportunistic infections.
If no improvement or worsening, consider 
additional immunosuppressants (eg, 
azathioprine, cyclosporine A)
*Local guidelines, or eg. ESC or AHA guidelines 
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines 
website:http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Continue hormone replacement/ suppression 
and monitoring of endocrine function as 
appropriate
Grade 3 or Grade 4
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Withhold 
, 
 M4112 therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency), or insulin (for 
type I diabetes mellitus) as 
appropriate. 
Resume 
 M4112 
therapy once symptoms and/or laboratory 
tests improve (with or without hormone 
replacement/suppression).
Continue hormone replacement/ 
suppression and monitoring of endocrine 
function as appropriate 
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Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Rule-out secondary 
endocrinopathies (ie, 
hypopituitarism/hypophysitis)
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (ie, subnormal 
serum Free T4 with 
inappropriately low TSH 
and/or low serum cortisol 
with inappropriately low 
ACTH) :
!
Refer to endocrinologist 
for dynamic testing as 
indicated and 
measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women) 
!
Start hormone 
replacement/ 
suppressive therapy as 
appropriate 
!
Perform pituitary MRI 
and visual field 
examination as 
indicated
If hypophysitis confirmed:
!
Continue
 
 M4112 
therapy if mild or 
moderate symptoms 
with normal MRI. 
Repeat the MRI in 
1 month
!
Withhold 
 
4112 
therapy if severe 
symptoms or 
life-threatening 
symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
high-dose 
corticosteroids (1 to 
2 mg/kg/day 
methylprednisolone iv or 
equivalent) followed by 
corticosteroids taper 
during at least 1 month.
Resume 
 M4112 
therapy once symptoms and hormone tests 
improve (with or without hormone 
replacement).
In addition, for hypophysitis with abnormal 
MRI, resume 
 M4112 
therapy only once shrinkage of the pituitary 
gland on MRI scan is documented. 
Continue hormone replacement/ 
suppression therapy as appropriate.
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Other irAEs (not described above)
Grade of other irAEs
(NCI-CTCAE 4.03)
Grade of other irAEs
(NCI-CTCAE 4.03)
Grade of other irAEs
(NCI-CTCAE 4.03)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE
Withhold 
 
M4112 therapy pending 
clinical investigation
If irAE is ruled out, manage as appropriate 
according to the diagnosis and consider 
re-starting 
 M4112 
therapy
If irAE is confirmed, treat as Grade 2 or 
3 irAE
Grade 2 irAE or first occurrence 
of Grade 3 irAE 
Withhold 
 
 M4112 therapy
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections 
Specialty consult as 
appropriate
If improves to Grade 1: 
Taper steroids over at least 1 month and 
resume
 M4112 
therapy following steroids taper 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue 
 M4112 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Specialty consult as 
appropriate
If improves to Grade 1: 
Taper steroids over at least 1 month 
Grade 4 
Permanently discontinue 
 M4112 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent 
and/or other 
immunosuppressant as 
needed
Add prophylactic antibiotics 
for opportunistic infections 
Specialty consult.
If improves to Grade 1: 
Taper steroids over at least 1 month 
Requirement for 10 mg per day or 
greater prednisone or equivalent 
for more than 12 weeks for 
reasons other than hormonal 
replacement for adrenal 
insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
Permanently discontinue 
 M4112 
therapy
Specialty consult
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = computed tomography; 
irAE = immune-related adverse event; MRI = magnetic resonance imaging; NCI-CTCAE 4.03 = National Cancer 
Institute-Common Terminology Criteria for Adverse Events Version 4.03; T4 = thyroxine; TSH = thyroid-stimulating 
hormone; ULN = upper limit of normal.
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6.6
Packaging and Labeling of the Investigational Medicinal 
Product
 
 
 
 
 
M4112 
M4112 will be packaged in child resistant and tamper sealed wallets. Each wallet will contain 
1 blister with 4 tablets of 25 mg or 200 mg M4112 tablets.
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines. All IMPs will be shipped in suitable transport 
containers according to each IMP’s storage and shipping conditions. Shipments are monitored 
with temperature control devices.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
 
 
 
 
 
 
 
 
 
 
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M4112
M4112 tablets are ready for use and do not require any preparation,
M4112 must be stored at < 25°C and must not be frozen until use, with a temperature log 
maintained daily. All medication boxes supplied to each study site must be stored carefully, 
safely, and separately from other drugs.
M4112 must not be used for any purpose other than the study. The administration of M4112 to 
subjects who have not been enrolled into the study is not covered by the study insurance.
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Any unused M4112 should be discarded in biohazard waste disposal with final disposal by 
accepted local and national standards of incineration.
Storage, handling, preparation, and disposal of IMP should be according to local institutional 
guidelines.
6.8
Investigational Medicinal Product Accountability
The Investigator is responsible for ensuring accountability for study drugs, including 
reconciliation of drugs and maintenance of drug records.
Upon receipt of study drugs, the Investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the 
Sponsor and returning it to the Sponsor. A copy will be retained for the Investigator File
The dispensing of the study drugs will be carefully recorded on the appropriate drug 
accountability forms provided by the Sponsor and an accurate accounting will be available for 
verification by the Sponsor’s Monitor at each monitoring visit.
Study drugs accountability records will include:
! Confirmation of study drugs delivery to the study site;
! The inventory at the site of study drugs provided by the Sponsor and prepared at the site
! The use of each dose by each subject
! The return to the Sponsor or alternative disposition of unused study drugs
! Dates, quantities, batch numbers, expiry dates and (for study drugs prepared at the site) 
formulation, as well as the subjects’ study numbers.
The Investigator should maintain records that adequately document:
! That 
the 
subjects 
were 
provided 
the 
doses 
specified 
by 
the 
clinical 
study 
protocol/amendment(s)
! That all study drugs provided by the Sponsor was fully reconciled.
Unused study drugs must not be discarded or used for any purpose other than the present study. 
Any study drug that has been dispensed to a subject must not be redispensed to a different 
subject.
The Sponsor’s Monitor will periodically collect the study drugs accountability forms and will 
check all returns (both unused and used containers) before arranging or authorizing their 
destruction by the study site.
At the conclusion or termination of this study, study site personnel and the Clinical Study 
Monitor will conduct a final product supply inventory on the Investigational Drug Accountability 
Forms and all unused containers will be destroyed. Instructions for destruction of product will be 
provided to the site. The Clinical Study Monitor will be supplied with a copy for filing of the 
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Investigational Drug Accountability Forms. This documentation must contain a record of clinical 
supplies used, unused, and destroyed and shall include information on:
! All administered units
! All unused units
! All destroyed units (during the study)
! All destroyed units at the end of study
! Date of destruction(s)
! Name and signature of the Investigator/Pharmacist.
It must be ensured at each study site that the study drugs are not used in the following instances:
! After the expiry date
! After the retest date unless the study drug is reanalyzed and its retest date extended.
This is to be closely monitored by the Study Monitor.
6.9
Assessment of Investigational Medicinal Product Compliance
In this study, subjects will receive study treatment at the investigational site. Well-trained 
medical staff will monitor and perform the on-site study drug administration. Subjects will be 
instructed by the Investigator/designee regarding off-site self-administration of M4112, and 
compliance checks performed at all study visits. The information of each study drug 
administration (date and dose of study drug) will be recorded on the eCRF. On evenings 
preceding PK sampling time of drug intake will also be recorded. Subjects will be provided with 
predosing drug diaries for Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2. The Investigator will 
ensure that the information entered into the eCRF regarding drug administration is accurate for 
each subject. Any reason for noncompliance should be documented.
6.10
Blinding
Not applicable
6.11
Emergency Unblinding
Not applicable
6.12
Treatment of Overdose
An overdose is defined as any dose ≥10% than the calculated dose for that particular 
administration. Any overdose must be recorded in the study treatments section of the eCRF.
For monitoring purposes, any case of overdose, whether or not associated with an AE (serious or 
nonserious), must be reported to Drug Safety in an expedited manner using the SAE Report 
Form in the eCRF (see Section 7.4.1.5).
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There are no known symptoms of overdose with any of the study treatments to date. There is no 
established treatment for overdose with the study treatments. The Investigator should use his or 
her clinical judgment when treating an overdose of the study treatments considering the 
presenting symptoms and standard evaluation results.
6.13
Medical Care of Subjects after End of Study
After a subject has completed the study or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the study site’s medical practice and depending on 
the subject’s individual medical needs. 
Upon withdrawal from the study, subjects may receive whatever care they and their physicians 
agree upon. 
7
Study Procedures and Assessments
7.1
Schedule of Assessments
A complete Schedule of Assessments is provided in Table 1, Table 2, and Table 3. Every effort 
should be made to perform assessments as close as possible to the scheduled time points.
Prior to performing any study assessments that are not part of routine medical care for the 
subject, the Investigator will obtain written informed consent as described in Section 9.2.
7.1.1
Screening and Baseline Procedures and Assessments
The screening procedures and baseline assessments will be completed up to 21 + 7 days before 
study treatment starts.
Subjects will be asked to sign the ICF at the start of the screening period and before any 
study-related investigations and assessments are started. The screening procedures and baseline 
assessments will be completed up to 21 + 7 days of signing the ICF and before receiving 
treatment. Failure to establish eligibility within 28 days would result in screening failure and the 
subject will be excluded from the study. 
The subjects’ information that will be documented during screening includes the demographic 
information (birth date as permitted by local regulations, sex, and race as permitted by local 
regulations) and the complete medical history, including the history of malignant disease, history 
of malignant disease drug therapy/radiotherapy/surgery, previous and ongoing medications, and 
baseline medical condition (concomitant medications and procedures and AEs will be monitored 
throughout the study treatment period). Moreover, an Emergency Medical Support card will be 
handed out at the baseline assessments visit.
During screening, subjects will undergo a complete physical examination, including recording 
body height and weight, vital signs, chest X-ray, 12-lead ECG, and a determination of the 
ECOG PS.
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The screening laboratory examination includes hematology, coagulation, full serum chemistry, 
and full urinalysis (dipstick plus microscopic evaluation if indicated), will also be assessed at 
Screening for all subjects. 
During screening, a serum β-human chorionic gonadotropin (βHCG) pregnancy test will be 
performed for females of childbearing potential, and blood hepatitis B virus and hepatitis C virus 
tests will be performed (may be analyzed locally) for all screened subjects as these conditions are 
study entry exclusion criteria (see Section 5.3.2). Females who are postmenopausal (age-related 
amenorrhea ≥12 consecutive months), or who have undergone hysterectomy or bilateral 
oophorectomy are exempt from pregnancy testing. If necessary to confirm postmenopausal 
status, FSH will be drawn at Screening.
The tumor evaluation (type and staging, etc.) will be performed using computed tomography 
(CT) scan or magnetic resonance imaging (MRI; if MRI is used, CT of chest is mandatory), as 
well as histopathological evaluation and tumor markers or any other established methods (see 
Section 7.2.5 for details). 
Free T4 and TSH samples will be collected at time points indicated in the Schedule of 
Assessments (Table 1, Table 2, and Table 3).
 
 
Please see the Schedule of Assessments (Table 1, Table 2, and Table 3) for the full, detailed list 
of screening and baseline procedures and assessments.
7.1.2
Treatment Period
For this protocol, a treatment cycle is defined as 28 days.
Study treatment will begin within 4 days of treatment assignment. The treatment assignment will 
be within the 21 + 7 day screening window. While on study treatment, subjects will be asked to 
visit the study site for assessments according to the Schedule of Assessments (Table 1, Table 2, 
and Table 3). 
The treatment period will begin at the first dose of M4112 in Cycle 1 Day 1 and consist of 
consecutive 28-day cycles of continuous M4112 BID (or a regimen determined by the SMC), 
either as monotherapy 
 administered as a 1 h 
infusion every 2 weeks.
On study site visit days, the morning dose of M4112 will be administered at the study site
 
 
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The following instructions should be followed:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In this study, study treatment will be given until disease progression, significant clinical 
deterioration (clinical progression), unacceptable toxicity, or any criterion for withdrawal from 
the study or study treatment is fulfilled (see Section 5.5.1).
A time window of ± 1 day for Cycle 1 and Cycle 2, ± 3 days for ≥Cycle 3 will be permitted for 
all study assessment visits. 
Assessments to be performed during the treatment period are presented in Table 1, Table 2, and 
Table 3.
At visits where assessment time points coincide with each other, the following procedure should 
be followed: perform vital signs assessments and ECG assessments slightly before the specific 
time point, PK assessments on the specified time point, ADA assessments on the specified time 
point, and lastly PD assessments. Use of agreed upon time windows will be allowed.
7.1.3
End of Treatment
All subjects who discontinue M4112 treatment or M4112 treatment 
 
must undergo the End of Treatment Visit within 7 days and the Safety 
Follow-up Visit within 30 ± 3 days and 
 
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 for a full safety evaluation. Subjects who discontinue treatment in the absence of 
disease progression will not be followed-up after the Safety Follow-up Visits.
7.1.3.1
End of Treatment Visit 
All subjects must undergo an End of Treatment Visit after discontinuation of treatment for any 
reason. This visit should be performed within 7 days of the decision to discontinue treatment but 
before any new antineoplastic therapy is started (if possible), whichever occurs earlier. Please 
see Table 1, Table 2, and Table 3 for the specific assessments to be performed. 
Any subject who experiences an AE that mandates discontinuation of study treatment should 
have an End of Treatment Visit as soon as possible after the decision to discontinue study 
treatment (within 7 days). At the End of Treatment Visit, the assessments indicated in the 
Schedule of Assessments (Table 1, Table 2, and Table 3) will be performed.
7.1.3.2
Safety Follow-up Visits
The Safety Follow-up Visit is scheduled 30 ± 3 days (monotherapy 
 
 after the last administration of M4112, 
 
until resolution to Grade 1, before the start of any new anticancer therapy, whatever occurs first. 
Subjects who discontinue treatment must be followed on study until resolution of toxicity or until 
confirmed disease progression. The Safety Follow-up Visits will include an assessment of safety 
parameters and other applicable assessments as described the Schedule of Assessments (Table 1, 
Table 2, and Table 3). 
7.2
Demographic and Other Baseline Characteristics
The assessments and procedures described in this section will be performed during the screening 
period.
7.2.1
Demographic Data
The following demographic data will be collected at Screening: date of birth, sex (gender), race, 
and ethnicity.
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7.2.2
Diagnosis of Tumor
The cancer disease information that will be documented and verified at the Screening Visit for 
each subject includes:
! Detailed history of the malignancy, including histopathological diagnosis, grading, and 
staging in accordance with the American Joint Committee on Cancer (AJCC)/International 
Union Against Cancer Tumor Node Metastasis Classification of Malignant Tumors (UICC) at 
diagnosis
! All therapy used for prior treatment of the malignancy (including surgery, radiotherapy and 
chemotherapy, immunotherapy)
! Any other conditions that were treated with chemotherapy, radiation therapy, or 
immunotherapy
! Current signs and symptoms of the malignancy and AEs from current and previous anticancer 
treatments
! Current disease status.
7.2.3
Medical History
In order to determine the subject’s eligibility to the study, a complete medical history of each 
subject will be collected and documented during screening, which will include, but may not be 
limited to, the following:
! Past and concomitant nonmalignant diseases and treatments
! All medications taken and procedures carried out within 4 weeks prior to Screening.
7.2.4
Vital Signs and Physical Examination
Vital signs and physical examinations will be recorded at Screening, study entry, and subsequent 
visits as indicated in the Schedule of Assessments (Table 1, Table 2, and Table 3).
Vital signs including oral temperature, respiratory rate, heart rate, and blood pressure will be 
recorded after 3 to 5 min rest in the semi-recumbent position. The resting time will have to be 
reported in the eCRF.
A complete physical examination (including, general appearance, skin, pulmonary, 
cardiovascular, gastrointestinal, external genitourinary only as medically relevant, lymphatic, 
neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, throat, and 
cognitive status) will be performed and the results documented.
The ECOG PS as well as the height and body weight will be documented in the eCRF.
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7.2.5
Computed Tomography or Magnetic Resonance Imaging 
Scans for Tumor Assessment at Baseline
Baseline imaging will be performed up to 21 + 7 days prior to the first M4112 administration in 
order to establish baseline disease status of target and nontarget lesions according to RECIST 1.1 
(Appendix III). A chest X-ray should be performed before a CT or MRI scan to exclude 
prohibitive entry criteria.
In addition to a baseline assessment prior to start of treatment, during treatment, CT scans (with 
contrast media, unless contraindicated) will be done for tumor assessments within 7 days prior to 
Day 1 of Cycles 3, 5, and 7 and thereafter every 3 cycles until progressive disease. These 
assessments can also be done by MRI (if MRI is used, CT of chest is mandatory), using the same 
method at all subsequent assessment time points. Imaging should be performed of the 
chest/abdomen/pelvis (plus other regions as specifically required for specific tumor types), and 
other established assessments of tumor burden if CT/MRI imaging is insufficient for the 
individual subject. A brain CT/MRI scan should be performed, if clinically indicated by 
development of new specific symptoms. Skin metastasis can be used as target lesions according 
to RECIST 1.1 (Appendix III) using measurements by caliper, if they fulfill RECIST 1.1 for 
target lesions. All the scans performed at baseline need to be repeated at subsequent visits for 
tumor assessment. In general, lesions detected at Baseline need to be followed using the same 
imaging methodology and preferably the same imaging equipment at subsequent tumor 
evaluation visits.
7.2.6
Cardiac Assessments
Triplicate digital 12-lead ECGs will be recorded at baseline and at subsequent visits as indicated 
in the Schedule of Assessments (Table 1, Table 2, and Table 3) immediately after measurement 
of vital signs and after the subject has rested in a semi-recumbent position for at least 5 min. The 
ECG results will be used to evaluate the heart rate, atrial ventricular conduction, QR and QT 
intervals, and possible arrhythmias. 
Triplicate digital 12-lead ECG will be recorded at Screening, predose and 2, 3, 4 and 8 h 
postdose just prior PK sample collections during Days 1 and 15 of Cycle 1, predose Day 8 of 
Cycle 1 and predose and at least 60 min postdose on Day 1 Cycle 2, Day 1 Cycle 4, Day 1 
Cycle 6 and then every second cycle thereafter and during the End of Treatment Visit and first 
Safety Follow-up Visit (Table 4 to Table 6). These ECGs will be approximately 2 min apart to 
determine mean QTc (average of triplicates) and will be read locally first. For Part IB and IC, 
Cycle 1 Day 1 and Day 15 triplicate digital ECGs will be also be read centrally for central 
tendency, outlier and exposure-QTc analyses.
For Part IA only, replicate ECGs (Holter) will also be collected on Days 1 and 15 of Cycle 1 for 
concentration-QTc analysis (Part IA only) as indicated in Table 4.
ECG recordings must be performed before PK sampling time points. Time points may change if 
Cmax is different from predicted, ECG time points may be changed.
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To assess the safety and tolerability of the IMP, an ECG can be repeated at the Investigator’s 
discretion at unscheduled visits.
The start of the resting time, ECG time, and PK sampling time will be recorded in the eCRF.
7.2.7
Clinical Laboratory Tests
Blood samples will be collected at Screening for clinical laboratory parameter evaluations. These 
clinical laboratory test results will serve not only as the baseline values for subsequent safety 
clinical laboratory evaluations during the study, but also help to make sure that each enrolled 
subject fulfills all the study entry criteria and does not meet any of the study exclusion criteria 
for laboratory parameters as listed in Section 5.3. Detailed description of laboratory assessments 
is provided in Section 7.4.3.
7.3
Efficacy Assessments
The tumor response assessments will be performed at time points indicated in the Schedule of 
Assessments (Table 1, Table 2, and Table 3) and as discussed in Section 7.2.5.
! Clinical endpoints: Time to tumor response, objective response, best overall response 
(BOR), DCR, duration of response (DOR), and progression-free survival per Investigator 
according to RECIST 1.1 (Appendix III). A CT or MRI scan is mandatory for confirming any 
CR and partial response (PR) after at least 4 weeks following first assessment.
! Progression Free Survival (PFS) time is defined as the time from start date to the date of the 
first documentation of objective progression of disease or death due to any cause, whichever 
occurs first. PFS data will be censored on the date of the last adequate tumor assessment for 
subjects who do not have an event (progressive disease or death), for subjects who start a new 
anticancer therapy prior to an event or for subjects with an event after 2 or more missing 
tumor assessments. Subjects who do not have a baseline tumor assessment or who do not have 
any post-baseline tumor assessments will be censored on the treatment start date unless death 
occurred on or before the time of the second planned tumor assessment in which case the 
death will be considered an event.
! Best Overall Response (BOR) will be determined according to RECIST 1.1 (Appendix III). 
It is defined as the best response obtained among all tumor assessment visits after the date of 
first study drug administration until documented disease progression. The BOR rate is defined 
as the number of subjects with BOR was either confirmed CR or PR, relative to the number of 
subjects belonging to the study of interest. 
! Only tumor assessments performed before the start of any further anticancer treatment will be 
considered in the assessment of BOR. Clinical deterioration will not be considered as 
documented disease progression.
! Disease Control Rate (DCR) is defined as a BOR of complete response (CR), PR or stable 
disease. Both CR and PR must be confirmed by repeat assessments performed no less than 
4 weeks after the criteria for response are first met. DCR is the proportion of subjects with 
disease control. 
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! Duration of Response (DOR) is defined, for subjects with an objective response, as the time 
from first documentation of objective response (CR or PR) to the date of first documentation 
of objective progression of disease or death due to any cause whichever occurs first. If a 
subject has not had an event (progressive disease or death), DOR is censored at the date of last 
adequate tumor assessment.
! Follow-up: See Schedule of Assessments (Table 1, Table 2, and Table 3). Subjects without 
progressive disease according to RECIST 1.1 (Appendix III) at the End of Treatment Visit 
will not be followed up for disease progression.
At baseline, tumor lesions will be categorized in target and nontarget lesions as described in 
RECIST 1.1 (Appendix III).
Results for these evaluations will be recorded with as much specificity as possible so that pre-
and post-treatment results will provide the best opportunity for evaluating tumor response. 
The Investigator may perform scans in addition to a scheduled study scan for medical reasons or 
if the Investigator suspects progressive disease. Subjects who withdraw from the study for 
clinical or symptomatic deterioration before objective documentation of progressive disease will 
be requested to undergo appropriate imaging to confirm progressive disease. Every effort should 
be made to confirm a clinical diagnosis of progressive disease by imaging.
7.4
Assessment of Safety
The safety profile of M4112 will be assessed through the recording, reporting and analysis of 
baseline medical conditions, AEs, AESIs, DLTs, physical examination findings including vital 
signs, laboratory tests (chemistry, hematology, and coagulation), ECOG PS and a 12-lead ECG 
in triplicate from the date of signature of first informed consent either until the 30 ± 3 days or 
until the 90 ± 6 days Safety Follow-up Visit (for Part IB and Part IC). Severity of AEs will be 
graded using the NCI-CTCAE 4.03 (publication date: 14 June 2010) toxicity grades. AEs related 
to study medication will be defined as any AE considered related to M4112 
 
Comprehensive assessment of any apparent toxicity experienced by the subject will be 
performed throughout the course of the study, from the time of the subject’s signature of 
informed consent. Study site personnel will report any AE, whether observed by the Investigator 
or reported by the subject (see Section 7.4.1.2). 
The reporting period for AEs is described in Section 7.4.1.3.
The safety assessments will be performed according to the Schedules of Assessments (Table 1, 
Table 2, and Table 3).
On Day 1 and Day 15 of every cycle, vital signs (blood pressure, pulse, respiratory rate, 
temperature) will be assessed predose (within 15 min of oral dosing and infusion), and then 
every 15 min 
, during infusion and for an 
additional 2 h post-infusion. If vital signs are not stable after 2 h (either blood pressure
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> 140/> 90 mmHg or < 90/< 60 mmHg compared to normal blood pressure at start or changes of 
> 20 reading points between measurements, for heart rate and respiration rate changes of ≥20% 
compared to start) then continue monitoring every 15 min until stable on 2 consecutive repeated 
measurements. If vital signs are stable after 2 h, subjects will be monitored for vital signs every 
60 min up to 8 h post-infusion on Days 1 and 15 of Cycle 1 only. These monitoring will be 
performed in an area with resuscitation equipment and emergency agents. In addition monitor 
subjects for signs/symptoms of infusion reactions including but not limited to pyrexia, chills, 
flushing, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate 
of infusion for mild or moderate infusion-related reactions. 
 
 
 
 
 In order to 
treat possible hypersensitivity reactions, for instance, dexamethasone 10 mg and epinephrine in a 
1:1000 dilution or equivalents should always be available along with equipment for assisted 
ventilation. 
 
 
 
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the NCI-CTCAE 4.03 (publication date: 14 June 2010), 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 a particular AE’s severity is not specifically graded by the guidance document, the Investigator 
is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or her 
best medical judgment.
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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 
According to Sponsor convention, 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 
described below.
If death occurs, the primary cause of death or event leading to death should 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 (for example, 
sudden death, unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to study treatment 
(M4112, 
 using the following definitions. Decisive factors for the 
assessment of causal relationship of an AE to the study treatment include, but may not be limited 
to, temporal relationship between the AE and the study treatment, known side effects of study 
treatment, medical history, concomitant medication, course of the underlying disease, study 
procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
The 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the study treatment under study in 
this clinical study protocol. A reasonable alternative explanation must be available.
Related:
Reasonably 
related 
to 
the 
IMP. 
The 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the study treatment under study in 
this clinical study protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality fulfills these criteria, the identified medical 
condition (for example, anemia, increased ALT) must be reported as the AE rather than the 
abnormal value itself.
Adverse Drug Reaction (ADR)
ADRs are defined in this study as any AEs suspected to be related to study treatment by the 
Investigator and/or Sponsor.
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SAE
An SAE is any untoward medical occurrence that at any dose:
! Results in death
! Is life-threatening (Note: The term “life-threatening” refers to an event in which the subject is 
at risk of death at the time of the event, not an event that hypothetically might have caused 
death if it was more severe)
! Requires inpatient hospitalization or prolongs an existing hospitalization
! Results in persistent or significant disability or incapacity
! Is a congenital anomaly or birth defect
! Is otherwise considered to be medically important. 
Note: important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is 
also considered an SAE, as described in Section 7.4.1.5.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study treatment or study procedures (for 
example, an overnight stay to facilitate therapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (for example, undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as baseline medical conditions, and are not to be considered AEs.
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) should not be reported as an (S)AE, unless the subject’s general 
condition is more severe than expected for the subject’s condition and/or unless the outcome is 
fatal within the AE reporting period (as defined in Section 7.4.1.3).
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Predefined AESIs for Safety Monitoring
Any AE that is suspected to be a potential irAE and infusion related reactions will be considered 
an AESI. 
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each study visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the 
eCRF. All SAEs must be additionally documented and reported using the appropriate SAE eCRF 
page as described in Section 7.4.1.5.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates [and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time]), its severity, its causal relationship with the study 
treatment, any other potential causal factors, any treatment given or other action taken, including 
dose modification or discontinuation of the study treatment, and its outcome. In addition, serious 
cases should be identified and the appropriate seriousness criteria documented. 
Specific guidance can be found in the eCRF Completion Guidelines.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in 
the study (date of first signature of informed consent) and continues through the 30 ± 3 days
Safety Follow-up Visit or 90 ± 6 days Safety Follow-up Visit (for Part IB and Part IC; as a phone 
call). After the Safety Follow-up Visit all SAEs and treatment-related nonserious AEs need to be 
documented up until stabilization or until the outcome is known, unless the subject is 
documented as “lost to follow-up”.
Any SAE assessed as related to IMP must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of IMP.
7.4.1.4
Procedure for Reporting Serious Adverse Events, Adverse 
Events of Special Interest, and Dose Limiting Toxicities 
SAEs
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 h after becoming aware of the event) inform the Sponsor 
or its designee using the SAE Report Form in the eCRF following specific completion 
instructions.
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In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an SAE Report Form in the eCRF must be completed immediately thereafter. 
Names, addresses, and telephone and fax numbers for SAE reporting will be included in the 
study‑specific SAE Report Form.
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, autopsy report). 
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee 
and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated with 
expedited safety reporting obligations.
Requests for follow-up will usually be made via the responsible monitor, although in exceptional 
circumstances the Drug Safety department of the Sponsor may contact the Investigator directly 
to obtain clarification or to obtain further information or to discuss the event.
AESIs
Comprehensive assessment of any apparent toxicity experienced by each subject will be 
performed from the time of giving informed consent and throughout the study. The Investigator 
will report any AESI, whether observed by the Investigator or reported by the subject. The AESI 
reporting period for safety surveillance begins when the subject is initially included in the study 
(date of first signature of informed consent) and continues until last Safety Follow-up Visit 
defined as 30 ± 3 days or 90 ± 6 days (as a phone call) after the last dose of M4112, 
 
 or before start of any anticancer therapy, whatever comes first.
DLTs
Each DLT has to be immediately recorded in the eCRF.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study subjects to the IEC/IRB that approved 
the study.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the study or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the study.” In particular and in line with 
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respective regulations, the Sponsor/designee will inform the Investigator of AEs that are both 
serious and unexpected and are considered to be related to the administered product (“suspected 
unexpected serious adverse reactions” or SUSARs). The Investigator should place copies of 
Safety Reports in the Investigator Site File. National regulations with regard to Safety Report 
notifications to Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related Detailed Guidance documents.
7.4.1.6
Monitoring of Subjects with Adverse Events
Any AE that occurs during the course of a clinical study must be monitored and followed up and 
are assessed for final outcome at the last Safety Follow-up Visit. 
All SAEs ongoing at the Safety Follow-up Visits must be monitored and followed up by the 
Investigator until stabilization or until the outcome is known, unless the subject is documented as 
“lost to follow-up”. Reasonable attempts to obtain this information must be made and 
documented. It is also the responsibility of the Investigator to ensure that any necessary 
additional therapeutic measures and follow-up procedures are performed. 
Monitoring of Specific Adverse Events
In addition to the standard AE and SAE monitoring, precautions to be taken in subjects exposed 
to
 M4112 and management of specific AEs or ADRs are provided in 
Section 6.5.4 and Section 6.5.5.
7.4.2
Pregnancy and In Utero Drug Exposure
Only pregnancies considered by the Investigator to be related to study treatment (for example, 
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. 
However, all pregnancies with an estimated conception date during the period defined in 
Section 7.4.1.3 must be recorded by convention in the AE page/section of the CRF. The same 
rule applies to pregnancies in female subjects and to pregnancies in female partners of male 
subjects. The Investigator must notify the Sponsor/designee in an expedited manner of any 
pregnancy using the paper Pregnancy Report Form, which must be transmitted according to the 
same timeline as described for SAE reporting in Section 7.4.1.5. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the study.
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The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form in the eCRF will be used if the 
subject sustains an event and the Parent-Child/Fetus Adverse Event Report Form if the 
child/fetus sustains an event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.5, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the study, the subject must 
be discontinued from study treatment immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Safety Assessments
Blood and urine samples will be collected for the following clinical laboratory safety tests 
(Table 10), following the timing noted in the Schedule of Assessments (Table 1, Table 2, and 
Table 3). All samples should be clearly identified.
The Sponsor should receive a list of laboratory reference ranges before shipment of study drug. 
Any change in laboratory normal ranges during the study should be forwarded to Sponsor.
All clinical laboratory samples for the assessment of the relevant safety parameters, will be 
collected and analyzed locally. Local laboratory samples and results will be recorded in the 
eCRFs according to the eCRF completion guidelines. The report of the results must be retained 
as a part of the subject’s medical record or source documents. Blood samples for the full safety 
tests will be taken from fasted subjects. If confirmation of a subject’s postmenopausal status is 
necessary, an FSH level will also be performed at Screening.
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Table 10
Clinical Laboratory Safety Assessments
Serum Chemistry
Hematology
Coagulation
Albumin
Absolute lymphocyte count
Activated partial thromboplastin time
Alkaline phosphatasea
Absolute neutrophil count
Prothrombin time/International normalized 
ratio (Quick, INR)
Alanine aminotransferasea
Hematocrit
Amylase
Hemoglobin
Aspartate aminotransferasea
Platelet count
Basic Urinalysis (dipstick, including 
macroscopic appearance, bilirubin, blood, 
color, glucose, ketones, leukocyte 
esterase, nitrite, pH, protein, specific 
gravity, urobilinogen)
Full urinalysis (dipstick plus microscopic 
evaluation) to be performed only at the 
Screening and End of Treatment Visit.
Gamma glutamyltransferase
Red blood cell count
Blood urea nitrogen/total ureaa
White blood cell count and differential 
count
Calciuma
Red blood cell morphology
Chloridea
Reticulocytes
Creatine kinase
Mean corpuscular hemoglobin
Creatininea
Mean corpuscular volume
Hormones
C-reactive protein
Mean corpuscular hemoglobin 
concentration
Follicle-stimulating hormone (if applicable) 
Serum/urine β-human chorionic 
gonadotropin (if applicable)
Glucosea
T4 and TSH
Lactate dehydrogenase
Lipase
Phosphorus/phosphatesa
Magnesiuma
Potassiuma
Sodiuma
Serology
Total bilirubin/indirect bilirubina
HBsAg, HBcAb 
Total protein
HBV DNA (quantitative PCR)
Troponin-T 
HCVAb, HCV RNA (quantitative PCR)
Uric acid
HBcAb = Hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C 
virus; HCVAb = hepatitis C virus antibody; T4 = thyroxine; TSH = thyroid-stimulating hormone.
a
Core serum chemistries. Blood samples for serum chemistry profile will be obtained prior to the administration 
of the study drugs. Full serum chemistry will be performed at Screening and in Cycle 1 on Day 1 and Day 15; 
core chemistry in Cycle 1 on Day 8 and Day 22. In Cycle 2 to 6 thereafter, full chemistry will be performed on 
Day 1 and core chemistry on Day 15. From Cycle 7 onwards, full chemistry will be performed on Day 1 of 
every cycle and at the End of Treatment and Safety Follow-up Visits
If a subject has a clinically significant abnormal laboratory test value that is not present at 
Baseline, the test will be repeated weekly and the subject will be followed until the test value has 
returned to the normal range or the Investigator has determined that the abnormality is chronic or 
stable.
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7.4.4
Vital Signs, Physical Examinations, and Other Assessments
Vital signs, (blood pressure, pulse, respiratory rate, temperature,) should be assessed predose 
(within 15 min of oral dosing and infusion), and then every 15 min
 
, during infusion and for an additional 
2 h post-infusion. If vital signs are not stable after 2 h (either blood pressure > 140/> 90 mmHg 
or < 90/< 60 mmHg compared to normal blood pressure at start or changes of > 20 reading 
points between measurements, for heart rate and respiration rate changes of ≥20% compared to 
start) then continue monitoring every 15 min until stable on 2 consecutive repeated 
measurements. Consider hospital observation for prolonged vital sign changes or instability. As a 
routine precaution, subjects enrolled in this study must be observed for at least 8 h after infusion 
during Day 1 and Day 15 (continue vital signs every 60 min) of Cycle 1 and 2 h post infusion in 
follow-on cycles, in an area with resuscitation equipment and emergency agents (see Table 1, 
Table 2, Table 3).
ECOG PS, and 12-lead ECG (see Section 7.2.6 for 12-lead ECG details) will be assessed at time 
points indicated in the Schedule of Assessments (Table 1, Table 2, and Table 3).
A physical examination will be conducted at Screening and at subsequent visits as indicated in 
the Schedules of Assessments (Table 1, Table 2, and Table 3) and documented in the eCRF. 
Abnormal findings are to be reassessed at subsequent visits.
Body weight will be recorded at Screening and at subsequent visits as indicated in the Schedules 
of Assessments (Table 1, Table 2, and Table 3) and documented in the eCRF. Height will be 
measured at Screening only.
All newly diagnosed or worsening conditions, signs, and symptoms observed from screening, 
whether related to study treatment or not, are to be reported as AEs.
For female subjects of childbearing potential, a serum βHCG pregnancy test will be carried out 
during the Screening phase and a urine βHCG pregnancy test at the subsequent visits and at the 
Safety Follow-up visit of 30 ± 3 days as indicated in the Schedules of Assessments (Table 1, 
Table 2, and Table 3). Results of the most recent pregnancy test (within the last 28 days) should 
be available prior to the next dosing of the study treatment. Subjects who are postmenopausal 
(age-related amenorrhea ≥12 consecutive months or FSH > 40 mIU/mL), or who had undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing.
Total volume of blood to be collected per subject will be approximately 20 mL for Screening and 
approximately 220 to 250 mL per cycle.
7.5
Pharmacokinetics
Venous blood samples (4mL each) will be collected for analysis of M4112 in plasma by a 
validated LC-MS/MS assay. Full details of the bioanalytical method used will be described in a 
separate bioanalytical report.
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The schedules for PK blood sampling are shown for M4112 administered as single agent 
(Table 4), 
 
 PK parameters for M4112 will be calculated 
predose and over 8 h postdosing on Day 1 and Day 15, with a predose sample collected on Day 8 
and predose and 2 h postdosing samples collected on Day 1 of Cycle 2. 
Following analysis of M4112 concentrations, remaining plasma may be used for evaluation of 
potential metabolites.
 
 
The exact date/time of sample collection will be recorded in the eCRF. Although every effort 
should be made to collect PK blood samples according to the schedule, blood samples collected 
outside of the planned window are not to be considered protocol deviations as long as the actual 
collection time is recorded, with the exception of the predose samples, which will be considered 
a deviation if not collected predose.
The PK sample should be collected after ECG and vital signs are collected when scheduled at the 
same time.
Details of blood sample labeling, processing, storage, and shipment requirements will be 
described in a separate laboratory manual. 
For each subject participating in the M4112 single agent dose escalation phase, a total of 
approximately 76 mL of blood (4 mL/sample; 19 samples over Cycle 1 and Cycle 2, Day 1) will 
be collected for determination of the M4112 plasma concentration. 
 
 
 
 
 
7.5.1
Body Fluid(s)
Further details will be summarized in the Laboratory Manual.
7.5.2
Pharmacokinetic Calculations
The software to be used and PK calculations and parameters will be specified in the integrated 
analysis plan (iAP).
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For M4112, PK calculations using standard noncompartmental analysis methods will be 
performed, if appropriate, using commercial software such as Phoenix® WinNonlin® 
(Version 6.3 or higher) at 
 by standard methods. Actual dates and times as recorded on 
the eCRF will be utilized for final analyses, however, nominal times may be used for PK 
determinations in support of the SMC review (See Section 8.6). 
All other data handling procedures will be detailed in the iAP.
Pharmacokinetic parameters to be calculated for M4112 are specified in Table 11.
Table 11
Pharmacokinetic Parameters for M4112
AUC0-8
Area under the plasma concentration-time curve from time zero to 8 h postdose
Cmax
Maximum plasma concentration observed postdose
tmax
Time to reach maximum plasma concentration
Cmin
Minimum observed postdose (trough) plasma concentration
AUC0-8/dose
Area under the plasma concentration-time curve from time zero to 8 h postdose/dose
Cmax/dose
Maximum observed plasma concentration/dose
Cmin/dose
Minimum observed postdose (trough) plasma concentration/dose
Racc(AUC0-8)
Accumulation of the M4112 AUC0-8 (Day 15/Day 1)
Racc(Cmax)
Accumulation of the M4112 Cmax (Day 15/Day 1)
Final PK parameters reported will be detailed in the iAP.
A population pharmacokinetic (PopPK) model will be constructed to allow for calculation of 
PopPK parameters for M4112 and the analysis of selected covariates. PopPK analyses will be 
detailed in a separate analysis plan.
Serum concentrations for 
 will be summarized and may be included in 
population PK analyses models constructed for each analyte, respectively.
 
 
 
 
 
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7.7
Other Assessments
7.7.1
Anti-Drug Antibody
 
 
 
 
 
 
 
 
.
 
 
 
 
 
 
 
 
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8
Statistics
8.1
Sample Size
A Bayesian model is applied to assist the SMC in dosing recommendations. Bayesian models 
will be set up for IDO monotherapy and 
 separately. 
For this sample size assessment, it is assumed that it is not necessary to enroll additional subjects 
at RP2D or MTD and no additional levels are tested (see Section 5.1).
It is anticipated that 24 to 30 evaluable subjects (6 projected dose levels with 3 to 12 subjects 
each) may be needed in order to test the planned dose range of IDO monotherapy. As it is not 
anticipated that MTD occurs in the planned dose range, DLTs are not expected to occur 
frequently. Therefore, the following scenario could be anticipated, assuming 2 DLTs: 
! For single agent escalation: 4 dose levels with 3 subjects each and 2 dose levels with 6 
subjects each. 
 
 
 
As inherent in dose escalation studies, the sample size cannot be prespecified. The SMC will 
recommend doses. Dose regimens are not prespecified as it is dependent on DLTs, PK, and PD 
observed.
8.2
Randomization
Not applicable
8.3
Endpoints
8.3.1
Primary Endpoints
Part IA (Dose Escalation – M4112 as Single Agent)
! DLTs in subjects receiving M4112 as single agent during the first 4 weeks (Day 1 to Day 28 
of Cycle 1) of treatment
! TEAEs and TRAEs according to NCI-CTCAE 4.03 (including deaths) in subjects receiving 
M4112 as single agent from start of treatment up to the last Safety Follow-up Visit
! Treatment-emergent changes from baseline in clinical laboratory measures, vital signs, ECOG 
PS, and physical examination findings in subjects receiving M4112 as single agent up to the 
last Safety Follow-up Visit.
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8.3.2
Secondary Endpoints
Part IA (Dose Escalation – M4112 as Single Agent)
! Plasma PK parameters for M4112: AUC0-8, Cmax, tmax, AUC0-8/dose, Cmax/dose, (Days 1 and 15), 
Racc(AUC0-8) and Racc(Cmax) (Day 15), Cmin, and Cmin/dose (Days 8 and 15 of Cycle 1 and Day 1 of 
Cycle 2)
! Slope of concentration-QTc (cQTc) regression based on time-matched ECG readings (3 or 
more replicates) and PK samples during Cycle 1 at Day 1 and Day 15, central tendency and 
outlier analyses for absolute QTcF, and delta QTc
! BOR, DOR, DCR, time to tumor response, and PFS using RECIST 1.1, up to confirmed 
tumor progression.
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8.3.3
Other Endpoints
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8.4
Analysis Sets
For purposes of analysis, the following populations are defined in Table 13. 
 
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Table 13
Analysis Sets
Population
Description
Screening 
All participants who sign informed consent.
Dose Escalation 
All subjects treated in dose escalation cohorts who do not miss > 5 planned total daily 
doses of M4112 
 in the first cycle (first 28 days) of 
the dose escalation part for other than DLT. T
 
Safety
The Safety Analysis Set will include all subjects who receive at least 1 dose of study 
treatment.
 
Concentration-QTc 
Analysis Set
The cQTc Analysis Set will include all subjects with at least baseline and one on 
treatment measurement of time-matched ECG and M4112 plasma concentration 
collected during the dose-escalation phase. The cQTc analysis set will be used for slope 
analysis of exposure response in QTc analysis.
M4112 
Pharmacokinetic
All subjects from the Safety Analysis Set without major protocol deviations/violations or 
events that would affect PK. Subjects in the PK Analysis Set must have received at least 
1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable 
the calculation of at least 1 PK parameter. Sufficient concentration data is defined as at 
least 3 valid, postdose concentration points in the PK profile to obtain any PK parameter.
Pharmacodynamics 
All subjects who received at least 1 dose of M4112 and provide the predose and at least 
1 postdose sample for PD assessment.
ADA = anti-drug antibody; cQTc = concentration-corrected QT interval (QTc); DLT = dose-limiting toxicities; 
ECG = electrocardiogram; PD = pharmacodynamics; PK = pharmacokinetic.
8.5
Description of Statistical Analysis
8.5.1
General Considerations
All analyses will be prepared by study part (eg, monotherapy escalation, 
 
 and dose level and will 
be described in detail in the iAP. 
There is no formal significance level for this study and all analyses are considered descriptive.
In general, continuous variables will be summarized using number of subjects (n); mean, 
standard deviation; median, 25th Percentile to 75th Percentile (Q1-Q3), minimum, and maximum. 
Categorical variables will be summarized using frequency counts and percentages.
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The calculation of proportions will be based on the number of subjects in the analysis set of 
interest, unless otherwise specified in the study iAP.
Baseline
In general, the last nonmissing measurement prior to the first study treatment will serve as the 
baseline measurement. 
8.5.2
Analysis of Primary Endpoints
For the dose escalation parts the analysis will focus on the number of subjects experiencing a 
DLT. The SMC will receive results of a Bayesian 2-parameter logistic model with overdose 
control updated with the observed DLT data for SMCs dedicated to dose escalation decisions (1, 
30). A separate model will be set up for monotherapy
Recommendation on next dose of the model is based on a loss function (probabilities of being in 
1 of the 4 toxicity probability intervals) will be multiplied with a loss term as follows:
0 × P (target dosing [0.17-0.35]) + 1 × P (for over [0.35-0.67] or under dosing [0-0.17]) + 2
× P (excessive dosing [0.67-1]).
In addition, only doses that have a corresponding probability of less than 25% that the true DLT 
rate is more than 35% (overdose control) are recommended by the model. The recommended 
dose level from the Bayesian model for the next cohort is the dose with the lowest loss function 
from all doses fulfilling the overdose control rule. This Bayesian escalation approach will be 
used to assist the SMC to select the next dose from a predicted set of acceptable doses (eg, 100, 
200, 400, 600, 800 and 900 mg BID). The SMC may choose a different dose or dosing regimen 
than suggested by the Bayesian escalation approach. 
 
 
 
 
If the SMC decides to change the dosing regimen, a separate model will be set up or the model 
extended to a partial order Continual Reassessment Method.
All subjects treated in dose escalation cohorts who miss > 5 planned total daily doses of M4112 
 in the first cycle (first 28 days) of the dose escalation part 
for other than safety reasons are not eligible for DLT assessment, will not be considered in the 
Bayesian model and will not formally be replaced. The SMC can still be adjourned and the 
Bayesian model will be updated with the data from the evaluable subjects. 
The target probability for the MTD suggested by the model will be 30%. If the DLT probability 
of a potential MTD reaches sufficient precision, the SMC will be informed.
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The 2-parameter logistic regression model will be set up as follows:
The relationship between dose and toxicity rate is defined by:
	
, ,  =
exp  + exp() ∗log  



1 + exp  + exp() ∗log  



Where dj ε{100 mg, 200 mg, 400 mg, 600 mg, 800 mg, 900 mg} (BID dosing) and (α, β) are 
bivariate normally distributed and the reference dose (dref) is 900 mg. 
The following parametrization is chosen for the monotherapy prior: 
E(α) = -0.8001
E(β) = 0.4647
Var(α) = 1.5², Var(β) = 1.5², Cov(α, β) = 0
This would correspond to:
Dose
100 mg
200 mg
400 mg
600 mg
800 mg
900 mg
Prior mean DLT rate
9% 
12% 
17% 
22% 
29%
36% 
Prior median DLT rate
1%
3%
7%
13%
22%
30%
DLT = Dose-limiting toxicity.
For more information on operating characteristics of the prior, see Appendix V.
Posterior distribution and the recommended next dose level will be calculated using 
R version 3.1.2 or higher with library package bcrm (38) or package CRMpack or EAST 
version 6.4 or higher.
At interim analysis, after end of dose escalation, and main analysis, the number and proportion of 
subjects experiencing DLTs will be reported by dose level, based on observations during the first 
treatment cycle. Posterior probabilities (2.5%, 25%, 50%, 75%, and 97.5% quantiles) will be 
estimated.
The Dose Escalation Analysis Set will be used for this analysis.
8.5.3
Analysis of Secondary Endpoints
Efficacy Endpoints
Summary statistics as described in Section 8.5.1 will be used for the summary of efficacy 
endpoints by dose level. The 95% exact Clopper Pearson confidence intervals (CIs) will be used 
for binary endpoints.
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Posterior probabilities assuming a beta (1,1) prior for the binary efficacy endpoints will also be 
estimated.
Kaplan-Meier estimates (product-limit estimates) will be presented for the analysis of PFS 
together with a summary of associated statistics (median survival time, 6-, 12-month survival 
rate estimates and estimates for every 6 months thereafter if applicable) including the 
corresponding 2-sided 95% CIs. The CIs for the median will be calculated according to 
Brookmeyer and Crowley (7) and CIs for the survival function estimates at above defined time 
points will be derived using the log-log transformation according to Kalbfleisch and Prentice 
(20). The estimate of the standard error will be computed using Greenwood's formula.
The Safety Analysis Set will be used for the efficacy analyses in Part I of the study.
 
 
 
 
 
 
 
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8.5.4
Pharmacokinetic Calculations
M4112 plasma concentrations will be listed, summarized, and graphically displayed by treatment 
and time point. Derived PK parameters will be listed and summarized by treatment. Descriptive 
summaries of plasma concentrations and derived PK parameters of M4112 will be presented for 
the PK analysis set. The PK variables will be summarized by the number of observations, mean, 
geometric mean, median, SD, standard error of mean, minimum, maximum, and/or coefficient of 
variation. Concentration values below the lower limit of quantification will be taken as zero for 
descriptive statistics. 
Individual plasma and mean (±SD) concentration time plots will be provided for each treatment 
using a linear and semi-logarithmic scale.
Graphical displays will be given, where appropriate. Details of the statistical analysis, including 
evaluation of dose proportionality and comparison of parameters between single agent treatment 
will be described further in the iAP.
A PopPK model will be constructed to allow for calculation of population pharmacokinetic 
parameters for M4112 and the analysis of selected covariates. PopPK analyses will be detailed in 
a separate analysis plan.
8.5.5
Concentration-QTc analysis
Time-matched, replicate ECGs and PK samples collected in the dose-escalation phase will be 
used to analyze for cQTc responses using slope analysis of exposure/response. Analyses will be 
further detailed in a separate analysis plan.
8.5.6
Analysis of Safety and Other Endpoints
Safety analyses will be performed on the Safety Analysis Set. The safety endpoints will be 
tabulated by dose-level, using descriptive statistics. Further details will be provided in the iAP 
based on current safety experience applying the latest MedDRA version.
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Adverse Events
All AEs will be coded according to MedDRA. Severity of AEs will be graded using the 
NCI-CTCAE 4.03 toxicity grading scale. 
AEs will be summarized according to MedDRA System Organ Classes (SOCs) and Preferred 
Terms. The incidence of the following will be analyzed:
! TEAEs and SAEs
! TEAEs and SAEs related to study treatment
! TEAEs with CTCAE Grade ≥3
! TEAEs with CTCAE Grade ≥3 related to study treatment
! TEAEs leading to withdrawal, dose modifications, temporary and permanent interruptions of 
study drug, and death.
AESIs will be summarized according to MedDRA SOCs and Preferred Terms.
Of note, missing classifications concerning relationships with study treatment will be considered 
related to the study treatment.
Subjects who terminated treatment will be summarized by primary withdrawal reason by dose 
level.
All deaths after first dose of study treatment as well as reasons for death will be tabulated.
Laboratory Values 
Laboratory results will be classified by grade according to NCI-CTCAE 4.03. The worst 
on-treatment grades for chemistry and hematology laboratory results will be summarized. Shifts 
in toxicity grading from baseline to highest grade during the on-treatment period will be 
displayed. For laboratory tests without an NCI-CTCAE grade definition, results will be presented 
categorically (eg, below, within, or above normal limits). 
Physical Examination Results and Electrocardiograms
Physical examination, including vital signs (body temperature, respiratory rate, heart rate, and 
blood pressure) and ECG, recorded at baseline and after drug administration will be presented. 
The ECG parameters will be summarized by descriptive statistics per time point, and changes 
from baseline will be calculated. Data will be further analyzed using concentration effect 
modeling for baseline corrected QTcF values. Time-matched replicate ECGs will be analyzed 
along with M4112 plasma concentrations in a cQTc analysis as described in Section 8.5.3.
 
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8.6
Interim and Additional Planned Analyses
This is an exploratory study. Available data will be evaluated during the study by the SMC.
The SMC will review the data during the conduct of the study. The cut off for dose escalation 
assessments by the SMC will usually be triggered by the completion of Cycle 1 (or dropout) of 
the last subject in the respective dose escalation cohort of usually 3 subjects. In cases where 
enrollment of last subject in a dosing cohort is delayed, the SMC may decide (based on available 
data) upon enrollment and dose for the next dosing cohort before all subjects in a cohort have 
completed Cycle 1. The Bayesian model will then be updated with the available data, and the 
data from the subject not having completed Cycle 1 at time of SMC will be considered in the 
next SMC.
The cut off for an exploratory interim analysis of the safety and preliminary antitumor activity 
data from the complete single agent dose escalation will be triggered when the last subject 
enrolled in monotherapy dose escalation reaches the first on-treatment tumor assessment or 
experiences death or premature withdrawal for any reason, whichever comes first. 
 
 
The main analysis of the study is planned to occur after the objectives of the study can be 
answered.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the study at the site and will ensure that the 
study is performed in accordance with this protocol, the ethical principles outlined in the 
Declaration of Helsinki, ICH GCP, and any other applicable regulations. The Investigator must 
ensure that only subjects who have given informed consent are included in the study.
According to United States Code of Federal Regulations Part 54.2 (e), for studies conducted in 
any country that could result in a product submission to the US FDA for marketing approval and 
could contribute significantly to the demonstration of efficacy and safety of an IMP (which are 
considered “covered clinical studies” by the FDA), the Investigator and all subinvestigators are 
obliged to disclose any financial interest which they, their spouses or their dependent children 
may have in the Sponsor or the Sponsor’s product under study. This information is required 
during the study and for 12 months following completion of the study.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for a subject’s participation in the study is his/her written informed 
consent. The subject’s written informed consent to participate in the study must be given before 
any study-related activities are carried out.
 
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. Adequate information must therefore be given to the subject by 
the Investigator or appropriate designee (if local regulations permit) before informed consent is 
obtained.
A subject information sheet must be prepared in the local language in accordance with ICH GCP 
and will be provided by the Sponsor for the purpose of obtaining informed consent. In addition 
to providing this written information to a potential subject, the Investigator or a designate will 
inform the subject verbally of all pertinent aspects of the study, using language chosen so that the 
information can be fully and readily understood by laypersons. The subject will be given 
sufficient time to read the information and the opportunity to ask questions and to request 
additional information and clarification.
If permitted by national regulations, a person other than the Investigator may inform the subject 
about the study and sign the ICF, as above.
After the information is provided by the Investigator, the ICF must be signed and dated by the 
subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived by the Investigator so that the forms can be retrieved at any time for 
monitoring, auditing, and inspection purposes. A copy of the signed and dated information and 
ICF should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor or designee and be submitted again to the IEC/IRB for 
review and favorable opinion. The agreed, revised information will be provided to each subject 
in the study for signing and dating. The Investigator will explain the changes to the previous 
version. The subject will be given sufficient time to read the information and the opportunity to 
ask questions and to request additional information and clarification about the changes.
9.3
Subject Identification and Privacy
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the study as well as in the clinical 
study database. All subject data collected in the study will be stored under the appropriate subject 
number. Only the Investigator will be able to link study data to an individual subject via an 
identification list kept at the site. For each subject, original medical data will be accessible for 
the purposes of source data verification by the Medical Monitor, audits and regulatory 
inspections, but subject confidentiality will be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data. Subjects will be informed accordingly, and will be requested to give 
their consent on data handling procedures in accordance with national regulations.
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 During this time, the samples may be reanalyzed for newly identified markers 
or with new or improved technology. After 10 years, the samples will be destroyed or fully 
anonymized or a new IEC/IRB approval and informed consent will be requested to keep the 
samples for an additional period. If tumor tissue remains, the site will be notified and the tumor 
tissue will be returned to the site upon request. If the site does not request the return of the tumor 
tissue, it will be destroyed.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by the study site for 
use during study participation in order to provide clinical study subjects with a way of 
identifying themselves as participating in a clinical study and to give health care providers access 
to any information about this participation that may be needed to determine the course of 
medical treatment for the subject. 
The first point of contact for all emergencies will be the clinical study Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action will follow the standard process established for 
Investigators.
In cases where the Investigator is not available, the Sponsor or designated CRO will provide the 
appropriate means to contact a Sponsor/CRO physician. This includes the provision of a 24 h 
contact number at a call center, whereby the health care providers will be given access to the 
appropriate Sponsor/CRO physician to assist with the medical emergency.
9.5
Clinical Study Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating to the study. Insurance 
conditions shall meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review 
Board
Prior to commencement of the study at a given site, this clinical study protocol will be submitted 
together with its associated documents (eg, ICF) to the responsible IEC or IRB for its favorable 
opinion or approval, which will be filed in the Investigator Site File. A copy will be filed in the 
Sponsor Trial Master File at the CRO.
The IEC or IRB will be asked to document the date of the meeting at which the favorable 
opinion or approval was given and the members and voting members present. Written evidence 
of favorable opinion or approval that clearly identifies the study, the clinical study protocol 
version and the Subject Information and ICF version reviewed should be provided. Where 
possible, copies of the meeting minutes should be obtained.
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Amendments to this clinical study protocol will also be submitted to the concerned IEC or IRB, 
before implementation of substantial changes (see Section 10.5). Relevant safety information 
will be submitted to the IEC or IRB during the course of the study in accordance with national 
regulations and requirements.
9.7
Health Authorities
The clinical study protocol and any applicable documentation (for example, Investigational 
Medicinal Product Dossier, Subject Information, and ICF) will be submitted or notified to the 
Health Authorities in accordance with all local and national regulations for each site.
10
Study Management
10.1
Case Report Form Handling
Refer to the Manual of Operations for eCRF handling guidelines. 
The main purpose of the eCRF is to obtain data required by the clinical study protocol in a 
complete, accurate, legible and timely. The data in the eCRF should be consistent with the 
relevant source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of 
this study is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data 
protection regulations. The Investigator must ensure that the eCRFs and any other associated 
documents forwarded to Sponsor or its designated organization contain no mention of any 
subject names.
The data will be entered into a validated database. The Sponsor or its designee will be 
responsible for data processing, in accordance with the Sponsor’s data management procedures. 
Database lock will occur once quality control and quality assurance procedures have been 
completed. PDF files of the eCRFs will be provided to the Investigators at the completion of the 
study.
10.2
Source Data and Subject Files
The Investigator must keep a file (medical file, original medical records) on paper or 
electronically for every subject in the study. It must be possible to identify each subject by using 
this subject file. This file will contain the demographic and medical information for the subject 
listed below and should be as complete as possible. 
! Subject’s full name, date of birth, sex, height, weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the study)
! Study identification, that is, the Sponsor study number for this clinical study, and subject 
number
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! Dates for entry into the study (informed consent) and visits to the site
! Any medical examinations and clinical findings predefined in this clinical study protocol
! All AEs
! Date that the subject left the study including any reason for early withdrawal from the study or 
IMP (if applicable).
All documents containing source data must be filed, including, but not limited to CT or MRI 
scan images, ECG recordings, and laboratory results. Such documents must bear the subject 
number and the date of the procedure. If possible, this information should be printed by the 
instrument used to perform the assessment or measurement. As necessary, medical evaluation of 
such records should be performed; all evaluations should be documented, signed, and dated by 
the Investigator.
Electronic subject files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the Monitor and kept in 
a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the study, the Investigator will be provided with an Investigator Site File 
containing all necessary study documents, which will be completed throughout the study and 
updated as necessary. The file must be available for review by the Monitor, during Sponsor 
audits and for inspection by Health Authorities during and after the study, and must be safely 
archived for at least 15 years (or longer, per local requirements or as otherwise notified by the 
Sponsor) after the end of the study. The documents to be archived include the Subject 
Identification List and the signed subject ICFs. If archiving of the Investigator Site File is no 
longer possible at the site, the Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per 
ICH GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance, and Inspection by Health 
Authorities
This study will be monitored in accordance with the ICH GCP and any other applicable 
regulations. The site Monitor will perform visits to the study site at regular intervals.
The clinical study protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical study report, will be subject to independent Quality Assurance 
activities. Audits may be conducted at any time during or after the study to ensure the validity 
and integrity of the study data. Representatives of the Quality Assurance unit from the Sponsor 
or a designated organization, as well as Health Authorities, must be permitted to access all study 
documents and other materials at the site, including the Investigator Site File, the completed 
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CRFs, all IMP and IMP accountability records, and the original medical records or files for each 
subject.
10.5
Changes to the Clinical Study Protocol
Changes to the clinical study protocol will be documented in writing. Substantive amendments 
will usually require submission to the Health Authorities and to the relevant IEC/IRB for 
approval or favorable opinion. In such cases, the amendment will be implemented only after 
approval or favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health 
Authorities only where requested by pertinent regulations. Any amendment that could affect the 
subject’s agreement to participate in the study requires additional informed consent prior to 
implementation following the process as described in Section 9.2.
10.6
Clinical Study Report and Publication Policy
10.6.1
Clinical Study Report
After completion of the study, a clinical study report will be written by the Sponsor in 
consultation with the Coordinating Investigator following the guidance in ICH Topic E3. 
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints and will 
include data from all study sites. The Investigator will inform the Sponsor in advance about any 
plans to publish or present data from the study. Any publications and presentations of the results 
(abstracts in journals or newspapers, oral presentations, etc.), either in whole or in part, by 
Investigators or their representatives will require review by the Sponsor before submission. The 
Sponsor will not suppress publication, but maintains the right to delay publication in order to 
protect intellectual property rights.
Posting of data on ClinicalTrials.gov is planned and will occur 12 months after the last study site 
visit of the final study subject or another appropriate date to meet applicable requirements.
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11
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12
Appendices
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Appendix I:
Contraceptive Guidance and Woman of Childbearing 
Potential
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
1. Premenopausal female with 1 of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview.
2. Premenarchal 
3. Postmenopausal female
! Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, an FSH will be drawn at Screening.
! Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
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Contraceptive Guidance
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of < 1% per year when used consistently and correctlya.
!
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of 
ovulationb
!
oral 
!
intravaginal 
!
transdermal 
!
Progestogen-only hormonal contraception associated with inhibition of ovulationb
!
oral 
!
injectable
Highly Effective Methods That Are User Independent 
!
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system (IUS)
!
bilateral tubal occlusion
!
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. 
!
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study drug. 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.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case 2 highly effective methods of contraception should be utilized 30 days prior to 
the first study treatment administration, during the treatment period and for at least 60 days  after the last dose of 
study treatment 
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Appendix II:
Strong Inhibitors and Inducers of CYP3A4 or Substrates 
with a Narrow Therapeutic Range and Drugs Causing QTc 
Prolongation
Table with Examples of Inhibitors or Inducers of CYP3A4 Enzymes or Substrates with a 
Narrow Therapeutic Range
Strong Inhibitors
Boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole
Strong Inducers
Avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort
Substrates With a Narrow Therapeutic Range
Alfentanil, astemizolea, cisapridea, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine,
sirolimus, tacrolimus, terfenadinea
CYP = cytochrome P450.
a
Withdrawn from the US and certain other markets because of safety reasons.
Note: This is not an exhaustive list. For an updated list, see Tables 5, 6, and 7 in the following link:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m080499.htm
Note: A strong inhibitor is defined as an inhibitor that increases the AUC of a substrate sensitive for that 
CYP ≥5-fold or decreases clearance by > 80%, and a strong inducer decreases AUC of a substrate by ≥ 80%.
Note: CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates 
that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious 
safety concerns (eg, Torsades de pointes).
Table with Examples of Drugs Causing QTc Prolongation
Antipsychotics 
Type IA Antiarrhythmics 
Type IC Antiarrhythmics 
Class III Antiarrhythmics 
Chlorpromazine
Quinidine
Flecainide
Sotalol
Haloperidol
Procainamide
Encainide
Amiodarone
Droperidol
Disopyramide
Quetiapine
Olanzapine
Amisulpride
Thioridazine
Tricyclic 
antidepressants
Other antidepressants
Antihistamines
Other
Amitriptyline
Mianserin
Astemizole
Chloroquine
Doxepin
Citalopram
Loratidine
Hydroxychloroquine
Imipramine
Escitalopram
Terfanadine
Quinine
Nortriptyline
Venlafaxine
Macrolides 
Desipramine
Bupropion
Erythromycin
Moclobemide
Clarithromycin
Note: This is not an exhaustive list.
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Appendix III:
Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
For details, see Eisenhauer et al. 2009 (10).
Definitions
At baseline (within 4 weeks of initiation of treatment), tumor lesions/lymph nodes will be 
categorized measurable or non-measurable as follows:
Measurable:
! Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
! 10 mm by CT scan (CT scan slice thickness ≤ 5 mm)
! 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
! 20 mm by chest X-ray
! Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be ≤ 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed. See also notes below on “Baseline documentation of target and non-
target lesions” for information on lymph node measurement.
Non-measurable
! All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with 10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions:
! Bone scan, positron emission tomography scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
! Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT, MRI, or other established 
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methods can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above.
! Blastic bone lesions are non-measurable.
Cystic lesions:
! Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) because they are, by 
definition, simple cysts. 
! ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions.
Lesions with prior local treatment:
! Tumor lesions situated in a previously irradiated area or other loco-regional therapy area are 
usually not considered measurable unless there has been demonstrated progression in the 
lesion. Study protocols should detail the conditions under which such lesions would be 
considered measurable.
Methods of measurement
! Measurement of lesions
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment.
! Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will 
only be considered measurable when they are superficial and 10 mm diameter as assessed 
using calipers (eg, skin nodules). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should 
be undertaken since it is more objective and may also be reviewed at the end of the study.
! Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
! CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
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slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. An MRI is also acceptable in certain situations (eg, for body scans).
! Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.
! Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in studies where recurrence following CR or 
surgical resection is an endpoint.
! Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
! Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease.
Tumor response evaluation
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only subjects with 
measurable disease at baseline should be included in protocols where objective tumor response is 
the primary endpoint. Measurable disease is defined by the presence of at least one measurable 
lesion. Response criteria are listed in Table A and Table B. 
Response Criteria
Table A
Evaluation of target lesions
Complete Response (CR)
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters.
Progressive Disease 
At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions 
is also considered progression).
Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
progressive disease, taking as reference the smallest sum diameters while on study
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Table B
Evaluation of non-target lesions
Complete Response (CR)
Disappearance of all nontarget lesions and normalization of tumor marker level. All 
lymph nodes must be nonpathological in size (<10 mm short axis).
Stable Disease 
Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker 
level above the normal limits.
Progressive Disease 
Unequivocal progression (see comments below) of existing nontarget lesions. (Note: 
the appearance of one or more new lesions is also considered progression).
Note: Although a clear progression of “nontarget” lesions only is exceptional, in such circumstances, the opinion of 
the treating physician should prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Evaluation of best overall response
It is assumed that at each protocol specified time point, a response assessment occurs. Table C
below provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline.
Table C
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-progressive 
disease
No
PR
CR
Not evaluated
No
PR
PR
Non- progressive disease 
or not all evaluated
No
PR
Stable disease
Non- progressive disease 
or not all evaluated
No
Stable disease
Not all evaluated
Non progressive disease
No
Not evaluable
Progressive disease
Any
Yes or No
Progressive disease
Any
Progressive disease
Yes or No
Progressive disease
Any
Any
Yes
Progressive disease
CR = complete response, PR =partial response.
The best overall response is determined once all the data for the subject is known.
Best response determination in studies where confirmation of CR or PR IS NOT required: Best 
response in these studies is defined as the best response across all time points (for example, a 
subject who has stable disease at first assessment, PR at second assessment, and progressive 
disease on last assessment has a best overall response of PR). When stable disease is believed to 
be best response, it must also meet the protocol specified minimum time from baseline. If the 
minimum time is not met when stable disease is otherwise the best time point response, the 
subject’s best response depends on the subsequent assessments. For example, a subject who has 
stable disease at first assessment, progressive disease at second and does not meet minimum 
duration for stable disease, will have a best response of progressive disease. The same subject 
lost to follow-up after the first stable disease assessment would be considered not evaluable.
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Best response determination in studies where confirmation of CR or PR is required: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point 
as specified in the protocol (at least 4 weeks apart). In this circumstance, the best overall 
response can be interpreted as in Table D.
Table D
Overall response
Overall response
BEST overall response
First time point
Subsequent time point
CR
CR
CR
CR
PR
Stable disease, progressive disease, or PRa
CR
Stable disease
Stable disease provided minimum criteria for stable 
disease duration met, otherwise, progressive disease
CR
Progressive disease
Stable disease provided minimum criteria for stable 
disease duration met, otherwise, progressive disease
CR
NE
Stable disease provided minimum criteria for stable 
disease duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
Stable disease
Stable disease
PR
Progressive disease
Stable disease provided minimum criteria for stable 
disease duration met, otherwise, progressive disease
PR
NE
Stable disease provided minimum criteria for stable 
disease duration met, otherwise NE
NE
NE
NE
CR = complete response, NE = not evaluable, PR = partial response.
a
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease progressive disease at that point (since disease 
must have reappeared after CR). Best response would depend on whether minimum duration for stable 
disease was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions 
were likely still present and in fact the subject had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR.
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Appendix IV:
Immune-Related Response Criteria
Below is a summary of irRECIST (Bohnsack 2014 [4]):
1. Total measured tumor burden (TMTB):  Baseline-selected target lesions and new measurable 
lesions should NOT be assessed separately. Measurements of those lesions should be 
combined into the TMTB, and one combined assessment provided.
2. New Measurable Lesions:  In irRECIST, criteria for unidimensional lesion measurement 
apply to both target and new measurable lesions:  a minimum 10 mm in the longest diameter 
for non-nodal lesions, and a minimum 15 mm in short axis for lymph nodes. Smaller lesions 
contribute to the non-target or new non-measurable tumor burden, but do not get measured.
3. irPR if no Target Lesions:  If new measurable lesions appear in subjects with no target 
lesions at Baseline, irPD will be assessed. That irPD time point will be considered a new 
Baseline, and all subsequent time points will be compared with it for response assessment. 
An assessment of irPR is possible if the TMTB of new measurable lesions decreases by 
≥30% compared with the first irPD documentation.
4. Non-Target Lesions:  In alignment with RECIST 1.1, Baseline selected non-target lesions 
can never convert to measurable lesions, not even if they increase in size at subsequent time 
points and become measurable. Only true new lesions can be measured and contribute to the 
TMTB.
Example: A subject has multiple lung metastases, all smaller than 10 mm and selected as 
no-target lesions at Baseline. If, at a subsequent time point some of these non-target lesions 
increase and become > 10 mm, and 1 new lesion > 10 mm appears, only the new measurable 
lesion will contribute to the TMTB, and not the Baseline selected non-target lesion that increased 
in size. Otherwise such an increase would make persisting non-target lesions switch into the new 
measurable lesion category, which would be inaccurate, as the lesion existed at Baseline.
5. irPD Based on Non-Target Lesions:  In irRECIST, a substantial and unequivocal increase of 
non-target lesions is indicative of progression.
6. irPD Based on New Non-Measurable Lesions:  According to irRECIST, the reviewer may 
assign irPD for the subject with multiple new lesions of 9 mm if they are considered to be a 
sign of unequivocal, massive worsening.
7. irPD Confirmation:  Progression confirmation no less than 4 weeks after the initial irPD 
assessment is recommended, especially in case of marginal disease growth and if the first 
irPD assessment is within the compound-specific tumor flare window.
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Appendix V: Operating Characteristics of Bayesian Dose Escalation 2-Parameter Logistic Regression 
Model with Selected Prior and Overdose Control Boundary at 35%
The following table shows the operating characteristics of the Bayesian logistic regression dose escalation model. It shows potential 
scenarios for dose escalation and associated estimated posterior probabilities of estimated DLT probability being in one of the toxicity 
intervals.
Prior Specifications: E(α)=-0.800119, E(β)=0.464697, Var(α) = 1.5², Var(β) = 1.5², Cov(α, β) = 0
Recommended Dose Considering
Posterior Probability of DLT Probability of 
Recommended Dose (Model and Overdose Control) 
being in Toxicity Interval
Scenario
Doses 
Tested
Dose-Limiting 
Toxicities/ 
Number of Subjects
Loss 
Function
Overdose 
Control 
Model and 
Overdose Control
[0,0.17]
“Under 
Dosing”
(0.17,0.35]
“Target 
Dosing”
(0.35,0.67]
“Over 
Dosing”
(0.67,1]
“Excessive 
Dosing”
1
100 mg
0/3
800 mg
600 mg
600 mg
0.67
0.19
0.12
0.02
1a
100 mg
1/3
100 mg
100 mg
100 mg
0.43
0.32
0.22
0.02
1b
100 mg
1/6
200 mg
200 mg
200 mg
0.49
0.36
0.15
<0.01
2
100 mg
200 mg
0/3
0/3
800 mg
800 mg
800 mg
0.54
0.24
0.18
0.04
2a
100 mg
200 mg
0/3
1/3
400 mg
200 mg
200 mg
0.59
0.31
0.10
<0.01
2b
100 mg
200 mg
0/3
1/6
400 mg
400 mg
400 mg
0.48
0.37
0.15
<0.01
3
100 mg
200 mg
400 mg
0/3
0/3
0/3
800 mg
800 mg
800 mg
0.61
0.23
0.14
0.02
3a
100 mg
200 mg
400 mg
0/3
0/3
1/3
600 mg
400 mg
400 mg
0.60
0.31
0.09
<0.01
3b
100 mg
200 mg
0/3
0/3
600 mg
600 mg
600 mg
0.48
0.36
0.15
<0.01
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Prior Specifications: E(α)=-0.800119, E(β)=0.464697, Var(α) = 1.5², Var(β) = 1.5², Cov(α, β) = 0
Recommended Dose Considering
Posterior Probability of DLT Probability of 
Recommended Dose (Model and Overdose Control) 
being in Toxicity Interval
Scenario
Doses 
Tested
Dose-Limiting 
Toxicities/ 
Number of Subjects
Loss 
Function
Overdose 
Control 
Model and 
Overdose Control
[0,0.17]
“Under 
Dosing”
(0.17,0.35]
“Target 
Dosing”
(0.35,0.67]
“Over 
Dosing”
(0.67,1]
“Excessive 
Dosing”
400 mg
1/6
4
100 mg
200 mg
400 mg
600 mg
0/3
0/3
0/3
0/3
900 mg
800 mg
800 mg
0.70
0.20
0.09
<0.01
4a
100 mg
200 mg
400 mg
600 mg
0/3
0/3
0/3
1/3
600 mg
600 mg
600 mg
0.57
0.33
0.10
<0.01
4b
100 mg
200 mg
400 mg
600 mg
0/3
0/3
0/3
1/6
800 mg
800 mg
800 mg
0.42
0.36
0.21
0.02
5
100 mg
200 mg
400 mg
600 mg
800 mg
0/3
0/3
0/3
0/3
0/3
900 mg
900 mg
900 mg
0.61
0.24
0.13
0.03
5a
100 mg
200 mg
400 mg
600 mg
800 mg
0/3
0/3
0/3
0/3
1/3
800 mg
800 mg
800 mg
0.49
0.36
0.15
<0.01
5b
100 mg
200 mg
400 mg
0/3
0/3
0/3
900 mg
900 mg
900 mg
0.42
0.34
0.20
0.03
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Prior Specifications: E(α)=-0.800119, E(β)=0.464697, Var(α) = 1.5², Var(β) = 1.5², Cov(α, β) = 0
Recommended Dose Considering
Posterior Probability of DLT Probability of 
Recommended Dose (Model and Overdose Control) 
being in Toxicity Interval
Scenario
Doses 
Tested
Dose-Limiting 
Toxicities/ 
Number of Subjects
Loss 
Function
Overdose 
Control 
Model and 
Overdose Control
[0,0.17]
“Under 
Dosing”
(0.17,0.35]
“Target 
Dosing”
(0.35,0.67]
“Over 
Dosing”
(0.67,1]
“Excessive 
Dosing”
600 mg
800 mg
0/3
1/6
6a
100 mg
200 mg
400 mg
600 mg
800 mg
900 mg
0/3
0/3
0/3
0/3
0/3
0/3
900 mg
1,000 mg
900 mg
0.79
0.17
0.03
<0.01
6aa
100 mg
200 mg
400 mg
600 mg
800 mg
900 mg
0/3
0/3
0/3
0/3
0/3
1/3
900 mg
900 mg
900 mg
0.43
0.37
0.19
0.01
6ba
100 mg
200 mg
400 mg
600 mg
800 mg
900 mg
0/3
0/3
0/3
0/3
0/3
1/6
900 mg
900 mg
900 mg
0.62
0.31
0.06
<0.01
a
Maximum of preplanned doses reached. Potential higher doses offered to the model are 1,000 mg and 1,200 mg. 
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Appendix VI:
Signature Pages and Responsible Persons for the Study
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Signature Page – Principal Investigator
Study Title
Phase 
I, 
First-in-Human, 
Open-Label, 
Multiple-Ascending Dose Study to Investigate the 
Safety, 
Tolerability, 
Pharmacokinetics, 
Pharmacodynamics and Clinical Activity of M4112 an 
IDO1/TDO2 
Inhibitor 
as 
Single 
Agent 
 
 
n Subjects with Metastatic or 
Locally Advanced Unresectable Solid Tumors
IND Number
EudraCT Number
To be determined
Clinical Study Protocol Date / 
Version
08 September 2017 / Version 2.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the study at this site and affirm that I 
understand and will conduct the study according to the clinical study protocol, any approved 
protocol amendments, International Council for Harmonization Good Clinical Practice (Topic 
E6) and all applicable Health Authority requirements and national laws.
I also affirm that I 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 the purpose of complying with the regulatory requirements. I therefore 
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:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Sponsor Responsible Persons not Named on the Cover Page
Name, academic degree:
Function/Title:
Clinical Trial Lead
Institution:
EMD Serono, Inc.
Address:
45A Middlesex Turnpike, Billerica, MA 01821, US
Telephone number:
Fax number:
-
E-mail address:
Name, academic degree:
Function/Title:
Biostatistician
Institution:
Merck KGaA
Address:
Frankfurter Strasse 250, 64293 Darmstadt, Germany
Telephone number:
Fax number:
-
E-mail address:
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Appendix VII:
Protocol Amendments and List of Changes
Previous Protocol Amendments 
Table of Amendments
Amendment 
Number
Substantial
(Y/N)
Date
Region or Country
Included in the 
current document
(Y/N)
1
Yes
08 September 2017
Global
Yes
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Amendment 1, 08 September 2017, Global Amendment
Rationale 
The purpose of this amendment is to amend the protocol following the FDA’s requests: received 
by 01 September 2017 (see major scientific changes).
This amendment also includes changes in schedule of assessments tables with the intent to:
! Align and provide consistency between treatment arms 
! Resolve discrepancies between tables and their footnotes for triplicate electrocardiogram 
(ECG) at Day 1 Cycle 2. 
Administrative and Editorial Changes
The name of the Clinical Trial Lead was updated to reflect the recent transition in this role.
Additional clarifications and minor editorial changes to correct, eg, typographical errors were 
implemented.
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Comparison with Clinical Study Protocol Version 1.0, 28 July 2017 (Amendment No. 1)
Addition of text is indicated in bold in below table. If the original text was bold, additional text is indicated in bold and underlined. 
Deleted text is indicated by strikethrough.
Change
Section
Previous Wording
New Wording
Safety monitoring of 
IRRs and cytokine 
release wording was
added to the protocol 
Schedule of Assessments 
Table 1 to Table 3, 
footnote g
Table 1:
Vital signs (blood pressure, pulse, respiratory 
rate, and oral temperature) will be assessed 
after the subject has rested in the semi-
recumbent position for 3 to 5 min. Height and 
weight at Screening only.
Table 2 and Table 3:
Vital signs (blood pressure, pulse, respiratory 
rate, and oral temperature) will be assessed 
after the subject has rested in semi-
recumbent position for 3 to 5 min. Vital signs 
should be assessed predose (within 15 min of 
start of infusion), then every 15 (± 5) min after 
the start of infusion (15, 30, 45, 60 [end 
infusion] and 30 (± 10), 60 (± 10) min after the 
end of infusion. Height at Screening only.
 
 
Table 1:
Vital On Day 1 and Day 15 of every cycle, vital signs (blood 
pressure, pulse, respiratory rate, and oral temperature) will be 
assessed predose (within 15 min of oral dosing after the 
subject has rested in the semi-recumbent position for 3 to 
5 min), and then every 15 min from dosing of M4112 for an 
additional 2 h. Observation can be extended per 
investigator’s discretion. Height and weight at Screening 
only.
Table 2 and Table 3:
Vital signs (blood pressure, pulse, respiratory rate, and oral 
temperature) will be assessed after the subject has rested in 
semi-recumbent position for 3 to 5 min.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Change
Section
Previous Wording
New Wording
 
 
 
Table 4 footnote a, Table 
5 and table 6 footnote b
Table 4 to Table 6
Including optional metabolite analysis from 
samples.
Table 4 to Table 6:
For all study medication administration, a physician must 
be present at the site or immediately available to respond 
to emergencies during all administrations. Critical care 
and 
resuscitation 
facilities 
should 
be 
available 
immediately. Including optional metabolite analysis from 
samples.
Section 6.4 
Noninvestigational 
Medicinal Products to be 
used
As with all monoclonal antibody therapies, 
there is a risk of allergic reaction. 
 
 
 
 
 
As with all monoclonal antibody therapies, there is a risk of for
hypersensitivity reaction. 
 
 
 
 
 
 
 
 
 
 
 
Section 6.5.4 Special 
Precautions, 
Section 7.1.2 Treatment 
Sequence for Dose 
escalation,
Section 7.4 Assessment 
of Safety,
Section 7.4.4 Vital signs 
and physical 
examinations.
 
 
 
 
 
 
 
 
All or some of below new wording has been included in the 
mentioned sections:
 
 
 
 
 
 
 
 
 
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Change
Section
Previous Wording
New Wording
 
 
Synopsis – Study 
centers/countries, 
Objectives, Methodology, 
Treatment Period, 
Planned number of 
subjects, Endpoints, IMP 
dose/mode of 
administration/dosing 
schedule
Figure 1: Study design for Part I (dose 
escalation) 
)
 
 
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Change
Section
Previous Wording
New Wording
Protocol – Section 2 and 
2.1, Section 4.1 to 4.3, 
Section 5.1 (including 
Figure 1), Section 5.2.2, 
Section 5.3.1 and 5.3.2, 
Section 6.2.2, 
Section 7.6.1, Section 8.1, 
Section 8.3.1 to 8.3.3, 
Section 8.4, Section 8.5.1
Schedule of 
Assessments tables 
(Table 1 to Table 6)
and the text in the 
footnotes updated for 
consistency and 
alignment between 
the different treatment 
arms
Table 2 and Table 3
Cycle 7
Table 1 and Table 2
Missing pregnancy test at Safety Follow-up 
(30 ± 3 days) visit
Incorrect PD blood sample at 7+n×3 Until 
Progression
Added 
serum 
pregnancy 
test 
at 
Safety 
Follow-up
(30 ± 3 days) visit
Deleted PD blood sample at 7+n×3 Until Progression visits 
and added it to End of Treatment visit
Table 3
Coagulation sample on Day 8 and Day 22 of 
Cycle 1 and Day 1 of Cycle 5 
Deleted coagulation sample on Day 8 and 22 of Cycle 1 and 
on Day 1 of Cycle 5
Table 1 and Table 3
Missing T4 and TSH samples on Day 1 of 
Cycle 7
Added T4 and TSH samples on Day 1 of Cycle 7 
Table 1 to Table 3 
footnote h 
Table 4 footnote f 
Table 5 footnote c
Table 6 footnote c
Missing text in footnotes on triplicate ECG at 
predose and + 2 h postdose on Cycle 2 Day 1
Included text in footnote:  triplicate ECG at predose and + 2 h 
postdose on Cycle 2 Day 1
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Change
Section
Previous Wording
New Wording
Additional information 
and specification of 
anti-drug antibodies 
added
Section 7.7.1
 
 
 
 
 
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Change
Section
Previous Wording
New Wording
Addition of PK and 
ADA analysis sets
 
Table 13
Pharmacokinetic
M4112 Pharmacokinetic
 
 
 
 
 
 
 
 
 
 
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Table 14
Subject Characterization Based on ADA Results
Category
Definition
Subject at Risk (Denominator for Incidence)
Never-positive
No positive results at any time point
Number of subjects with at least one valid ADA result at any time point
Ever-positive
At least one positive result at any time point
Number of subjects with at least one valid ADA result at any time point
Transient 
positive
If treatment emergent subjects have (a single positive 
evaluation, or duration between first and last positive 
result < 16 weeks) and last assessment not positive.
Number of subjects with at least one valid post-baseline ADA result and 
without positive baseline ADA result (including missing, NR)
Persistent 
positive
If treatment emergent subjects have duration between 
first and last positive result ≥ 16 weeks or a positive 
evaluation at the last assessment
Number of subjects with at least one valid post-baseline ADA result and 
without positive baseline ADA result (including missing, NR)
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SAP_000.pdf: 
1\14112 
MS201408-000S 
Clinical Study Protocol 
Identification No. 
Title 
Study Phase 
Investigational Medicinal 
Product(s) 
Clinical Study Protocol 
Version 
Integrated Analysis Plan 
Author 
Integrated Analysis Plan 
Date and Version 
Integrated Analysis Plan 
Reviewers 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
Integrated Analysis Plan 
MS201408-0005 
Phase I, First-in-Human, Open-Label, Multiple-Ascending Dose 
Study to Investigate the Safety, Tolerability, Phannacokinetics, 
Phannacodynamics and Clinical Activi 
of M4112 an 
IDO1/ID02 Inhibitor as Sin e A ent 
I 
Ill 
Subjects with Metastatic or Locally Advanced Unresectable 
Solid Tumors 
I 
M4112 as single agent 
1111 
08 September 2017 / Version 2.0 
Coordinating Author 
fPD', Merck KGaA 
Function 
PPD 
PPD 
PPD 
I 
PD 
Author I Data Analyst 
PD 
PD 
PD 
07 February2019 / Version 1.0 
Function 
Name 
Medical Responsible, Merck KGaA 
PD 
:;::_[PPD
~
=::::.' 
.,PD 
I, EMO Serono 
.,PD 
I, Merck 
.,PD 
KGaA 
PD 
:;::.:[PPD
~
=.-
.,PD 
, EMO Sero 
.,PD 
I, Me 
no 
~ 
rck KGaA 
P"'PD___.--.. 
.,PD 
I, Merck KGaA 
f PD 
t't'U 
I , EMO Serono 
._fPO 
__ _ 
This document is the property of Merck K~ 
Germany, or one of its affiliated companies. 
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 affiliate. 
Copyright Cl 2019 by M,rck K GaA, Darmstadt, Germany or its affiliatt. AU 1ights resen•ed. 
1/68 


1\14112 
MS201408-000S 
Signature Page 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
Integrated Analysis Plan: MS201408-0005 
Phase I, First-in-Human, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, 
Tolerability, Pharmacokinetics, Pharma--od 
cs and Clinical Activi 
of M4112 an 
ID0l!TD02 Inhibitor as Single Agent 
in Subjects with Metastatic or Lo 
y A 
Merck Responsible 
~po 
Date 
Signature 
Via ELDORADO approval process 
2/68 


1\14112 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
MS201408-000S 
1 
Table of Contents 
Signature Page 
2 
1 
Table of Contents ................................................................................. .3 
2 
List of Abbreviations and Definition of Terms .................................... 5 
3 
Modification History ............................................................................ 8 
4 
Pwpose of the Integrated Analysis Plan ............................................... 8 
5 
Objectives and Endpoints ..................................................................... 9 
5.1 
Part IA (Dose Escalation - M4112 as Single Agent) ........................... 9 
6 
Overview of Planned Analyses ........................................................... I 0 
7 
Changes to the Planned Analyses in the Clinical Study Protocol ...... 10 
8 
Protocol Deviations and Analysis Sets ............................................... 11 
8.1 
Definition of Protocol Deviations and Analysis Sets ......................... 11 
8.2 
Definition of Analysis Sets and Subgroups ........................................ 12 
9 
General Specifications for Data Analyses .......................................... 12 
10 
Study Subjects .................................................................................... 16 
10.1 
Disposition of Subjects and Discontinuations .................................... 16 
10 .2 
Protocol Deviations ............................................................................ 17 
10.2.1 
Important Protocol Deviations ............................................................ 17 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set ................... 17 
11 
Demographics and Other Baseline Characteristics ............................. 17 
11.1 
Demographics ..................................................................................... 18 
11.2 
Medical History .................................................................................. 18 
11.3 
Disease History and Prior Anti-Cancer Therapies .............................. 19 
12 
Previous or Concomitant Medications/Procedures ............................. 20 
13 
Treatment Compliance and Exposure ................................................. 21 
14 
Efficacy Analyses ............................................................................... 22 
14.1 
Progression Free Survival ................................................................... 22 
14.2 
Best Overall Response & Disease Control Rate ................................. 23 
14.3 
Swimlane Plots ................................................................................... 26 
15 
Safety Analyses .................................................................................. 26 
15.1 
Dose Limiting Toxicities .................................................................... 26 
15.2 
Adverse Events ................................................................................... 26 
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FIH Study of M4112 as Single Ageut aud in Combiuatious 
MS201408-000S 
15.2.1 
All Adverse Events ............................................................................. 27 
15.3 
Deaths, Other Serious Adverse Events, and Adverse Events of 
Special Interest.. .................................................................................. 28 
15.3.1 
Deaths ................................................................................................. 28 
15.3.2 
Serious Adverse Events ...................................................................... 29 
15.3.3 
Adverse Events of Special Interest ..................................................... 29 
15.4 
Clinical Laboratory Evaluation. .......................................................... 29 
15.5 
Vital Signs .......................................................................................... 31 
15.6 
Electrocardiograms ............................................................................. 31 
15.6.1 
Relationship of QTc Changes to Treatment Exposure ...................... .32 
15.7 
ECOG Perfonnance Status ................................................................ .33 
16 
Analyses of Other Endpoints ............................................................. .33 
16.1 
Pharmacokinetics ................................................................................ 33 
16.1.1 
Plasma Concentrations ........................................................................ 33 
16.1.2 
Plasma Pharmacokinetic Parameters ................................................. .34 
• --
17 
18 
18.1 
18.2 
References .......................................................................................... .38 
Appendices ......................................................................................... 39 
Protocol Deviations Identified by Programming and Clinically 
Important Events ................................................................................. 39 
Integrated Analysis Plan for SMCs .... Error! Bookmark not defined. 
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1\14112 
MS201408-000S 
2 
AE 
AESI 
ATC 
AUC 
AUCo-s 
AUCo-s/Dose 
■ 
BMI 
BOR 
CI 
CIPD 
Cm.x 
Cm../Dose 
Cp,. 
Cp,./Dose 
CnDn 
CR 
CRF 
CRO 
CSR 
CTMS 
CV% 
DCR 
DLT 
ECG 
ECOG 
GeoCVo/o 
GeoMean 
GBS 
IAP 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
List of Abbreviations and Definition of Terms 
Adverse Event 
Adverse Event of Special Interest 
Anatomical Therapeutic Chemical 
Area under the concentration-time curve 
AUC from time zero(= dosing time) to 8 hours postdose 
Dose-normalized AUCo-s 
-
Body Mass Index 
Best Overall Response 
Confidence Inteival 
Clinically Important Protocol Deviation 
Maximum Observed Concentration 
Dose-normalized Cm.x 
Predose (trough) observed concentration 
Dose-normalized Cp,. 
Cycle and Study Day, e.g., Cycle 1 Day 1 (ClDl), Cycle 2 Day 1 (C2Dl) 
Complete Response 
Case Report Form 
Contract Research Organization 
Clinical Study Report 
Clinical Trial Management System 
Coefficient of Variation 
Disease Control Rate 
Dose Limiting Toxicity 
Electrocardiogram 
Eastern Cooperative Oncology Group 
Geometric Coefficient of Variation 
Geometric Mean 
Global Biostatistics 
Integrated Analysis Plan 
5168 


1\14112 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
MS201408-000S 
ICH 
International Conference on Hannonization 
irAE 
Immune-Related Adverse Event 
LLN 
Lower Limit of Normal 
LLOQ 
Lower limit of quantification of the assay 
LPS 
Lipopolysaccharide 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
N 
Number of subjects 
n 
Number of non-missing values 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
NR 
No Result 
PCSA 
Potentially Clinically Significant Abnormalities 
PD 
Progressive Disease 
Pd 
Pharmacodynamics 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Tenn 
QTcF 
QT interval with Frederica's correction 
R.«(AUC0-8) 
Accumulation factor to assess the increase in exposure via AUC0-s following 
multiple dosing 
R.«(em.x) 
Accumulation factor to assess the increase in maximum concentration following 
multiple dosing 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
SMC 
Safety Monitoring Conunittee 
SOC 
System Organ Class 
6168 


1\14112 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
MS201408-000S 
StDev 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
t..x 
Time to reach the maximum observed concentration 
■ 
-
ULN 
Upper Limit of Normal 
ULOQ 
Upper limit of quantification of the assay 
WHO-DD 
World Health Organization Drug Dictionary 
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1\14112 
MS201408-000S 
3 
Unique 
Identifier for 
Version 
1.0 
4 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
Modification History 
Date of 
Author 
Changes from the Previous Version 
IAP Version 
07 Feb 2019 
PPD 
I 
N/A - First version 
Purpose of the Integrated Analysis Plan 
The purpose of this Integrated Analysis Plan (IAP), authored together by Biostatistics and 
Quantitative Pharmacology, is to document technical and detailed specifications for the final 
analysis of data collected for the M4112 monotherapy dose escalation phase of protocol 
MS201408-000S. Due to termination of the study prior to commencement of Part IB and Part IC, 
only analyses for Part IA are covered in this IAP. Results of the analyses described in this IAP 
may be included in the Clinical Study Report (CSR) or a separate report. Additionally, the planned 
analyses identified in this IAP may be included in regulatory submissions or future manuscripts. 
Any post-hoc, or unplanned analyses performed to provide results for inclusion in the CSR but not 
identified in this prospective IAP will be clearly identified in the CSR 
A separate Statistical Analysis Plan (SAP) has been created to document analyses prepared for 
Safety Monitoring Committee (SMC) meetings (Appendix 18.2). The IAP is based upon Section 
8 (Statistics) of the study protocol and protocol amendments and is prepared in compliance with 
ICHE9. 
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FIB Study ofM4112 as Single Agent and in Combinations 
5 
5.1 
Primary 
Objective 
Secondary 
Objectives 
Exploratory 
Objectives 
Objectives and Endpoints 
Part IA (Dose Escalation - M4112 as Single Agent) 
Objective 
Endpoint 
• To determine safety and tolerability 
• DL Ts in subjects receiving M4112 as single 
or, if observed, tile MTD, and to 
agent during the first 4 weeks (Day 1 to 
define the RP2D of M4112 as single 
Day 28 of Cycle 1) of treatment 
agent in subjects with solid tumors 
• TEAEs and TRAEs according to NCI-
CTCAE 4.03 (including deaths) in subjects 
receiving M4112 as single agent from start 
of treatment up to tile last Safety Follow-up 
Visij 
• Treatment-€mergent changes from 
baseline in clinical laboratory measures, 
vital signs, ECOG PS, and physical 
examination findings in subjects receiving 
M4112 as single agent up to the last Safety 
Follow-up Visit 
• To characterize the PK parameters 
• Plasma PK parameters for M4112: AUC.,., 
of M4112 as single agent 
Cmax, !max, AUC0-Mlo6e, C""""o" (Days 1 
and 15 of Cycle 1 ); Raoc{AucO<IJ and 
R.cc{cmaxi (Day 15/Day 1 of Cycle 1 J; Cpre, 
and c...,,, ... (Days 8 and 15 of Cycle 1 and 
Day 1 of Cycle 2) 
• To assess QT prolongation potential 
• Slope of concentration-QTc (cQTc) 
by central tendency, outlier analysis 
regression based on time-matched ECG 
and tile slope of exposure-a Tc 
readings (3 or more replicates) and PK 
analysis to evaluate preliminary 
samples during Cycle 1 at Day 1 and Day 
clinical activity parameters using 
15, central tendency and outlier analyses 
RECIST 1.1 
for absolute QTcF, and delta QTc 
• To evaluate preliminary clinical 
• BOR, OCR, and PFS using RECIST 1.1, up 
activity parameters using RECIST 
to confirmed tumor progression 
1.1 
IAP 
Section 
15.1 
15.2, 
15.3 
15.4, 
15.5, 
15.7 
16.1.2 
15.6.1 
14.1, 
14.2 
16.2 
16.2 
9168 


1\14112 
MS201408-000S 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
AUC = area under tile concentration-time curve; AUCo-s = AUC from time zero(= dosing time) to 8 hours 
postdose; AUC~Dose = dose-normalized AUCo-s; BOR = best overall response; Cmax = maximum observed 
concentration; Cmar/Oose = dose-normalized Cmax; Cp<e = predose (trough) observed concentration; Cp,e/Oose = 
dose-normalized C0,.; OCR = disease control rate; DL T = dose limiting toxicity; PFS = progression free survival; 
PK = pharmacokinetic; Raccc,.ucO<IJ = accumulation factor to assess the increase in exposure via AUC.,,, following 
multiple dosing; R.,~cma,:J = accumulation factor to assess the increase in maximum concentration following 
multiple dosing; TEAE = treatment emergent adverse event Ima,= time to reach the maximum observed 
concentration. 
6 
Overview of Planned Analyses 
The planned analyses have been impacted by the decision to terminate this study early, prior to 
commencement of Parts m and IC. In addition to the SMC analyses (detailed in a separate SAP, 
finalized on 30 Jan 2018), only a single, abbreviated final analysis will be performed. This final 
analysis will occur only after the last subject has completed the treatment phase of the study, with 
all study data in-house, all data queries resolved, and the database locked. 
A data review meeting will be held prior to database lock. In addition, no database can be locked 
until this IAP has been approved. 
7 
Changes to the Planned Analyses in the Clinical Study 
Protocol 
The following protocol-specified analyses will not be completed: 
• Duration of response (DOR) and time to tumor response 
• Concentration-QTc slope analysis of time-matched, replicate ECGs and PK samples 
o Summary statistics and scatterplots will be produced instead of linear modeling 
(Section 15.6.1) 
The PK parameters specified for calculation in the protocol included Cmm (defined a~ minimum 
observed postdose [trough] concentration) and Cmm/Dose. These parameters have been 
revised/clarified to Cp,. and Cp,./Dose, where Cp,. is defined as the predose (trough) observed 
concentration and may not reflect the true value at the end of the dosing interval. 
The Dose Escalation Analysis Set was renamed to ''DLT Analysis Set''. The definition was updated 
for clarifications. 
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l\14112 
MS201408-000S 
FIB Study ofM4112 as Single Agent and in Combinations 
8 
8.1 
Protocol Deviations and Analysis Sets 
Definition of Protocol Deviations and Analysis Sets 
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject's rights, safety, or well-being. They are coded as "Critical" or "Major" in the Clinical Trial 
Management System (C1MS) if identified via monitoring; they may also be identified from the 
database by medical review or programmatically. 
The subject-level important protocol deviations to be identified by programming for this study 
are defined in Section 18.1. 
The following types of deviations will be identified and confumed prior to or at the Data Review 
Meeting at the latest: 
• Deviations from the inclusion and exclusion criteria 
• Deviations post inclusion 
• Clinically important protocol deviations (CIPDs) are defined as deviations leading to the 
exclusion of a subject from an analysis set (refer to Section 8.2) 
Other events/factors related to PK, which include, but may not be limited to, events that could 
affect PK, will be evaluated on a case-by-case basis by the PK Scientist: 
• Vomiting immediately following oral dosing 
• Sample processing errors that may lead to inaccurate bioanalytical results 
• Incomplete data (e.g. due to lost samples, insufficient sample volumes for assay) 
• Inaccurate dosing, dose reductions, missed dose(s) just prior to a PK dose, or dosing errors 
In case of a deviation or event that may affect PK data, collected PK data which is likely to be 
affected may be excluded from the study results after consultation and agreement with Sponsor or 
Sponsor representative. 
In general, data will not be excluded from the PK Analysis Set because of large PK sampling time 
deviations (since actual elapsed times will be used for PK analysis) or inadequate fasting prior to 
or following a PK dose. Additionally, given the patient population involved, data will not be 
excluded for an inaccurate dosing interval prior to a PK dose (though the affected doses will be 
identified in a data listing), or for concomitant medication violations. 
All important protocol deviations are documented in SD1M datasets whether identified through 
site monitoring, medical review, or programming 
Protocol deviations will be classified as CIPDs or not, and confumed prior to or at the Data Review 
Meeting before database lock. 
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l\14112 
MS201408-000S 
8.2 
FIB Study ofM4112 as Single Agent and in Combinations 
Definition of Analysis Sets and Subgroups 
The analysis sets of subjects whose data will be included in the analyses described in this IAP are 
defined in Table I. 
Table I 
Analysis Sets 
Population 
Description 
Screening (SCR) 
All subjects who sign informed consent 
DLT 
All subjects who received at least one dose of study intervention and meet at least 
one of tile following cliteria: 
- Received at least 5 planned cumulative total daily doses of M4112 in the first 
cycle (first 28 days) 
or 
- E)(l)erienced at least one DL T during tile DL T period, regardless of the 
administered number of doses of study intervention/completion of the DL T period 
Safety 
The Safety Analysis Set will include all subjects who receive at least 1 dose of study 
treatment. 
Concentration-QTc 
The cQTc Analysis Set will include all subjects with at least baseline and one on 
Analysis Set 
treatment measurement of time-matched ECG and M4112 plasma concentration 
collected durino the dose-escalation chase. 
M4112 Pharmacokinetic 
All subjects from tile Safety Analysis Set withoU1 clinically important protocol 
deviations/violations or events that would affect PK (see Section 8.1 ). Subjects in the 
PK Analysis Set must have received at least 1 dose of M41 12 and must have 
sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK 
parameter. Sufficient concentration data is defined as at least 3 valid, postdose 
concentration points in the PK profile to obtain any PK parameter. 
Phanmacodynamics 
All subjects who received at least 1 dose of M4112 and provide the predose and at 
least 1 postdose sample for Pd assessment. 
cQTc = concentration-QTc response; OLT = dose-limiting toxicities; ECG = electrocardiogram; 
Pd = pharmacodynamics; PK= pharmacokinetic; QTc = corrected QT interval. 
There are no subgroup analyses planned for this study. 
9 
General Specifications for Data Analyses 
All analyses will be prepared by planned dose level, unless indicated otherwise. 
Details on PK data presentation can be found in Section 16.1. 
Data handling after cut-off date: 
In general, this is not applicable, as the analyses described will be conducted after all subjects have 
completed their involvement in the study. 
Pooling of centers: 
Because of the small number of subjects in each center, data will be pooled across centers. 
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Significance level: 
There is no formal significance level for this study and all analyses are considered descriptive. 
Presentation of continuous and qualitative variables for Demographics and Other Baseline 
Characte1istics, Efficacy, and Safety: 
Continuous variables will be summarized using descriptive statistics, i.e. 
• number of subjects (N), number of nonmissing values (n) 
• mean, standard deviation 
• median, 25th Percentile - 75th Percentile (Ql-Q3), minimum, and maximum 
If there are no missing values this should be indicated by a 0. 
Qualitative variables will be summarized by counts and percentages. 
Unless otherwise stated, the calculation of proportions will be based on the number of subjects of 
the analysis set of interest. Therefore, counts of missing observations will be included in the 
denominator and presented as a separate category. 
In case the analysis refers only to certain visits, percentages will be based on the number of subjects 
still present in the study at that visit, unless otherwise specified. 
Definition of baseline: 
In general, the last nonmissing measurement prior to the first study treatment will serve as the 
baseline measurement. If an assessment is planned to be performed prior to the first dose of study 
treatment in the protocol and the assessment is performed on the same day as the first dose of study 
treatment, it will be assumed that it was performed prior to study treatment administration if 
assessment time point is not collected or is missing. If assessment time points are collected, the 
observed time point will be used to determine predose on Study Day 1 for baseline calculation. 
Unscheduled assessments will be used in the determination of baseline. However, if time is 
missing, an unscheduled assessment on Study Day 1 will be considered to have been obtained after 
study treatment administration. 
Definition of duration: 
Duration will be calculated by the difference of start and stop date + 1, if not otherwise specified 
(e.g., survival time (days) = date of death-date of first study treatment + 1). 
The time since an event (e.g., time since first diagnosis) will be calculated as reference date minus 
date of event. 
Definition of study day/treatment day: 
Treatment day is defined relative to the date of first dose of any study treatment. Day 1 represents 
the first day of treatment; the day before is defined as Day-1 (no Day O is defined). 
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Definition of treatment pe1iod: 
On-treatment period is defined as the time from the first dose of study treatment through minimum 
(30 days + last dose of study treatment, start day of new anticancer drug therapy- 1 day). 
Conversion factors and reporting standards: 
The following conversion factors will be used to convert days into months or years: 
1 week= 7 days, 1 month= 30.437S days, 1 year= 36S.2S days. 
For reporting conventions, mean, median, Ql, Q3, min, and max will have the same precision 
(number of digits) as SDTM data for non-derived values; standard deviation will have one 
additional decimal place. Percentages will be reported to one decimal place. The rounding will be 
performed to closest integer/first decimal using the common midpoint between the two 
consecutive values (e.g., S. l to S.4 will be rounded to an integer of S, and S.S to S.9 will be rounded 
to an integer of 6). 
Unscheduled visits: 
Data collected at unscheduled visits will be included and analyzed in the same fashion as the data 
collected at sclJeduled visits except where otherwise noted in the sections that follow. Descriptive 
statistics (mean, StDev, median, minimum, maximum, and quartiles) by nominal visit or time point 
for safety endpoints such as laboratory measurements, ECGs, and vital signs will include only data 
from scheduled visits. 
Summary statistics ove1· time: 
For descriptive statistics over time by nominal visit or time point (for non-PK data only), only 
those planned visits/time points that have at least S subjects overall (regardless of the number in 
each planned dosing cohort) will be included in the summary tables and figures. The exception is 
the End-of-Treatment and Safety Follow-up visits, which will be included in the summary statistics 
regardless of the number of subjects who completed the visit. 
Visit windoning: 
The assignment of visit window is described in Table 2 for the pUlJ)Ose of by-visit analyses of 
laboratory assessment, vital sign, and ECG data: 
• Baseline will be derived as described above. 
• Both scheduled and unsclJeduled assessments are included for visit windowing. 
• No visit windowing will be performed at End-of-Treatment or Safety Follow-up visits. 
Instead, the earliest nonmissing observation among the unscheduled or scheduled 
assessments for each visit will be used for the analysis. 
• If there are multiple assessments for any specified visit and some of them are from scheduled 
visits with nonmissing assessment results, the assessment from scheduled visit that is closest 
to the planned study day will be used for analysis. If two scheduled visits are equally spaced 
around the assigned study day, the earlier of the two will be used. 
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• If there are multiple assessments for any specified visit and none of them are from scheduled 
visits, the assessment with nonmissing results and closest to the planned study day will be 
used for analysis. 
• If there are two or more unscheduled assessments with nonmissing results and the same 
distance to the planned study day, the assessment prior to the planned study day will be used 
in deriving visit window. For example, if the lab assessment was done on both Study Day -1 
and 1, then the assessment on Study Day -1 will be used for visit windowing. 
Table 2 
Visit '\Vindow Definition for Safety Assessment 
Assigned Study Day 
Planned Study 
Analysis 
Anal~-sis Visit 
A.sstssme-nts 
(lnclusrre) 
Day 
Visit (N) 
(AVIsm 
(AWTARGEn 
(AVISITN) 
From 
To 
(A\\'LO) 
(AWHI) 
-28 
I 
0 
Screening 
Lab, VS, ECG 
-1 
2 
I 
I.I 
Cycle I Day I 
Lab, VS, ECG 
7 
9 
8 
1.8 
Cycle I Day 8 
Lab, VS, ECG 
14 
16 
15 
1.15 
Cycle I Day 15 
Lab, VS, ECG 
21 
23 
22 
1.22 
Cycle I Day 22 
Lab, VS 
28 
30 
29 
2.1 
Cycle 2 Day I 
Lab, VS, ECG 
42 
44 
43 
2.15 
Cycle 2 Day 15 
Lab, VS 
54 
60 
57 
3.1 
Cycle 3 Day I 
Lab, VS 
68 
74 
71 
3.15 
Cycle 3 Day 15 
Lab, VS 
82 
88 
85 
4.1 
Cycle4 Day I 
Lab, VS, ECG 
96 
102 
99 
4.15 
Cycle 4 Day 15 
Lab, VS 
110 
116 
113 
5.1 
Cycle 5 Day I 
Lab, VS 
124 
130 
127 
5.15 
Cycle 5 Day 15 
Lab, VS 
Further windows can be calculated based on the following general algorithm starting from the 
planned study day in Cycle X: 
Planned study days in Cycle X = (X- 1) * 28 + 1 and (X - l ) * 28 + 15 
Assigned study days (inclusive) = [(X- 1) * 28 - 3] days to [(X - l) • 28 + 3] days 
Handling of missing data: 
Unless otherwise specified, missing data will not be replaced. 
In all subject data listings, imputed values will be presented and flagged as such. 
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Missing statistics (e.g., when they cannot be calculated) should be presented as "nd". For example, 
if n= 1, the measure of variability (StDev) cannot be computed and should be presented as "nd". 
Where tables are presented over different time points, the total of missing and nonmissing 
obseivations at each time-point should reflect the population still in the study at that time. This 
does not apply when imputations are made beyond study withdrawal. For example, if a subject is 
still in the study at the time-point but with missing data, they should be counted in the number of 
missing obseivations. 
Handling of missing data for PK parameter calculations are discussed under Section 16.1. 
Pharmacokinetic parameters will be derived using the validated compute!..P!,ogram Phoenix® 
WinNonlin® 6.4 or higher, and/or SAS® (Statistical Analysis System,f PD 
,- .- '--,.'--'"' J 
) Windows Version 9 .4 or higher. All other analyses will be performed usmg SAS® 
~e-.---=~ 
Windows Version 9.4 or higher. For the outputs of the Bayesian two parameter logistic model 
updates, East 6.0 or R (version 3.1.0 or higher [3]) and the R package berm (4] or CRMpack or 
SAS proc MCMC will be used. 
10 
Study Subjects 
The subsections in this section include specifications for reporting subject disposition and 
treatment/study discontinuations. Additionally, procedures for reporting protocol deviations are 
provided 
10.1 
Disposition of Subjects and Discontinuations 
The following will be summarized overall and by planned dose level, with the percentages 
calculated based on the number of subjects in the Screening Analysis Set. 
• Total number of subjects screened (i.e., subjects who gave informed consent) 
• Number of subjects who discontinued from the study prior to treatment overall and grouped 
by the main reason (e.g., the failed specific inclusion or exclusion criteria, withdrawal of 
consent) 
• Number of treated subjects 
• Number of subjects who completed the dose escalation period 
• Number of subjects who discontinued the treatment, grouped by main reason 
• Number of treated subjects who discontinued the study, grouped by main reason 
The percentages for subjects treated will be based on the number of subjects in the safety 
population for each treatment sequence and on the number of screened subjects in the overall 
group. 
In the corresponding individual listing, date of informed consent, protocol version, first and last 
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date of dosing and study termination date will be presented, as well as primary reason for study 
and treatment discontinuation. 
The listing of screening failures will include the following information: 
• 
Date of informed consent 
• 
Protocol version 
• 
Date of screening failure 
• 
Reason for noninclusion 
The disposition listings will be sorted by dose group and subject ID. 
10.2 
10.2.1 
Protocol Deviations 
Important Protocol Deviations 
The following summary tables and listings of important protocol deviations will be provided 
(separately for pre-/postinclusion deviations): 
• Frequency table per reason of important protocol deviations 
• Listing of important protocol deviations 
Important protocol deviations will be determined for all subjects by either medical or PK review 
processes or programming hased on the inclusion/exclusion criteria or other criteria presented in 
the protocol or described in Section 18.1. 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set 
The exclusion of subjects from analysis populations, e.g. due to clinically important protocol 
deviations, will be summarized by counts and frequencies for all occurring reasons of exclusion 
for each analysis population. 
Exclusions will also be listed, including: 
• 
Population that the subject is excluded from 
• 
Reason of exclusion 
11 
Demographic.s and Other Baseline Characteristics 
If not stated otherwise, •mmmariP.s will be presented for the Safety Analysis Set. 
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11.1 
Demographic.s 
Demographic characteristics will be listed (sorted by dose group and subject ID) and summarized 
by dose group and overall as follows: 
• Demographic characteristics 
-
Gender: Male, Female 
-
Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Not Collected, Other 
-
Ethnic origin: Hispanic/Latino (Yes/No), Japanese (Yes/No) 
-
Age (years): summary statistics 
-
Age categories: 
• < 65 years, ~ 65 years 
• < 65, 65 - 74, 75 - 84, ~ 85 
-
Eastern Cooperative Oncology Group (ECOG) Performance Status 
• Physical measurements 
-
Height (cm) 
-
Weight (kg) 
-
Body Mass Index (BMI) (kglm2) 
Specifications for computation: 
• Age [years] = (date of given informed consent - date of birth + 1) / 365.25 
-
In case of missing day for at least one date, but month and year available for both dates: 
• For the derivation of age, the day of informed consent and the day of birth will be 
set to 1 and the formula above will be used 
-
In case of missing month for at least one date, but year available for both dates: 
• For the derivation of age, the day and the month of informed consent and the day 
and month of birth will be set to 1 and the formula above will be used 
• Site codes will be used for the determination of the subject's geographic region. 
11.2 
Medical History 
Medical history will be coded using the most cUITent available version of Medical Dictionary for 
Regulatory Activities (MedDRA). Medical history will be summarized as the numbers and 
percentages of subjects by MedDRA preferred term (PT) as event category and MedDRA primary 
system organ class (SOC) as summary category. Each subject will be counted only once within 
each Pf or SOC. 
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Medical history will be displayed in terms of frequency tables: ordered by primary SOC and PT 
in alphabetical order. 
A supportive listing of medical history data by subject will include all the relevant data fields as 
collected on the "Medical History" CRF pages. 
11.3 
Disease History and Prior Anti-Cancer Therapies 
Information regarding disease characteristics collected on the "Disease History'' CRF page will be 
summarized and/or listed as follows: 
• Primary tumor histology 
• Site and subsite(s) of primary tumor 
• Time since initial cancer diagnosis (months), defined as ( date of first study treatment - date 
of initial diagnosis)/30.437S 
• Time since documented locally advanced, inoperable, or metastatic disease diagnosis 
(months), defined as (date of first study treatment - date of documented locally advanced, 
inoperable, or metastatic disease diagnosis)/30.437S 
• Time since of last progression of disease prior to study entry (months), defined as (date of 
first study treatment - date oflast disease progression)/30.437S 
• 1NM classification at initial diagnosis and at study entry 
The prior anticancer treatments and procedures are collected under "Prior anti-cancer therapy", 
"Prior anti-cancer radiotherapy", and "Prior anti-cancer surgeries" pages from the CRF. 
Prior anti-cancer drug therapy will be listed including the following information: 
• 
Regimen number 
• 
Intent and type of therapy 
• 
Reason for discontinuation 
• 
Best response 
• 
Date of documented progression disease (if applicable) 
• 
For each drug given as part of the regimen: 
-
Name of drug (coding as described in Section 12) 
-
Start and end date 
Prior anti-cancer radiotherapy will be listed including the information: 
• 
Regimen number 
• 
Location 
• 
Start and end dates 
• 
Total dose 
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• 
Number of fractions 
Prior anti-cancer surgeries will be listed including the following information: 
• 
Name of surgery 
• 
Date of surgery 
• 
Intent of surgery 
• 
Outcome of surgery 
A summary of prior anti-cancer therapies will be added to the disease history, displaying number 
of surgeries, radiotherapy regimes and anti-cancer drug regimes. 
Baseline characteristics with respect to vital signs, physical examinations, ECGs, and laboratory 
tests will be part of Section 15 (Safety Evaluation). 
12 
Previous or Concomitant Medications/Procedures 
Concomitant treatments are medications, other than study medications, which are taken by 
subjects any time during the study ( on or after the first day of study drug treatment for each subject) 
or within 30 days after last dose of study drug. 
Concomitant treatment will be summarized from the "Concomitant Medications" CRF page. ATC-
2nd level and preferred term will be tabulated as given from the WHO-DD dictionary current 
version. In case multiple ATCs are assigned to a drug, all ATC-2nd levels will be used for reporting. 
In case the date values will not allow unequivocal categorization of a medication as concomitant, 
the medication will be considered as concomitant medication. 
Pr evious medications are medications, other than study medications and premedications for study 
drug, which started before first administration of study drug. 
Previous treatment will be summarized from the "Relevant Previous Medications" CRF page. 
ATC-2nd level and preferred term will be tabulated as given from the WHO-DD dictionary cUITent 
version. In case multiple ATCs are assigned to a drug, all ATC-2nd level will be used for reporting. 
In case the date values will not allow unequivocal categorization of a medication as previous, the 
medication will be considered as previous medication. 
All reported previous medications will be listed. 
All concomitant procedures, which were undertaken at any time during the study, will be 
summarized according to the CRF page "Concomitant Procedures". Concomitant procedures will 
be classified by medical review. 
The number of subjects with concomitant procedures overall and by type of procedure (as 
classified by medical review) will be tabulated. 
All relevant concomitant medication and procedure data will be listed. 
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13 
Treatment Complianc.e and Exposure 
All dosing calculations and summaries will be based on the "M4 l 12 Administration Details" CRF 
page. The Safety Analysis Set will be used for these analyses. 
Handling of missing data 
• If the total actual dose is missing, the planned dose level as entered in the CRF will be used. 
• In case the last medication end date is incomplete, the date ofM4112 administration will be 
taken from the "M4 l l 2 Tennination" page. 
The duration of therapy (in weeks) is defined as: 
Duration= [(date of last dose - date of first dose)+ l] / 7 
The cumulative dose ofM4112 (in mg) is defined as: 
Cumulative dose (mg)= [(tablets dispensed) - (tablets returned)] • dose level (mg) 
(Summed over all dose levels taken by the subject, if dosing changes occUITed.) 
Dose intensity (mg/week) will be calculated as follows: 
Do 
· t 
·ty ( ~/meek) 
(Total cumulative dose of M4112 (mg)) 
se m ens1 
m5' ~ 
= ---.-------"-'= 
Duran on of therapy (weeks) 
The relative dose intensity(%) is defined as the dose intensity divided by the planned cumulative 
dose per cycle, calculated as follows: 
R 1 ,; 
d 
. t 
·ty (o/c) 
(Total cumulative dose ofM4112 (mg)) • lOOo/c 
e auve ose m ens1 
o = ----------"-'= 
o 
Total planned dose of M4112 (mg) 
The following ~nmmary tables by dose group and overall will be provided: 
• Duration of therapy (weeks) 
• Total number of doses taken overall 
• Cumulative dose (mg) 
• Dose intensity (mg/week) 
• Relative dose intensity (%) 
• Dose adjusttnents and missed doses 
A listing of treattnent exposure and compliance will also be created to summarize the relevant 
information for each subject: 
• 
Cycle and day in cycle 
• 
Date and time of administration 
• 
Actual dose 
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• 
Whether dose has been adjusted, and if yes, reason why 
• 
Reason for no dose (if applicable) 
14 
Efficacy Analyses 
The Safety Analysis Set will be used for all efficacy analyses, unless otherwise noted. All efficacy 
endpoints will be listed and summarized descriptively. 
14.1 
Progression Free Survival 
Progression free survival (PFS) time, according to RECIST 1.1 as assessed by the Investigator, is 
defined as the time from first study treatment to the date of the first documentation of objective 
PD or death due to any cause, whichever occurs first. 
PFS data will be censored on the date of the last adequate tumor assessment for patients who do 
not have an event (PD or death) or for patients with an event after two or more subsequent missing 
response assessments (i.e., twice the scheduled time interval between two subsequent response 
assessments -this interval is 8 weeks through Cycle 7, and 12 weeks thereafter). Patients who do 
not have a baseline tumor assessment or who do not have any postbaseline tumor assessments will 
be censored at treatment start date unless death occurred on or before the time of the second 
planned tumor assessment, in which case the death will be considered an event. 
Data will be taken from the "Assessment of Disease Based on hnaging" CRF page. The date of 
the overall response assessment is the earliest date for imaging of target, nontarget, and new lesions 
taken at that response assessment. 
The censoring and event date options to be considered for the PFS analysis are presented in 
Table 3. The last adequate tumor assessment is defined as a tumor assessment with a result other 
than "NE" or "NA" . 
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Table 3 
Outcome and E,•ent Dates for PFS Analysis 
ScenaJ'io 
Date of Event / Censoring 
Outc.ome 
No baseline assessment 
Date of first study treatment 
Censored' 
Progression or death :S xx weeks after last 
Date of progression or death 
Event 
tumor assessment or :S xx weeks after 
treatment start date, where xx is 16 weeks 
if the last assessment is at Screening or 
Cyc.Je 3 (Evaluation Visit 1 ), 20 weeks if 
the last assessment is at Cyc.Je s 
(Evaluation Visit 2), and 24 weeks if the 
last assessment is at Cyc.Je 7 (Evaluation 
Visit 3) or later. 
Progression or death > xx weeks after the 
Date of last adequate tumor 
Censored 
last tumor assessment, where xx is 16 
assessment 
weeks if the last assessment is at Screening 
or Cycle 3 (Evaluation Visit I), 20 weeks 
if the last assessment is at Cycle s 
(Evaluation Visit 2), and 24 weeks if the 
last assessment is at Cyc.le 7 (Evaluation 
Visit 3) or later. 
No progression 
Date of last adequate tumor 
Censored 
assessment 
Treatment discontinuation due to 
Not applicable 
Information collected on treatment 
"Disease progression" without 
discontinuation page is ignored since 
documented progression 
outcome should be derived based on 
documented progression only. General 
censoring rule is applied 
New anti-<:a.ncer therapy given 
Date of last adequate tumor 
Censored 
assessment before anti-<:ancer 
therapy is given 
•If the subject dies 5 16 weeks after treatment start date, the death is an event with date on death date. 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summaiy of 
associated statistics (median swvival time; 6- and 12-month swvival rate estimates) including the 
corresponding two-sided 95% confidence inteivals (Cls). The CI for the median will be calculated 
according to Brookmeyer and Crowley (1982), and Cls for the swvival function estimates at the 
aforementioned time points will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (1980) (conftype=loglog default option in SAS PROC LIFETEST). The 
estimate of the standard error will be computed using Greenwood's formula. 
14.2 
Best Overall Response & Disease Control Rate 
Best Overall Response (BOR) will be determined according to RECIST 1.1. It is defined as the 
best response obtained among all tumor assessment visits after the date of first study drug 
administration until documented disease progression. The BOR rate is defined as the number of 
subjects with BOR either confumed CR or PR, relative to the number of subjects belonging to the 
study of interest. 
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Only tumor assessments performed before the start of any further anticancer treatment will be 
considered in the assessment ofBOR Clinical deterioration will not be considered as doctm1ented 
disease progression. BOR will be based on the investigator assessment of overall response and is 
defined as the best result obtained among all tumor assessment visits from baseline until end of 
treatment or determination of progressive disease. Local evaluations of target, non-target and new 
lesions are used to assess BOR The date of the overall response assessment is the earliest date for 
imaging of target, non-target and new lesions of images taken at that response assessment. 
BOR will be defined as the best response across all time points (for example, a subject who has 
SD at the first assessment, PR at the second assessment, and PD at the last assessment has a BOR 
of PR). The order to obtain the BOR is the following: CR, PR, SD, PD and NE. 
BOR will be sllllllllarized by tabulating the ntm1ber and percentage of subjects with CR, PR, SD, 
PD or NE as BOR The table will also include the objective response rate (ORR) and the 
corresponding 95% Clopper-Pearson confidence intervals (Clopper & Pearson, 1934). The ORR 
will be defined as the rate of subjects who achieve either a CR or PR 
Disease control rate (DCR) is based on each subject's confirmed BOR according to RECIST 1.1 
as assessed by the Investigator. Ttmlor assessments after the treatment start date, and prior to 
doctm1ented disease progression or start of further anticancer treatment are taken into 
consideration in deriving the BOR Clinical deterioration is not considered as doctm1ented disease 
progression. If a tumor assessment was performed on the same day as the start of a new anti-cancer 
therapy, it is assumed that the tumor assessment was performed prior to the start of the new anti-
cancer therapy; therefore, this tumor assessment is included in the assessment ofBOR 
Table 4 summarizes the derivation rules described by Eisenhauer, et al. for the BOR when 
confirmation from subsequent assessment is needed. 
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Table4 
Ovel'all Response 
1st Time Point 
CR 
CR 
CR 
CR 
CR 
PR 
PR 
PR 
PR 
PR 
NE 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
Best Overall Response \Vben Confir mation of Response is Required 
Overall Response 
Subsequent Time 
Best Overall Response 
Point 
CR 
CR 
PR 
SD,PD or PR' 
SD 
SD provided minimum criteria for SD duration met; otherwise, PD 
PD 
SD provided minimum criteria for SD duration met; otherwise, PD 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
CR 
PR 
PR 
PR 
SD 
SD 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
NE 
NE 
CR= complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = nonevaluable. 
• If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would 
depend on whether minimum duration for SD was met. Howe,,er, sometimes 'CR' may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the subject had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR 
Disease control is defined as BOR of CR, PR, or SD. Both CR and PR must be confumed by repeat 
assessment performed at least 4 weeks after the criteria for response are first met. Confumation of 
response must not necessarily be at the next scan, but could be at any subsequent scan before PD. 
When SD is believed to be the best response, the assessment must be at least 6 weeks after the start 
of a trial drug, and measurements must have met the SD criteria at least once. If thP minimum time 
of 6 weeks is not met, the subject's BOR depends on the subsequent assessments. For example, a 
subject who has SD at the first assessment, PD at the second assessment and does not meet the 
minimum duration for SD, will have a BOR of PD. The same subject lost to follow-up after the 
first SD assessment would be considered NE for BOR 
DCR will be calculated by dose level and overall, along with the overall two-sided 95% CI using 
the Clopper-Pearson method (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option). 
The listing of tumor assessments (including e.g. lesion number, description and location, type of 
lesion, imaging date, assessment method, diameter (mm), sum of diameter of target lesions (mm), 
BOR (confumed and unconfumed) will be provided by subject as recorded from the "Target 
Lesions", "Sum of Diameters", ''Non-Target Lesions", "New Lesions" and "Assessment of disease 
based on imaging" CRF pages. 
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14.3 
FIB Study ofM4112 as Single Agent and in Combinations 
Swimlane Plots 
A swimlane plot displaying some key radiological milestones will be produced, color-coded by 
planned dose level. Time in weeks will be displayed along the horizontal axis, and subject ID along 
the vertical axis. Subjects will be arranged from top to bottom in descending order of follow-up 
time. For each subject, the time from treatment start until end of follow-up will be represented by 
a horizontal bar. In addition, there will be different symbols to mark the following events: 
confirmed CR, confirmed PR, ongoing SD, PD, end of treatment, and death. 
15 
Safety Analyses 
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical studies such as adverse events (AEs), laboratory tests and vital signs. 
Safety analyses will be done on the Safety Analysis Set, unless otherwise specified. 
15.1 
Dose Limiting Toxicities 
The occurrence of dose limiting toxicities (DLTs) during the DLT evaluation period (i.e., during 
the first treatment cycle of28 days) is a primary endpoint of this study. The DLT set will be used 
for the analysis of the primary endpoint. Please refer to Section 6.2.4 of the Clinical Study Protocol 
MS201408--000S for the detailed definition of a DL T. 
The number and proportion of subjects experiencing DLTs will be reported by dose level Posterior 
probabilities (2.5%, 25%, SO%, 75%, and 97.5% quantiles) for a DLT by tested dose level will be 
estimated using the BLRM specified in the protocol. 
Details of the DLTs will be presented in a listing sorted by SOC and PT, including: DLT, SOC, 
PT, relationship to M4112, seriousness, dose group, time since last and first administration of 
M4112, and subject's age/sex/site of primary tumor. 
In addition, a DLT profile plot of all subjects in the Safety Analysis Set will be produced. This 
will show a closed square for all subjects who were considered evaluable (in DLT set) and did not 
have a DLT during Cycle 1, an open square for those who experienced a DLT during Cycle 1, and 
an open circle for those who were excluded from the DLT Set. This plot will have Cohort Number 
on the x-axis and dose level (mg) on the y-axis. 
15.2 
Adverse Events 
The severity of AEs will be graded using the NCI-CTCAE v4.03. If a particular AE's severity is 
not specifically graded by this guidance, the Investigator uses the general NCI-CTCAE definitions 
of Grade 1 through Grade S following his or her best medical judgment. The latest MedDRA 
version at the time of data cut-off will be used to code AEs according to System Organ Class 
(SOC) and Preferred Term (PT). 
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• Treatment Emergent Adverse Events (TEAEs) are events with onset dates occturing 
during the on-treatment period, or those that worsen in severity during the on-treatment 
period. All analyses will be based on TEAEs unless otherwise specified. 
• Related Advene Events have a relationship to study treatment of"Related" as reported by 
the Investigator on the Adverse Events CRF page, or unknown (i.e., no answer to the 
question "Relationship M4112"). 
• Se1ious Adverse Events (SAEs) are those recorded on the Adverse Events CRF page as 
Serious Adverse Event= "Yes". 
• Adverse Events Leading to Treatment Discontinuation are those recorded on the Adverse 
Events CRF page as Action(s) taken with M4112 = "Drug withdrawn". 
• Adverse Events Leading to Dose l\fodifications are those recorded on the Adverse Events 
CRF page as Action(s) taken with M4112 = "Dose reduced". 
• Adverse Events Leading to Treatment Interruption are those recorded on the Adverse 
Events CRF page as Action(s) taken with M4112 = "Drug interrupted". 
• Adverse Events Leading to Death are those recorded on the Adverse Events CRF page as 
Outcome= "Fatal" as well as AEs of Grade 5. 
• Adverse Events of Special Interest (AESis) for M4112 include liver toxicities and 
immune-related AEs (irAEs) / autoimmune disorders. Any AESI is indicated as such by the 
Investigator on the Adverse Events CRF page and is also reported as an SAE. 
Incomplete AE-related dates will be handled as follows: 
• In case the onset date is missing completely or missing partially but the onset month and 
year, or the onset year are equal to the start of study treatment then the onset date will be 
replaced by the minimum of start of study treatment and AE resolution date. 
• In all other cases the missing onset day or missing onset month will be replaced by 1. 
• Incomplete stop dates will be replaced by the last day of the month (if day is missing only), 
if not resulting in a date later than the date of subject's death. In the latter case the date of 
death will be used to impute the incomplete stop date. 
• In all other cases the incomplete stop date will not be imputed. If stop date of AE is after date 
of cut-off, outcome of AE is ongoing at cut-off. 
• Further information after cut-off (like fatal outcome) might be taken from safety database 
and included separately into CSR 
15.2.1 
All Adverse Events 
Adverse events will be summarized by worst severity per subject, using MedDRA PT as event 
category and SOC as summary category, in alphabetical order. If an AE is reported for a given 
subject more than once during treatment, the worst severity and the worst relationship to study 
treatment will be tabulated. 
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There will be a listing of all AEs, sorted by SOC and Pf. 
The following frequency tables will be prepared, by dose level and overall; in addition, the tables 
will be provided by Pf and primary SOC in alphabetical order: 
• AnyTEAE 
• TEAEs related to M4112 
• Any serious TEAEs 
• Any nonserious TEAEs 
• Any serious TEAEs related to M4112 
• TEAEs with NCI-CTCAE severity Grade ~ 3 
• TEAEs related to M4112 with NCI-CTCAE severity Grade ~ 3 
• TEAEs leading to treatment discontinuation, dose modification, treatment interruption, and 
death 
• TEAEs related to M4112 leading to treatment discontinuation, dose modification, treatment 
interruption, and death 
• AESis 
• TEAEs by SOC and Pf 
Clinical hial.gov and EudraCT requirements 
Summary tables for nonserious AEs, applying frequency threshold of S% when excluding SAEs, 
by SOC and Pf, will be provided. 
15.3 
Deaths, Other Serious Adverse Events, and Adverse Events of 
Special Interest 
15.3.1 
Deaths 
The following will be tabulated based on information from the "Death" CRF page. 
• Number of deaths 
• Number of deaths within 30 days after last dose ofM4112 
• Number of deaths within 60 days after first dose ofM4112 
• Reason for death 
In addition, date and cause of death will be provided in an individual subject data listing together 
with selected study treatment information ( dose level and date of first / last administration). This 
listing will also include flags for death within 30 days of last study treatment and death within 60 
days of first study treatment, as well as MedDRA coding for AEs with fatal outcome (including 
those with a toxicity grade of S and those with an outcome of "fatal"). 
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15.3.2 
Serious Adverse Events 
A listing will display all SA.Es, sorted by SOC and PT, including: AE, SOC, PT, relationship to 
M4112, planned dose level, time since last and since first administration ofM4112, and subject's 
age, sex, and race (also see Section 15.2.1). 
15.3.3 
Adverse Events of Special Interest 
A listing of all AESis will be provided, sorted by SOC and PT, including: AE, SOC, PT, 
relationship to M4112, planned dose level, time since last and since first administration ofM4 l 12, 
and subject's age, sex, and race (also see Section 15.2.1). 
15.4 
Clinical Laboratory Evaluation 
On-study laboratory assessments are any sample collected after the first administration of any 
study drug, and within 30 days from last study drug administration. 
Laboratory results will be classified according to the NCI-CTC Version 4.03 as provided by the 
central laboratory. Additional laboratory results that are not part ofNCI-CTC will be presented 
according to the categories: below normal limits, within normal limits and above normal limits 
( according to the laboratory normal ranges). 
The worst on-study grade (from any visit, scheduled or unscheduled) will be summarized 
considering only subjects with postbaseline laboratory samples: Laboratory tests by NCI-CTC 
grade (0, 1, 2, 3, 4, any). 
Quantitative data will be examined for trends using descriptive statistics (mean, StDev, median, 
Ql , Q3, minimum, and maximum) of actual values and changes from baseline to each visit over 
time. Qualitative data based on reference ranges will be described according to the categories (i.e., 
Low, Normal, and High). The number of subjects with clinical laboratory values below, within, or 
above normal ranges at baseline compared to endpoint will be tabulated for each test by dose level. 
Shift tables of baseline versus endpoint (as well as the worst value at any post-baseline visit) will 
be presented. Abnormalities classified according to NCI-CTCAE toxicity grading version 4.03 
will be described using the worst grade. In case of missing data at the end of the treatment period, 
the last known postbaseline value will be carried forward. 
NCI-CTC grades available: 
Shifts from baseline in NCI-CTC grade to the worst postbaseline grade will be summarized 
separately for hematology and chemistry laboratory parameters. Each summary will be presented 
by parameter for each dose level and overall. 
The categories for worst post-baseline grade are as follows: 
• Any higher grade 
• Grade3 or4 
• Grade4 
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NCI-CTC grades not available: 
For parameters where there is no toxicity grade defined, shifts from baseline will be considered 
from within normal limits to above the upper limit of normal (ULN) or to below the lower limit of 
normal (LLN). 
All CTC gradable and non-CTC gradable parameters will be listed for each measurement. 
Parameters will be grouped by category. Abno11ll3l laboratory values will be listed. 
Listings will include at least the following items: 
• 
Planned dose level 
• 
Subject identification number 
• 
First/last dosing date 
• 
Parameters 
• 
Visit 
• 
Date (treatment day) 
• 
Analysis value 
• 
Slunit 
• 
Change from baseline 
• 
Reference range status (Low, Normal, High) 
• ere grade (with associated CTC name) 
• 
Baseline flag (Yes/No) 
• Worst value on-treatment flag (Yes/No) 
Laboratory values that are outside the normal range will also be flagged in the data listings, along 
with corresponding normal ranges. Any out-of-range values that are identified by the Investigator 
as being clinically significant will be shown in a data listing. These are grade c::3 non hematologic 
toxicities and grade c:: 4 hematologic toxicities. 
Subjects without postbaseline laboratory samples will be excluded from analyses with respect to 
values after the baseline. 
Hepatotoxicity assessment: 
A plot of peak ALT versus peak total bilirubin, both relative to the ULN, will be provided. This 
eDISH ( evaluation of drug-induced serious hepatotoxicity) plot will have reference lines at 3xULN 
for ALT and 2xULN for total bilirubin. Each subject will get a special character/color combination; 
the color will represent dose level, and the characters within each color will be used to distinguish 
the subjects from one another, with ID numbers presented in a legend (sorted by dose level and 
subject ID number). 
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15.S 
Vital Signs 
The maximum on-treatment changes from baseline in vital sign measurements will be grouped as 
indicated in Table 5: 
Table S 
Analysis Categ01ies for Vital Sign Parameters 
Parameters 
Categories of Change from Baseline 
Body temperature increase 
< 1-C, 1-<2°C, 2-<3°C, ~ 3 °C 
Heart rate increase from baseline 
Q0 bpm, > 20 - 40 bpm, >40 bpm 
<100 bpm; ~ 100 bpm 
Heart rate decrease from baseline 
Q0 bpm, > 20 - 40 bpm, >40 bpm 
<100 bpm; ~ 100 bpm 
SBP increase from baseline 
Q0 mmHg, >20 - 40 mmHg, >40 mmHg 
<140 mmHg; ~ 140 mmHg 
SBP decrease from baseline 
Q0 mmHg, >20 - 40 mmHg, >40 mmHg 
<140 mmHg; ~ 140 mmHg, 
OBP increase from baseline 
Q0 mmHg, >20 - 40 mmHg, >40 mmHg 
<90 mmHg; ~ 90 mmHg 
OBP decrease from baseline 
Q0 mmHg, >20 - 40 mmHg, >40 mmHg 
<90 mmHg; ~ 90 mmHg 
Respiration rate increase from baseline <20 bpm; ~ 20 bpm 
~5 bpm, >5 - 10 bpm, >10 bpm 
Respiration rate decrease from baseline <20 bpm; ~ 20 bpm 
~5 bpm, >5 - 10 bpm, >10 bpm 
For each patient the worst on-treatment value will be calculated. Missing values will define a 
separate category. 
The following summaries will be prepared for vital sign parameters as grouped above considering 
only subjects with postbaseline values: 
• Maximal shifts ( changes in categories) 
• Listing of highest change per subject 
An additional subject data listing will present all changes from baseline reported in the highest 
categories. 
15.6 
Electrocardiograms 
Triplicate 12-lead electrocardiogram (ECG) results will be presented in a listing, which will 
include planned dose level, subject identifier, age, sex, race, study visit and day, date/time of 
assessment, planned ECG time point, ECG parameter (unit), result, and clinical significance. 
Parameters to be included are as follows: 
• Heart rate (beats/min) 
• RR duration (msec) 
• PQIPR duration (msec) 
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• QRS duration (msec) 
• QT duration (msec) 
• QTc - Fridericia's correction (msec) 
• ECG interpretation (normal vs. abnormal) as assessed by Investigator 
Quantitative data for the aforementioned parameters will also be summarized using descriptive 
statistics, based on the average values of the triplicate measurements. 
The incidence and percentage of subjects with potentially clinically significant abnormalities 
(PCSA) for 12-lead ECG parameters will be summarized during the on-treatment period. The 
PCSA criteria are provided in Table 6 below. 
Table 6 
Potentially Clinically Significant Abnormalities Cr ite1·ia for ECG 
Test 
Potenrially Clinic.illy Signific.int Abnormalities (PCSA) Crite1ia 
Heart Rate (HR) 
~ SO bpm and decrease from baseline ?: 20 bpm 
?: 120 bpm and increase from baseline?: 20 bpm 
PR Interval 
?: 220 ms and increase from baseline ?: 20 ms 
QRS 
?: 120 ms 
QTcF absolute 
Interval ?: 4 SO - < 480 msec 
Interval ?: 480 - < 500 msec 
Interval ?: 500 msec 
QTcF change from baseline 
Increase from baseline ?: 30 - < 60 msec 
Increase from baseline ?: 60 msec 
QTc will be corrected based on Fridericia's formula (QTcF= QT/ 3./RR) where RR=60/HR. 
Baseline QTcF will be derived from the visit that other ECG parameters are flagged as baseline. 
If there are multiple assessments at the same visit and time point, the average will be calculated 
for each parameter and used for the analysis. 
15.6.1 
Relationship of QTc Changes to Treatment Exposure 
A secondary objective of the protocol was to assess QT prolongation potential by central tendency, 
outlier analysis and the slope of exposure-QTc analysis. Time-matched ECG readings (3 or more 
replicates) were to be collected at -4S, -30, and -1S minutes predose and at O.S, 1, 2, 3, 4, 6, and 8 
hours postdose, just prior to PK sample collections during Cycle 1 at Day 1 and Day 1S during 
Part IA (M4 l l 2 monotherapy) and uploaded for central ECG reading. ECG readings collected on 
Cycle 1 Day 8 (predose) and Cycle 2 Day 1 (predose and 2 hours postdose) were also to be 
uploaded. As the study was terminated early, the following analyses are planned to address the 
potential relationship ofQTc changes to the plasma M4112 exposure, based on the Concentration-
QTc Analysis Set: 
• 
The average QTc value at each time point will be plotted for each planned dose level for 
ClDl, ClD8, ClDlS and C2Dl. 
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• 
The change from baseline will be calculated as the mean change in QTc at each time 
point (including ClDl, C1D8, C1D15 and C2Dl) minus the mean of3 predose time 
points (-45, -30 and-15 minutes) on ClDl and plotted for each time point (if possible, 
these will be plotted in a joint plot - change in QTc on the left axis and M4 l l 2 plasma 
concentration on the right axis with time on the x-axis). 
• 
The change from baseline for each time-matched sample will be plotted against the 
corresponding M4112 plasma concentration for all days and all planned dose levels 
( combined and separately) in a scatter plot. 
Because the data is limited, no linear modeling will be applied. 
15.7 
ECOG Performance Status 
The ECOG shift from baseline to highest score during the on-treatment period will be summarized. 
ECOG performance status with shift from ECOG = 0 or 1 to ECOG = 2 or higher will also be 
presented in a data listing with subject identifier and other relevant information 
16 
16.1 
16.1.1 
Analyses of Other Endpoints 
Pharmacokinetic.s 
Plasma Concentrations 
1\14112 Concentrations 
All descriptive summaries of M4 l 12 plasma concentrations will be performed on the PK Analysis 
Set. Any concentrations excluded from the PK Analysis Set will be listed and flagged. 
Pharmacokinetic concentrations will be reported and analyzed with the same precision as the 
source data provided by the bioanalytical laboratory or clinical laboratory. Actual elapsed sample 
collection times will be analyzed unrounded (maximum of 14 significant digits), but will be 
rounded to two decimal places with units of hours for reporting pwposes in by-subject listings. 
Predose samples that occur before drug administration will be assigned a time of O hours, as if the 
sample had been taken simultaneously with the study drug administration. 
Concentration values below the lower limit of quantification of the assay (LLOQ) will be taken as 
zero for smnroary statistics of PK concentration data. 
In case of concentrations above the upper limit of quantification of the assay (ULOQ), the 
concentration will be set to missing. 
Missing concentrations ( e.g., no sample, insufficient sample volume for analysis, no result, or 
result not valid) will be reported and used generally as no result ("NR"). 
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M4112 plasma concentration data will be descriptively swrunarized by study day and nominal 
time using: number of subjects (N); number of nonmissing values (n), arithmetic mean (Mean), 
standard deviation, coefficient of variation (CV%), minimum (Min), Median, and maximum 
(Max). IfN is less than 3, onlyn, Min, and Max will be presented. 
Descriptive statistics of plasma concentration data will be calculated using values with the same 
precision as the source data, and rounded for reporting purposes only. The following conventions 
will be applied when reporting descriptive statistics for concentrations: 
Mean, Min, Median, Max: 
3 significant digits 
Standard Deviation: 
CV%: 
4 significant digits 
1 decimal place 
Individual concentration-time profiles showing all subjects separately by dose group and study day 
(ClDl and C1D15), and showing study days (ClDl and C1D15) separately by subject will be 
created using the actual time points and the numeric concentration data. Arithmetic mean 
concentration-time profiles by dose group separately for each study day (ClD 1 and C 1D15), and 
by study day (ClDl and C1D15) separately for each dose group will be provided using scheduled 
(nominal) time points and the numeric concentration data. All concentration-time plots for PK data 
will be presented both on a linear and on a semi-logarithmic scale. Mean plots will include standard 
deviation bars when plotted on a linear scale. 
16.1.2 
Plasma Pbarmacokinetic Parameters 
Pharmacokinetic parameters will be calculated using standard noncompartmental methods and the 
actual administered dose. Pharmacokinetic parameters will be calculated using the actual elapsed 
time since dosing, given with a precision of 14 significant digits. In cases where the actual 
sampling time is missing, calculations will be perfolllled using the nominal time. Otherwise, there 
will be no further imputation of missing data. 
The following parameters will be calculated from M4112 plasma concentrations on the study days 
specified. 
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Symbol 
AUCo.s 
AUCo.s/Dose 
Cmax 
Cmax/Dose 
tmax 
c;,,.. 
Cp,..!Dose 
R.cc(AUC0-8) 
R.cccem.x> 
FIH Study of M4112 as Single Ageut aud in Combiuatious 
Definition 
The area under the concentration-time curve (AUC) from time zero(= dosing 
time) to 8 hours postdose, calculated on ClDl and C1D1S. Calculated using 
the mixed log linear trapezoidal rule (linear up, log down). 
The dose-normalized AUCo-s, calculated on ClDl and C1D1S. Normalized 
using the actual dose, using the formula AUCo-s /Dose. 
Maximum observed concentration, calculated on ClDl and C1D1S. 
The dose-normalized Ca.ax, calculated on ClD 1 and C 1D1 S. Normalized using 
the actual dose, and the formula C...,./Dose. 
The time to reach the maximum observed concentration (in case of 
multiple/identical Ca.ax values, the first occurrence will be used), calculated on 
ClDl andC1D1S. 
Predose (trough) observed concentration, calculated on C1D8, C1D1S, and 
C2Dl. 
The dose-nonnalizerl c;,.., calculated on C1D8, C1D1S, and C2D1. 
Normalized using the actual dose, and the formula Cp,../Dose. 
The accumulation factor to assess the increase in exposure via AUCo-s 
following multiple dosing. R.«(AUC0-8) = (AUCo-s after multiple dose [ ClD 1 S])/ 
(AUCo-s after single dose [ClDl]). 
The accumulation factor to assess the increase in maximum concentration 
following multiple dosing. R.«(Cmax) = (Cmax after multiple dose [C1D1S])/ 
(Cmaxafter single dose [ClDl]). 
For all dose-normalized parameters, no adjustment of dose (e.g., for molecular weight differences 
between salt and free form) is required as M4112 is not a salt. 
Partial area (AUCo-s) will be calculated using the nominal dosing inteival if the PK sample at 
8 hours postdose is taken at ~8 hours. If the 8-hour sample is taken earlier than 8 hours, then the 
actual time and concentration at the nominal 8-hour time point will be used to calculate this 
parameter as long as the time deviation at 8 hours is not> 10 min (ie, the protocol-allowed window 
at this time point); otherwise this parameter will be set to missing. 
Concentrations below the LLOQ at any point in the profile will be taken as zero for calculating 
AUC. Predose samples that occur before the first drug administration will be assigned a time of 
0 hours, as if the sample had been taken simultaneously with the study drug administration. 
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The Phoenix WinNonlin NCA Core Output will be provided in a separate listing. 
All statistical analyses and descriptiv1> summaries of PK parameters will be performed on the PK 
Analysis Set. Any PK parameters excluded from the PK Analysis Set will be listed and flagged. 
Phannacokinetic parameters will be analyzed unrounded, but will be rounded to 3 significant digits 
for reporting, except for parameters directly obtained from the source data (such as Caw.) which 
will be reported with the same precision as the source data, and tmn which will be reported to 2 
decimal places. In export datasets, as well as in the SD1M PP/XD domain, PK parameters will be 
provided with full precision, and will not be rounded. 
Calculated PK parameters will be descriptively summarized by study day using: N, n, Mean, 
standard deviation, CV%, Min, Median, Max, geometric mean (GeoMean), and geometric 
coefficient of variation (GeoCV%). GeoMean and GeoCV% will not be presented for tmn. IfN is 
less than 3, only n, Min, and Max will be presented. 
Descriptive statistics of PK parameter data will be calculated using full precision values, and 
rounded for reporting pwposes only. 
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data, except for tmax which will use the same level of decimal precision (instead of significant 
digits) as specified below: 
Mean, Min, Median, Max, GeoMean: 
Standard Deviation: 
CV%, GeoCV%: 
3 significant digits 
4 significant digits 
1 decimal place 
Individual Cp,.. values on ClD8, ClD15, and C2Dl will be plotted against actual time points (in 
days) on a linear scale, for all subjects by dose group. Arithmetic mean Cp,.. (with standard 
deviation bars) will also be plotted versus nominal time (in days) by dose group, on a linear scale. 
The analysis of dose proportionality of PK parameters ofM4112 over the range of administered 
dose levels will be quantified as part of an exploratory analysis using the power model on the 
original parameters (ln[PK parameter]= a + ~ x In[ dose D- This analysis will be based on AUCo-s 
(ClDl and C1Dl5), Caw. (ClDl and C1Dl5), and Cp,.. (C1D8, ClD15, C2Dl) and will be 
conducted separately by parameter and study day. The intercept a and the slope ~ together with 
90% Cis will be estimated and presented. A p-value testing whether ~ = 1 will also be presented. 
For a given parameter, a minim•= of 3 values must be available for a dose level, for that dose 
level to be included in the dose proportionality analysis. 
Dose proportionality will also be assessed graphically by presenting scatter plots of individual and 
geometric mean values of AUCo_g (ClDl and ClD15), Caw. (ClDl and ClD15), and Cp,.. (ClD8, 
C1Dl5, C2Dl) and dose-nonnalized AUC0-s (ClDl and ClD15), Caw. (ClDl and ClD15), and 
Cp,.. (ClD8, ClD15, C2Dl) versus Dose on a linear scale. Plots will be prepared separately by PK 
parameter and study day. 
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References 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317: 1098. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
R Core Team R: A language and environment for statistical computing. R Foundation for 
Statistical Computing, Vienna, Austria. 2014, URL http://www.R-project.org/. 
Sweeting M, Mander A, Sabin T. berm: Bayesian Continual Reassessment Method Designs for 
Phase 
I 
Dose-Finding 
Trials. 
J 
Statist 
Software 
2013;54(13):1-26. 
URL 
http://www.jstatsoft.org/article/view/v054il 3 
Adobe Acrobat 
Document 
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Appendic.es 
18 
18.1 
Protocol Deviations Identified by Programming and Clinically Impo11ant Events 
Inclusion and exclusion criteria are referenced according to Protocol MS201408-0005 version 2.0 dated 08-Sep-2017. 
Desc1iptiou 
Inclusion / Exclusion C1ite1ia 
Violated eligibility criteria 
Ally .. no .. response to inclusion criteria and/or 
any "yes" response to exclusion criteria, and 
subject was subsequently entered into the study 
Info1med Consent / Subject Information 
Late ICF signature 
ICF was sig,:,ed after study procedure was done 
Investigational Pt·oduct 
0,,-erdose 
Subjectrecei-1=110% of the calculated dose 
for that particular administration 
Pbarmacokin~1ics-Related 
Vomiting 
Vomiting irnroediately following oral dosing that 
can affect a PK result 
Sample processing errors 
Eaors that lead to inaccurate bioanalytical 
results 
Inaccurate dosing, dose 
Inaccurate dosing, dose reductions, dose errors, 
reductions, dose errors, missed 
or missed doses that can af!ect the PK results on 
doses 
one or more PK days 
Document N 
_
_ 
Object No. 
Clinically 
PI"otocol 
PI"oposed Check/ 
Code 
lmpoI"taut? 
Section 
Comment 
INCEXCOI 
Violations should be 
documented on the Study Entry 
CRF page, which is mapped to 
the IE domam in SDIM 
INFCON03 
Check that no dates are prior to 
!CF date 
INVPR06 
Flag if relati,-e dose intensity 
=1.10 
PKOOI 
Mamial cbeclc by PK scientist 
PK002 
Mamial cbeclc by PK scientist 
PK003 
Mamial cbeclc by PK scientist 
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Version 1.0 
18.2 
Integrated Analysis Plan for SMCs 
Clinical T1ial Protocol 
Identification No. 
Title: 
T1ial Phase 
Investigational Medicinal 
Product(s) 
MS201408--000S 
Phase I, First-in-Human, Open-Label, Multiple-Ascending 
Dose Study to Investigate the Safety, Tolerability, 
Phannacokinetics, 
Phannacodynamics 
and 
Clinical 
Activi 
of M4112 an IDOlfTD02 Inhibitor as s· 
A nt 
I 
Clinical T1ial Protocol Version 
08 September 2017 / Version 2.0 
Statistical Analysis Plan Author 
Statistical Analysis Plan 
Date and Version 
Statistical Analysis Plan 
Reviewen 
PD 
and PD 
------
30 Jan 2018 / Version 1.0 
-----
, Medical Responsible, Merck KGaA 
PD 
, EMD Serono, 
.----------------
Inc. 
PD 
MerckKGaA 
----------------
PD 
MerckKGaA 
------------
PD 
EMD Serono, 
----------------
Inc. 
PD 
EMD 
.,_ _________________ _ 
Serono Inc. 
This document is the property of Merck KG~ 
Germany, or one of its affiliated companies. 
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 affiliate. 
Cop yright © 2018 by Merck KGaA, Darmstadt, Germany or its affiliate. AD rights reserved. 
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1\14112 
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FIB Study of M4112 as Single Agent and in Combinations 
Version 1.0 
1 
Signature Page 
Integrated Analysis Plan for Sl\1Cs: MS201408-0005 
Phase I, First-in-Human, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, 
Tolerability, Pharmacokinetics, P~and Clinical Activi ofM4112 an 
ID01/ID02 Inhibitor as Single Agent- -
in Subjects with Metastallc or Loe y A anc 
Unresecta e So 
Tumors 
Approval of t he !AP by all Mer ck Data Analysis Responsible is documented 
within 
ELDORADO. Wit h t he approval wit hin Eldorado, t he Merck responsibl e for each of 
t he anal ys is also t akes respons ibi l it y t hat all reviewers ' 
comments are 
addressed adequately. 
Merck responsible 
Date 
Signature 
PD 
PD 
Merclc KGaA 
Frankfurter Strasse 250 
64239 Darmstadt 
Germany 
PD 
Medical Responsible 
Merclc KGaA 
Frankfurter Strasse 250, 
64293 Darmstadt 
Germany 
EMD Serono, Inc. 
45A Middlesex Turnpike 
Billerica, MA 01821 
Via ELDORADO eSignature 
approval process 
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EMD Serono, Inc. 
45A Middlesex Turnpike 
Billerica, MA 01821 
PD 
EMD Serono, Inc. 
45A Middlesex Turnpike 
Billerica, MA O 1821 
FIB Study of M4112 as Single Agent and in Combinations 
Version 1.0 
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2 
Table of Contents 
1 
Signature Page .................................................................................... 41 
2 
Table ofContents ................................................................................ 43 
3 
List of Abbreviations and Definition of Terms ................................. .45 
4 
Modification History .......................................................................... 47 
5 
Pwpose of the integrated Analysis Plan ............................................ .47 
6 
Summary of Clinical Trial Features .................................................. .47 
7 
Sample Size/R.andomization ............................................................... 54 
8 
Overview of Planned Analyses ........................................................... 54 
8.1 
Sequence of Analysis .......................................................................... 55 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol ........ 55 
10 
Analysis Sets ....................................................................................... 55 
11 
General Specifications for Statistical Analyses .................................. 56 
12 
Trial Subjects ...................................................................................... 57 
13 
Demographics and Other Baseline Characteristics ............................. 58 
14 
Previous or Concomitant Medications/Procedmes ............................. 58 
15 
Treatment Compliance and Exposure ................................................. 58 
16 
Endpoint Evaluation ........................................................................... 58 
16.1 
Primary Endpoint Analyses ................................................................ 58 
16.2 
Secondary Endpoint Analyses ............................................................ 61 
16.2.1 
M4112 Concentration and Pharmacokinetic Analyses ....................... 61 
16.3 
Other Endpoint Analyses .................................................................... 62 
17 
Safety Evaluation ................................................................................ 64 
17.1 
AdverseEvents ................................................................................... 64 
17.1.1 
AllAdverseEvents ............................................................................. 65 
17.1.2 
Adverse Events Leading to Treatment Discontinuation ..................... 66 
17 .2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ................................................................................... 67 
17.2.1 
Serious Adverse Events ...................................................................... 67 
17.2.2 
Adverse Events of Special Interest ..................................................... 67 
17.3 
Clinical Laboratory Evaluation. .......................................................... 67 
17 .4 
Vital Signs .......................................................................................... 67 
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17.S 
Other Safety or Tolerability Evaluations ............................................ 67 
18 
Benefit Risk Asses.sment .................................................................... 67 
19 
References ........................................................................................... 67 
20 
Appendices ......................................... Error! Bookmark not defined. 
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3 
ADA 
AE(s) 
AESI(s) 
AUC 
AUCo-s 
BID 
BOR 
Cm.,. 
Cm;,, 
CTCAE4.03 
cQTc 
DCR 
DLT 
DOR 
ECG 
ECOGPS 
eCRF 
eDISH 
iAP 
ICso 
IDO • 
MedDRA 
MTD 
OBD 
PD 
PFS 
PK 
PT 
QD 
FIB Study of M4112 as Single Agent and in Combinations 
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List of Abbreviations and Definition of Terms 
Anti-drug antibody 
Adverse event(s) 
Adverse event(s) of special interest 
Area under the drug concentration-time curve 
Area under the drug concentration-time curve from O to 8 h postdosing 
Twice daily 
Best overall response 
Maximum plasma concentration observed postdose 
Minimum observed postdose (trough) plasma concentration 
Common Terminology Criteria for Adverse Events Version 4.03 
Concentration-QTc 
Disease control rate 
Dose-limiting toxicities 
Duration of response 
Electrocardiogram 
Eastern Cooperative Oncology Group Performance Status 
Electronic case report form 
Evaluation of drug-induced serious hepatotoxicity 
Integrated analysis plan 
Half maximal effective concentration 
Indoleamine- 2, 3- di oxygenase 
-
Medical Dictionary for Regulatory Activities 
Maximum tolerated dose 
Optimal biological dose 
Pharmacodynamics 
Progression-free survival 
Pharmacokinetic(s) 
Preferred Term 
Once daily 
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QTc 
RP2D 
SAE 
SMC 
soc 
TDO 
TEAE 
1LFs 
bx 
TRAE 
■ 
ULN 
FIB Study of M4112 as Single Agent and in Combinations 
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Corrected QT interval 
Recommended Phase II dose 
Serious adverse event 
Safety Monitoring Committee 
System Organ Class 
Tryptophan-2,3-dioxygenase 
Treatment emergent adverse event 
Tables, Listings, and Figures 
Time to reach maximum concentration 
Treatment related adverse event 
-
Upper limit of normal 
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4 
Unique 
Identifier 
for 
iAP 
Version 
1.0 
5 
FIB Study of M4112 as Single Agent and in Combinations 
Version 1.0 
Modification History 
Date of iAP Author 
Changes from the Previous Version 
Version 
30 January 2018 
PPD 
i r 
N/A - first version 
Purpose of the integrated Analysis Plan 
The purpose of this integrated Analysis Plan (iAP) is to document technical and detailed 
specifications for the analyses performed for the Safety Monitoring Committee (SMC) reviews of 
data collected for protocol MS201408-0005. Results of the analyses described in this iAP will be 
used (amongst other data) by the SMC to decide upon dose and size of future cohorts. This iAP 
will specify the Bayesian two-parameter logistic regression model used to make a recommendation 
to the SMC for dose escalation. Additionally, this iAP will describe pI"'Iiroinary PK analyses for 
M4112, as well as Tables, Listings, and Figures (TLFs) summarizing safety data. The latter will 
only be applicable if an SMC meeting is adjourned and at data of at least 6 treated subjects in the 
•
. 
treatment arm. The TI,Fs (except for the overall listing of AEs, the PK analyses and 
analyses) will be produced on the SDTM data available at cut-off (usually from previous 
exceptalistingofallAEandalistin ofallAE>= 
de3 thatwillbe roducedinJReview 
alon with the atient rofiles. 
The iAP is based upon Section 8 (Statistics) of the trial protocol and protocol amendments and is 
prepared in compliance with ICH E9. 
6 
Summary of Clinical Trial Features 
Objectives: 
Primary Objectives 
Part IA (Dose Escalation - M4112 as Single Agent) 
• To determine safety and tolerability or, if observed, the maximum tolerated dose (MID), 
and to define the recommended Phase II dose (RP2D) ofM4112 as single agent in subjects 
with solid tumors. 
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• 
Secondary Objectives 
Part IA (Dose Escalation - M4112 as Single Agent) 
• To characterize the PK parameters ofM4112 as single agent 
• To assess QT prolongation potential by central tendency, outlier analysis and the slope of 
exposure-QTc analysis 
• To evaluate preliminary clinical activity parameters using RECIST 1.1. 
Methodology: 
This study is a Phase I, open-label study designed to determine the safety, tolerabili 
and 
limin 
antitumor activi ofM4112 as single agent (Part IA only) 
The target population for Part I 
se Esc anon 
compnses o su ~ects wi a anc 
or metastatic solid malignancies for whom no effective 
standard therapy exists or has failed or subjects who are intolerant to established therapy known 
to provide clinical benefit for their condition. 
Part IA 
Dose Escalation 
A broad dose range in monotherapy will be investigated to determine the safety profile, 
tolerability, PK, and PD markers and to explore signs of antitumor activity in subjects with 
advanced solid tumors. 
Subjects will receive M4112 at the starting dose of 100 mg BID (100 mg BID which equals to 
200 mg total daily dose) at least 1 h prior to a meal and at least 2 h after a meal. Cohorts will 
consist of 3 subjects each, if not decided differently by the SMC. The first subject of each dose 
level will be observed for at least 5 days before the second subject can be treated. Subsequent 
subjects may receive first dosing at no less than 48 h intervals between subjects for the first 
2 cohorts of mono and combination therapy. If the safety profile is acceptable and agreed by 
the SMC, the 48 h observation after Subject 2 may be removed). The safety and tolerability 
data and available PK and PD data (as minimum Da l and Da 15 PK and PD data from 
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previous cohort and all available PK and PD data from the current cohort) will be reviewed by 
the SMC at the end of each cohort. In cases where enrollment oflast subject in a dosing cohort 
is delayed, the SMC may decide (based on available data) upon enrollment and dose for the 
next dosing cohort before all subjects in a cohort have completed Cycle l . The SMC will be 
assisted in their dosing and regimen (administration schedule) decisions by PK, PD, and a 
Bayesian 2-parameter logistic regression model modeling dose-limiting toxicity (DLT) rate 
with overdose control. The model incorporates nonclinical toxicity data in the prior and DLTs 
observed \Ultil the SMC to provide a recommended dose for the next cohort. During the dose 
escalation part of the study, the SMC will advise, primarily based on safety (DLTs) and 
additional data relevant for the treatment, on dose escalation, dose de-escalation, dose level 
expansion or regimen change, or it may recommend suspension of enrollment, with the final 
decision being a Sponsor decision. The SMC may also recommend a cohort size different from 
3 subjects as the Bayesian design allows dose recommendation based on less or more than 3 
subjects. 
Prespecified ascending doses of 100,200,400, 600,800, and 900 mg BID (means respectively, 
100 mg BID for 200 mg total daily dose, 200 mg BID for 400 mg total daily dose, 400 mg BID 
for 800 mg total daily dose, 600 mg BID for 1,200 mg total daily dose, 800 mg BID for 
1,600 mg total daily dose, 900 mg BID for 1,800 mg total daily dose) as single agent in 28-day 
I 
II • 
d 
A BID dosing regimen will be followed, based on PK modelling, to achieve the target Cmm 
over the dosing interval at a lower total daily dose and thereby reducing Cm.x and AUC over 
the day to potentially improve safety and tolerability when compared to once daily (QD) 
dosing. Based on PK data from subjects, the SMC will evaluate whether this regimen can be 
sustained or needs to be changed. 
In principle, dose escalation of single agent M41 l 2 (Part IA) will proceed according to the 
recommendation of the SMC to atleast the upper end of the above given dose range, unless the 
MTD has been reached or there is excess of PK nonlinearity, or the SMC recommends to end 
dose escalation following review of safety, tolerability, PK and PD results. Depending on the 
observed toxicity profile and available PK and PD, a dose regimen different to or dose(s) 
hi er/lower than the 
e 
cified doses ma be tested. 
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The following criteria will be applied to define the RP2D ofM4112 as single agent: 
• 
• 
This dose level will then be studied in ~ 6 evaluable subjects to establish safety, tolerability, 
PK, and PD and will be defined as the RP2D of M4 l l 2 as single agent. 
The starting dose ofM4112 
Separate Bayesian logistic regression models will be used for guidance of dose escalation for 
each of the combinations. 
I . t 
I 
• 
t 
I 
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• 
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Once safety and PD effects are confirmed in~ 6 additional subjects, these dose levels will be 
used as the RP2D of the respective combination therapies. 
DLT Definition 
DLTs will be used to determine dose escalation, dose de-escalation, and the MTD (if reached), 
using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
Version 4.03 (CTCAE 4.03). DLTs are defined in the clinical study protocol. 
Subjects with nausea and vomiting will maintain normal schedule without re-dosing. 
The MTD is defined by the SMC. An MTD is suggested from the Bayesian logistic regression 
model with target toxicity of 30%. 
Subjects who tolerate M4112 and their combination partner without significant clinically 
relevant toxicities will continue to receive their assigned dose until discontinuation criteria are 
met, withdrawal of consent or the study ends, whatever occurs first. 
Follow-up Pe1iod: 
Subjects who discontinue treatment must be followed on study until resolution of toxicity or 
until confirmed disease 
o ession. 
Planned number of subjects: 
oximately 24 subjects, 
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Primary endpoints: 
FIB Study of M4112 as Single Agent and in Combinations 
Version 1.0 
Part IA (Dose Escalation - M4112 as Single Agent) 
• Occurrence ofDLTs in subjects receiving M4112 as single agent during the first 4 weeks 
(Day 1 to Day 28 of Cycle 1) of treatment 
• Occurrence of treatment-emergent adverse events (TEAEs) and TRAEs according to 
NCI-CTCAE4.03 (including deaths) in subjects receivingM4112 as single agent from start 
of treatment up to the last Safety Follow-up Visit 
• Treatment-emergent changes from baseline in clinical laboratory measures, vital signs, 
Eastern Cooperative Oncology Group Performance Status (ECOG PS), and physical 
examination findings in subjects receiving M4112 as single agent up to the last Safety 
Follow-up Visit. 
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Secondary endpoints: 
FIB Study of M4112 as Single Agent and in Combinations 
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Part IA (Dose Escalation - M4112 as Single Agent) 
• Plasma PK parameters for M4112: AUCo.s, C....,., t...x, AUCo-8/dose, ½iax/dow, (Days 1 and 
15), R.oc(AUCO-S) and R.oc(em.x) (Day 15), Cm;,,, and Cmmld ... (Days 8 and 15 of Cycle 1 and 
Day l of Cycle 2) 
• Slope of concentration-QTc (cQTc) regression based on time-matched electrocardiogram 
(ECG) readings (3 or more replicates) and PK samples during Cycle 1 at Day 1 and Day 15, 
central tendency and outlier analyses for absolute QTcF, and delta QTc 
• BOR, DOR, OCR, time to tumor response, and PFS using RECIST 1.1, up to confirmed 
tumor progression. 
I 
I 
I 
Concentration-QTc and safety ECG: 
Time-matched ECG readings (3 or more replicates) will be collected at -45, -30, and -15 min 
predose and at 0.5, 1, 2, 3, 4, 6, and 8 h postdose, just prior to PK sample collections during 
Cycle 1 at Day 1 and Day 15 during Part IA (M4112 monotherapy). 
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7 
• Pharmacokinetics: 
• Phannacokinetic parameters for M4112 will be based on plasma concentrations collected 
predose and at 0.5, 1, 2, 3, 4, 6 and 8 h postdosing on Days 1 and 15 of Cycle 1. Predose 
concentrations on Day 8, Cycle 1 and predose and 2 h postdose on Day 1, Cycle 2 will be 
assessed. 
Safety assessments: 
The safety profile ofM4 l 12 will be assessed through the recording, reporting and analysis of 
baseline medical conditions, adverse events (A.Es), adverse events of special interest (AESis), 
DLTs in Cycle 1 and any treatment-emergent immune-related AE observed in subsequent cycle 
(Cycle 2) that in the opinion of the SMC needs to be taken into accmmt for safety and proposal 
of dose escalation, physical examination findings including vital signs, laboratory tests 
(chemistry, hematology, and coagulation), ECOG PS, and a 12-lead ECG in triplicate from the 
date of si ature of first informed consent until the either until the 30 ± 3 da Safe Follow-
u Visit, 
or be ore 
Sample Size/Randomization 
As inherent in dose escalation studies, the sample size cannot be prespecified. The planned size of 
each dosing cohort is 3 subjects; however, based on the results of a Bayesian two-parameter 
logistic model, the SMC may elect to change the size of future cohorts. 
8 
Overview of Planned Analyses 
The following analyses requiring an SAP/iAP are planned for this trial: 
• 
SMC analyses (this iAP) 
• 
End of monotherapy dose escalation analysis (separate iAP) 
• 
Primary analysis of escalation part of the trial (separate iAP) 
Patient Profiles based on the raw data will also be produced for SMCs, and no separate iAP is 
needed for this deliverable. 
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Cut-off date: 
FIB Study of M4112 as Single Agent and in Combinations 
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SMCs are usually planned after the last subject of each cohort has finished the DLT assessment 
period of 28 days or dropped out of the study. In cases where enrolhnent of the last subject in a 
dosing cohort is delayed, the SMC may decide (based on available data) upon enrolhnent and dose 
for the next dosing cohort before all subjects in a cohort have completed the dosing cycle and thus 
set an earlier data cut-off, except the first SMC which needs all three subjects have finished the 
DLT period. For each SMC, a two-parameter logistic Bayesian model will be updated with the 
observed safety data based observed DLTs to help the SMC in its dosing decision. 
When monotherapy and combination therapy cohorts are open at the same time, efforts will be 
made to have a joint SMC with a data cut-off at the end of the DLT period for the last subject to 
be included in the joint SMC. 
8.1 
Sequenc.e of Analysis 
Summary TLFs based upon cumulative data within each treatment arm will be created upon 
availability of data of~ 6 treated subjects in the respective treatment arm. Analyses and decisions 
will be made separately for each treatment arm. 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol 
There are no changes to the planned analyses. 
10 
Analysis Sets 
Analysis sets relevant to SMCs are defined in Table 1. 
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Table I 
Analysis Sets 
Population 
Screening 
Dose Escalation 
Safety 
M4112 Pharmacokinetic 
Pharmacodynamics 
Description 
All participants who sign informed consent. 
All subjects treated in dose escalation cohorts who do not miss> 5 planned 
total daily doses of M4112 
in the first 
cycle (first 28 days) of the ose esca a ,on pa 
or o er an 
. The latter 
only applies to subjects in the combination dose escalation. 
The Safety Analysis Set will include all subjects who receive at least 1 dose 
of study treatment. In case of combination treatment, study treatment 
includes also the combination agents. 
All subjects from the Safety Analysis Set without major protocol 
deviations/violations or events that would affect PK. Subjects in the PK 
Analysis Set must have received at least 1 dose of M4112 and must have 
sufficient M4112 plasma concentration data to enable the calculation of at 
least 1 PK parameter. Sufficient concentration data is defined as at least 3 
valid, postdose concentration points in the PK profile to obtain any PK 
parameter. 
All subjects who received at least 1 dose of M4112 and provide the predose 
and at least 1 postdose sample for PD assessment. 
ADA= anti-drug antibody; cQTc = concentration-corrected QT interval (QTc); DLT = dose-limiting toxicities; 
ECG = electrocardiogram; PD = pharmacodynamics; PK = pharmacokinetic. 
11 
General Specifications for Statistical Analyses 
es will be se arate for each tre~monotherapy, ....__.. 
-----andsowilld~ 
Significance level: 
There will be no statistical tests performed in these SMC analyses. If confidence or credibility 
intervals are mentioned, the level will be 95% unless otherwise specified. 
Presentation of continuous and qualitative variables: 
Continuous variables will be summarized using descriptive statistics, i.e. 
• 
number of subjects (N), number of subjects with non-missing values 
• 
mean, standard deviation 
• 
median, 25th Percentile - 75th Percentile (Ql-Q3) 
• 
m101m1~ maxunum 
If there are fewer than 5 observations summarized, only the number of subjects (N), number of 
subjects with non-missing values, the mean, and the values themselves will be given. 
Qualitative variables will be summarized by counts and percentages. 
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Unless otherwise stated the calculation of proportions will be based on the number of subjects in 
the analysis set of interest. Therefore, counts of missing observations will be included in the 
denominator and presented as a separate category. 
Definition of baseline: 
In general the last non-missing measurement prior to the first study drug administration will be 
used as the baseline measurement. 
Definition of duration: 
If not otherwise specified, duration will be calculated by the difference of start and stop date + 1 
(e.g. swvival time (days) = date of death-date of randomization + 1). 
The time since an event (e.g. time since first diagnosis) will be calculated as reference date minus 
date of event. 
Conversion factors: 
The following conversion factors will be used to convert days into months or years: 1 month = 
30.4375 days, 1 year= 365.25 days. 
Handling of missing data: 
Unless otherwise specified (Section 13, 15, 16 and 17), missing data will not be replaced. 
In all listings, imputed information will be flagged. 
Missing statistics, e.g. when they cannot be calculated, should be presented as "nd". 
Where tables are presented over different time points, the total of missing and non-missing 
obseivations at each time-point should reflect the population still in the trial at that time. This does 
not apply when imputations are made beyond trial withdrawal. For example, if a subject is still in 
the trial at the time-point but with missing data, they should be counted in the number of missing 
obseivations. 
Treatment day is defined relative to the date of first study drug administration. Treatm~ 
treatment start date of first administration of any of the following study drugs (M4 l 12_, 
-; 
the day before is defined as Treatment Day -1 (no Treatment Day 0 is defined). 
All analyses ( except calculations of posterior distributions, recommended next dose and associated 
outputs) will be performed using SAS® Software version 9.2 or higher. For the outputs of the 
Bayesian two-parameter logistic model updates, East® 6.0 or R (version 3.1.2 or higher [Core 
Team, 2014]) and the R package berm [Sweeting, 2013] or crmpack will be used. 
12 
Trial Subjects 
Only displayed in Patient Profiles. 
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Demographic.s and Other Baseline Characteristics 
Only displayed in Patient Profiles. 
14 
Previous or Concomitant Medications/Procedures 
Only displayed in Patient Profiles. 
15 
Treatment Compliance and Exposure 
Only displayed in Patient Profiles. 
16 
16.1 
Endpoint Evaluation 
Primary Endpoint Analyses 
The primary objective of the SMC meetings is to regularly monitor the overall safety of the 
subjects enrolled in the trial. An important part of that is reviewing DLTs. The primary analysis of 
DLTs is performed using a Bayesian two-parameter logistic modeling approach to model the 
relation of dose to the occurrence ofDLTs. The results from updating this model will assist the 
SMC in their dosing decisions. 
The SMC will receive patient profiles containing· 
• 
Subject disposition (still in trial, or withdrawn with reason for withdrawal) 
• 
Demographics and baseline characteristics ( e.g., cancer diagnosis, staging) 
• 
Medical history 
• 
History of disease under study 
• 
Previous and concomitant medications 
• 
Prior anti-cancer drug therapies 
• 
Prior anti-cancer radiotherapy 
• 
Prior anti-cancer surgeries 
• 
Concomitant procedures 
• 
Study drug administration, dose completion, and dose adjustment 
• 
All serious and non-serious AEs, including but not limited to: 
• 
DLTs 
• 
AESis 
• 
AEs leading to dose reduction or temporary discontinuation 
• 
AEs leading to permanent treatment discontinuation 
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• 
AEs leading to death 
• 
Laboratory data (hematology, coagulation, biochemistry, urinalysis) 
• 
ECG results, including change from baseline in QTc interval 
• 
Vital signs 
Patient profiles will be provided for the cU1Tent cohorts under review and updated patient profiles 
will be provided for the previous cohorts (i.e. the cohorts of the last previous SMC in same study 
part). 
In addition, a DLT profile plot of all subjects in the SAF Analysis Set will be produced. This will 
show an open square for all subjects who did not have a DLT during Cycle 1, a closed square for 
those who experienced a DLT during Cycle 1, and an open circle for those who were excluded 
from the DE Analysis Set. This plot will have Cohort Number on the x-axis and dose level (mg) 
on the y-axis. 
Bayesian two-parameter logistic model 
Upon completion of the DLT observation period of each cohort, SUlllllllll)' statistics of the posterior 
probability distribution of the true DLTrate (2.5%, 25%, 50%, 75%, and 97.5% quantiles) for each 
predefined dose level will be updated and estimated according to the logistic model. Using data 
from all subjects completing the DLT period or experiencing a DLT during this period at the 
completion of a new cohort (and data from all previous cohorts: DE analysis set), the Bayesian 
logistic model provides a recommended dose level for the next cohort. 
Recommendation is based on a loss function (probabilities of being in 1 of the 4 intervals will be 
multiplied with a loss term as follows: 
0 * P(target dosing (estimated DLT rate in (0.17-0.35])) + 1 * P(for over dosing (estimated DLT 
rate in (0.35--0.67]) or under dosing (estimated DLT rate in [0--0.17])) + 2 • P(excessive dosing 
(estimated DLT rate in (0.67-1])). 
In addition, only doses with estimated probability of~ 25% that the true DLT rate is more than 
35% ( overdose control) will be recommended by the model. The recommended dose level resulting 
from the model for the next cohort is the dose with the lowest loss function from all doses fulfilling 
the overdose control rule. This Bayesian escalation approach will be used to assist the SMC to 
select the next dose from a predicted set of acceptable doses, i.e., 100 mg, 200 mg, 400 mg, 600 
mg, 800 mg and 900 mg BID. It is possible to choose a dose(s) not within the pre-specified dose-
escalation plan. Using a Bayesian model-based design aids the SMC in dosing decisions by 
providing more information compared to a 3+3 design (e.g., an estimated dose-toxicity curve with 
confidence information utilizing data on all subjects in DE analysis set at time of analysis). 
The model will continue to be updated at each SMC \Ultil the SMC has decided to stop dose 
escalation. 
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Prior distribution and likelihood are used to calculate the posterior probabilities based on Bayes 
theorem. 
The likelihood is defined based on a binomial distribution, modelling the rate of subjects with at 
least l DLT. 
The prior distribution is set-up as follows: 
The relationship between dose and toxicity rate is defined by 
exp ( a + exp(P) * Jog (a~:,)) 
P(DLTjdj,a,p) = 
d 
1 + exp (a+ exp(P) * Jog (a;~,)) 
Where cl; e{l OO mg, 200 mg, 400 mg, 600 mg, 800 mg, 900 mg} (or different) and (a,~) are 
bivariate normally distributed. 
Assuming a target toxicity rate of 31 % at a reference dose of 900 mg and a toxicity of 11 % at a 
dose of 400 mg the following could be derived: 
E(a)=log(0.31/0.69) ~ 0.8001 
E@)= log((log(0.11/0.89)-log(0.31/0.69))/log( 400/900))=0.4647 
Variances are chosen as follows: Var(a)=l.52, Var$)=l.52, Cov(a, ~)=O 
The prior distribution has not been changed compared to the protocol defined. 
Exemplary code for the update of the prior in R using package berm: 
library(bcrm) 
## Pre-defined doses 
dose<-c(100,200,400,600,800,900) 
## Target toxicity /eve/ 
target.tox<-0.3-0 
## Toxicity cut-points 
tox.cutpoints<-c(0.17,0.35,0.67) 
## Losses associated with toxicity intervals (0,0.17]=1, (0.17,0.35]=0, (0.35,0.67]=1, (0.67, 1)=2 
loss<-c(1,0, 1,2) 
## definition of prior ####; 
sdose<-log(dose/900) 
mu<-c(log(0.31/0. 69),/og((log(0. 11/0. 89)-log(0.31/0. 69))/log(400/900))) 
Sigma<-rbind(c(1.S1'2,0),c(0, 1.5"2)) 
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###following lines: example input of observed data, line needs adjustment according to subject number, 
doses and DL Ts observed, I put example scenarios ####; 
data1 <-data.frame(patient= 1 :3,dose=c(rep(1,3)),tox=c(rep(0,3))) 
data2<-data.trame(patient=1:6,dose=c(rep(1,3),rep(2,3)),tox--c(rep(0,6))) 
data3<-data.frame(patient=1:6,dose=c(rep(1,3),rep(2,3)),tox--c(rep(0,5), 1)) 
data4<-data.frame(patient=1:9,dose=c(rep(1,3),rep(2,3),rep(3,3)), tox=c(rep(0,9))) 
#### example modeling step, nmax needs adjustment ####; 
TwoPLogistic.tox.intervals.bcnn<-
bcnn(stop=list(nmax=3),data=data1,sdose=sdose,dose=dose,ff="logit2',prior.alpha=/ist(4,mu, Sigma),targ 
et.tox=target.tox,constrain=FALSE,tox.cutpoints=tox.cutpoints,loss=loss,method="rjags•,bumin.itr=10000 
OO,production.itr=1000000) 
print(TwoPLogistic.tox.intervals.bcnn) 
plot(TwoPLogistic.tox.intervals.bcnn) 
TwoPLogistic.tox.intervals.bcnn<-
bcnn(stop=list(nmax--6),data=data2,sdose=sdose,dose=dose,ff="logit2',prior.alpha=/ist(4,mu, Sigma),targ 
et.tox=target.tox,constrain=FALSE,tox.cutpoints=tox.cutpoints,loss=/oss,method='rjags',bumin.itr=10000 
OO,production.itr=1000000) 
print(TwoPLogistic.tox.intervals.bcnn) 
plot(TwoPLogistic.tox.intervals.bcnn) 
TwoPLogistic.tox.intervals.bcnn<-
bcnn(stop=list(nmax--6),data=data3,sdose=sdose,dose=dose,ff="logit2',prior.alpha=/ist(4,mu, Sigma),targ 
et.tox=target.tox,constrain=FALSE,tox.cutpoints=tox.cutpoints,loss=loss,method="rjags•,bumin.itr=10000 
OO,production.itr=1000000) 
print(TwoPLogistic.tox.intervals.bcnn) 
plot(TwoPLogistic.tox.intervals.bcnn) 
TwoPLogistic.tox.intervals.bcnn<-
bcnn(stop=list(nmax=9),data=data4,sdose=sdose,dose=dose,ff="logit2',prior.alpha=/ist(4,mu, Sigma),targ 
et.tox=target.tox,constrain=FALSE,tox.cutpoints=tox.cutpoints,loss=Joss,method='rjags',bumin.itr=10000 
OO,production.itr=1000000) 
print(TwoPLogistic.tox.intervals.bcnn) 
plot(TwoPLogistic.tox.intervals.bcnn) 
sessionlnto0 
Analyses done with R package berm (reference to Sweeting, 2013 to be included) or package 
crmpack will be repeated with East for validation of results. 
16.2 
16.2.1 
Secondary Endpoint Analyses 
M4112 Concentration and Pharmacokinetic Analyses 
Available individual M4112 plasma concentrations will be summarized by dose, study day and 
collection time and presented as summaiy tables, including summary statistics where data allows. 
Individual as well as mean concentration-time profiles will be plotted on linear and log scales. 
For M4112, PK parameters, as described in the protocol, will be calculated using commercial 
software (Phoenix® WinNonlin®) following global Merck standard procedures. Nominal 
collection times may be used for PK determinations in support of the SMC review. Key PK 
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parameters (Cmax, AUC0-8, Cmin [predose on Day 8, Day 15 and/or Day 1, Cycle 2 as available], 
and corresponding dose-normalized parameters) will be plotted by dose and study day (individual 
and mean) 
16.3 
Other Endpoint Analyses 
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17 
Safety Evaluation 
The primary endpoints of this trial are safety-related, and analyses are described in section 16.1. 
Safety analyses will be performed on the SAF Analysis Set (unless otherwise specified). All safety 
parameters will be summarized, by dose level and overall within each treatment ann, unless 
otherwise stated. 
17.1 
Adverse Events 
The severity of adverse events will be graded using the NCI-CTCAE version 4.03, except where 
CTCAE grades are missing. No imputation of missing grades will be performed. Adverse events 
will be coded according to the latest MedDRA version at the time of the data cut-off. 
• 
TEAEs: Any AEs that are reported (serious and non-serious) will be considered treatment 
emergent adverse events (TEAEs), with the exception of those that started prior to the first 
dose of study treatment (unless a worsening of the event is recorded after the first dosing, 
in which case the event will be counted as a TEAE), or AEs starting more than 30 days 
after the last dose of study treatment. 
• 
Related Adverse Events: AEs with relationship to study treatment of 'Related' reported 
by the investigator, as well as those of unknown relationship (i.e., no answer to the 
questio~tudy treatment'). Relationship is judged separately for 
M4112, ........ 
• 
SAEs: Serious adverse events (as recorded on the AE eCRF page, Serious Adverse Event 
= 'Yes'). 
• 
AEs Leading to Treatment Discontinuation: AEs leading to permanent discontinuation 
of study treatment (as recorded on the AE eCRF page, Action taken with study treatment 
iiiiiiiil: 
Treatment discontinuation is recorded separately for M4112, 
• 
AEs Leading to Death: AEs leading to death (as recorded on the AE eCRF page, Outcome 
= 'Fatal'). 
AEs will be summarized by MedDRA PT as event category and MedDRA primary SOC as 
summary category. In general, each subject will be counted only once within each PT or SOC. 
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AEs with missing classifications regarding relationship to study treatment, and those with start 
date on or after the start of study treatment, will be considered as related to the study treatment. 
Incomplete AE-related dates will be handled as follows: 
• If the onset date is missing completely or missing partially-but the onset month and year, 
or year, are equal to that of the study treatment start - then the onset date will be replaced 
by the minimum of the start of study treatment and the AE resolution date. 
• 
In all other cases, the missing onset day or month will be replaced by 1. 
• 
Incomplete stop dates will be replaced by the last day of the month (if only day is missing), 
if not resulting in a date later than the date of subject's death or data cut-off. In the latter 
case, the date of death or data cut-off will be used to complete the stop date. 
• 
In all other cases the incomplete stop date will not be imputed. If the stop date of an AE is 
after the date of cut-off, the outcome of the AE is ongoing at cut-off. 
• 
Further information after cut-off (such as fatal outcome) might be taken from the Safety 
database and reported separately. 
All AE tables will be restricted to TEAEs only. The AE tables will include the number and 
percentage of subjects with at least one TEAE, by MedDRA SOC and PT (both sorted 
alphabetically), unless otherwise stated. 
17.1.1 
All Adverse Events 
All AEs will be tabulated in an overall summary table for each treatment aim, to include: 
• 
AnyTEAE 
• 
TEAEs leading to death 
• 
Serious TEAEs 
• 
TEAEs, grade ~ 3 
• 
TEAEs leading to permanent treatment discontinuation ofM41 l2 
• 
TEAEs leading to dose reduction ofM4l 12 
• 
AESis 
• 
Related to M4112 TEAEs 
• 
Related to M41 l 2 TEAEs, grade ~ 3 
• 
Related to M4112 serious TEAEs 
• 
Related to M41 l2 TEAEs leading to death 
• 
Related to M41 l2 TEAEs leading to permanent treatment discontinuation ofM4112 
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• 
Related to M4112 TEAEs leading to dose reduction ofM4112 
A listing of all TEAEs will be provided, split into those occuning within the first and after the first 
cycle. This listing will be sorted by dose level and subject. This listing will additio-all 
contain 
SOC, PT, 
de SAE (yes/no), DLT (yes/no), relatedness to M4112 (yes/no), 
(.yes/no), to~(yes/no), start date (+treatment day), stop date (+treatment day), an outcome. 
This listing~ produced on the current cut-off in JReview. 
Additionally, a listing of all adverse events grade >=3 will be provided, sorted by SOC and PT 
within each dose level and subject These will also include seriousness, dose level, time since last 
and since first administration of study dru~ex, and race of the subject) and relatedness to 
M4112 (.yes/no), _ 
(.yes/no), to-(.yes/no). This listing is to be produced on the 
current cut-off in JReview. 
17.1.2 
Adverse Events Leading to Treatment Discontinuation 
A listing ofTEAEs leading to treatment discontinuation, interruption, or dose reduction of each 
study drug will be provided. This listing, sorted b SOC and PT, will include: AE, SOC, PT, 
relationship to M4112, 
and 
(as applicable), seriousness, treatment 
discontinuation for M4112, 
, and 
as applicable), dosing cohort, time since last 
and since first administration o M4112, an su ~ect's age, sex, and race. 
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17.2 
Deaths, Other Serious Adverse Events, and Other Signific.ant 
Adverse Events 
17.2.1 
Serious Adverse Events 
A listing of all SAEs ~ovi~rted by SOC and PT, including: AE, SOC, PT, 
relationship to M4112,_ 
and- (as applicable), dosing cohort, time since last and 
since first administration ofM4112, and subject's age, sex, and race. 
17.2.2 
Adverse Events of Special Interest 
A listing of all AESis-· 
be rovide.orted by SOC and PT, including: AE, SOC, PT, 
relationship to M4112, 
and 
(as applicable), dosing cohort, time since last and 
since first administration o M4112, an 
~ect's age, sex, and race. 
17.3 
Clinical Laboratory Evaluation 
The severity of laboratory results for hematology and chemistry parameters will be graded 
according to the NCI-CTCAE version 4.03. 
All clinical laboratory analyses will be performed on the SAF Analysis Set. 
Hepatotoxicity assessment 
A plot of peak ALT versus peak total bilirubin, both relative to the ULN, will be provided. This 
eDISH ( evaluation of drug-induced serious hepatotoxicity) plot will have reference lines at 3xULN 
for ALT and 2xULN for total bilirubin. Each subject will get a special character/color combination; 
the color will represent dose level, and the characters within each color will be used to distinguish 
the subjects from one another, with ID numbers presented in a legend (sorted by dose level and 
subject ID number). 
17.4 
Vital Signs 
Vital signs will only be presented in the Patient Profiles. 
17.5 
Other Safety or Tolerability Evaluations 
ECG results will only be presented in the Patient Profiles. 
18 
Not applicable. 
19 
Benefit Risk Assessment 
References 
R Core Team R: A language and environment for statistical computing. R Foundation for 
Statistical Computing, Vienna, Austria. 2014, URL http://www.R-project.org/. 
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Sweeting M, Mander A, Sabin T. berm: Bayesian Continual Reassessment Method Designs for 
Phase 
I 
Dose-Finding 
Trials. 
J 
Statist 
Software 
2013;54(13):1-26. 
URL 
http://www.jstatsoft.org/article/view/v054il 3 
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Document: ctp-ms201408-0005-escalation-iap-vl-1 
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