Clinical trial NCT03138538
Conditions: Advanced Solid Tumors Metastatic Renal Cell Carcinoma
Keywords: Advanced Solid Tumors Metastatic Renal Cell Carcinoma M8891 Methionine Aminopeptidase 2 Inhibitor
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2017-08-08; Completion date: 2020-09-16
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to determine the maximum tolerated dose (MTD), safety, tolerability, Pharmacokinetic (PK), pharmacodynamic and clinical activity of M8891 as single agent in participants with advanced solid tumors in Part 1.

Detailed description:

Arms: arm 1: Participant received M8891 at dose of 7 milligrams (mg) orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. arm 2: Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. arm 3: Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. arm 4: Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. arm 5: Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. arm 6: Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
Interventions: intervention 1: Part 1: M8891
Intervention descriptions: intervention 1: Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Protocol documents:
Prot_000.pdf: 


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Replaces Version 
27 August 2019 / Version 3.0 
 
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 © 2020 by 
Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights reserved. 


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Protocol Amendment Summary of Changes 
Protocol History 
 
Version Number 
Type 
Version Date 
4.0 
Global substantial 
amendment 
11-Mar-2020 
3.0a 
Global substantial 
amendment 
27-Aug-2019 
2.0 
Global substantial 
amendment 
02-Jan-2018 
1.0 
Original Protocol 
28-Mar-2017 
a: No subjects were enrolled under Version 3.0. 
 
Protocol Version 4.0 (11 March 2020) 
Overall Rationale for the Amendment 
This amendment provides some minor clarifications to protocol Version 3.0 prior to the actual 
implementation of Version 3.0 at sites.   
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Tables 2 and 3, 
Schedules of 
Assessment for 
Part 2  
Change in frequency of assessment 
following Cycle 5 and alignment of 
tumor assessments with other 
assessments. 
Decreased burden on subjects, while maintaining 
appropriate monitoring. 
Tables 2 and 3, 
Schedules of 
Assessment for 
Part 2A and Part 
2B 
Reduced blood volume for plasma 
marker samples and specified more 
clearly sample acquisition timing 
schedules in footnotes. 
Decreases burden on subjects and clearer sample 
acquisition timing information. 
Table 3, 
Schedule of 
Assessments 
Remove a sample for M8891 PK. 
Decrease burden on subjects. 
Tables 4 and 5. 
Schedule of 
Assessments 
Clarification and alignment of timings 
with Tables 2 and 3. 
Clarification 
5.1.4, Follow-up 
Clarification of EOT visit timepoint for 
Part 1 and Part 2. 
Clarification 
5.1.3.4 Maximum 
tolerated dose … 
8.1.2.1, [Sample 
size] Part 2A] 
 
Clarify that minimum number of treated 
subjects on maximum tolerated dose 
applies to Part 1 not Part 2. 
Clarify that minimum of 6 subjects treated for 
maximum tolerated dose continues for Part 1 but 
is not necessary for Part 2.  
5.1.3.2.2 
[Treatment 
period] Part 2B 
Add a potential meeting of the Safety 
Monitoring Committee at the start of 
Part 2B. 
Additional evaluation of safety and tolerability. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Sponsor 
Signature 
Update of address. 
Clarification 
Sponsor 
Responsible 
Persons 
Updated to changes in personnel. 
Clarification 
Throughout 
Minor edits 
Correct formatting, English usage, etc. 
This Version 4.0 is identical to Version 3.0, except for clarifications as noted above.  No patient 
has been enrolled in Version 3.0 of the protocol. 
(The revisions made in Version 3.0, which are retained in this Version 4.0, are summarized in 
Appendix IV.) 
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Protocol Table of Contents 
Protocol Table of Contents ..................................................................................................5 
Table of In-Text Tables .......................................................................................................9 
Table of In-Text Figures ......................................................................................................9 
List of Abbreviations .........................................................................................................10 
1 
Synopsis ..............................................................................................13 
2 
Sponsor, Investigators and Trial Administrative Structure ................33 
3 
Background Information .....................................................................34 
3.2 
Background .........................................................................................35 
3.3 
Benefit/Risk Assessment ....................................................................36 
3.3.1 
M8891 .................................................................................................36 
3.3.2 
Cabozantinib .......................................................................................37 
3.3.3 
M8891 combined with cabozantinib ..................................................37 
4 
Trial Objectives ..................................................................................38 
4.1 
Part 1, M8891 Single Agent, Solid Tumors .......................................38 
4.1.1 
Primary Objectives .............................................................................38 
4.1.2 
Secondary Objectives .........................................................................38 
4.2 
Part 2, M8891 combined with Cabozantinib, mRCC .........................39 
4.2.1 
Part 2A, Dose Escalation ....................................................................39 
4.2.2 
Part 2B, Expansion Cohort .................................................................41 
5 
Investigational Plan ............................................................................42 
5.1 
Overall Trial Design and Plan ............................................................42 
5.1.1 
Screening Period .................................................................................46 
5.1.2 
Doppler Ultrasonography: ..................................................................46 
5.1.3 
Treatment Period: ...............................................................................47 
5.1.4 
Follow-up ............................................................................................55 
5.2 
Discussion of Trial Design .................................................................55 
5.2.1 
Dose Selection ....................................................................................55 
5.2.2 
Endpoint Selection ..............................................................................57 
5.2.3 
Inclusion of Special Populations ........................................................57 
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5.3 
Selection of Trial Population ..............................................................58 
5.3.1 
Inclusion Criteria ................................................................................58 
5.3.2 
Exclusion Criteria ...............................................................................60 
5.4 
Criteria for Initiation of Trial Treatment ............................................63 
5.5 
Criteria for Subject Withdrawal ..........................................................63 
5.5.1 
Withdrawal from Trial Therapy ..........................................................63 
5.5.2 
Withdrawal from the Trial ..................................................................63 
5.6 
Premature Termination of the Trial ....................................................64 
5.7 
Definition of End of Trial ...................................................................65 
6 
Investigational Medicinal Product and Other Drugs Used in the 
Trial .....................................................................................................65 
6.1 
Description of the Investigational Medicinal Product ........................65 
6.1.1 
M8891 .................................................................................................65 
6.1.2 
Cabozantinib (Cabometyx) .................................................................66 
6.2 
Dosage and Administration ................................................................66 
6.2.1 
Part 1, M8891 Single Agent, Solid Tumors .......................................66 
6.2.2 
Part 2, M8891 with Cabozantinib, mRCC ..........................................66 
6.3 
Assignment to Treatment Groups .......................................................67 
6.4 
Non-investigational Medicinal Products to be Used ..........................67 
6.5 
Concomitant Medications and Therapies ...........................................67 
6.5.1 
Permitted Medicines ...........................................................................67 
6.5.2 
Prohibited Medicines ..........................................................................67 
6.5.3 
Other Interventions .............................................................................68 
6.5.4 
Special Precautions .............................................................................68 
6.5.5 
Management of Specific Adverse Events or Adverse Drug 
Reactions .............................................................................................68 
6.6 
Packaging and Labeling of the Investigational Medicinal Product ....72 
6.7 
Preparation, Handling, and Storage of the Investigational 
Medicinal Product ...............................................................................72 
6.8 
Investigational Medicinal Product Accountability .............................72 
6.9 
Assessment of Investigational Medicinal Product Compliance .........73 
6.10 
Blinding ..............................................................................................73 
6.11 
Emergency Unblinding .......................................................................73 


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6.12 
Treatment of Overdose .......................................................................73 
6.13 
Medical Care of Subjects after End of Trial .......................................73 
7 
Trial Procedures and Assessments ......................................................74 
7.1 
Schedule of Assessments ....................................................................74 
7.2 
Demographic and Other Baseline Characteristics ..............................74 
7.3 
Efficacy Assessments .........................................................................74 
7.4 
Assessment of Safety ..........................................................................74 
7.4.1 
Adverse Events ...................................................................................75 
7.4.2 
Pregnancy and In Utero Drug Exposure .............................................80 
7.4.3 
Clinical Laboratory Assessments .......................................................80 
7.4.4 
Vital Signs, Physical Examinations, and Other Assessments.............81 
7.4.5 
Electrocardiograms .............................................................................81 
7.5 
Pharmacokinetics ................................................................................82 
7.5.1 
Part 1, M8891 Single Agent, Solid Tumors .......................................82 
7.5.2 
Part 2, M8891 with Cabozantinib, mRCC ..........................................83 
7.6.1 
Part 1, M8891 Single Agent, Solid Tumors .......................................84 
7.6.2 
Part 2, M8891 with Cabozantinib, mRCC ..........................................85 
7.7 
Other Assessments ..............................................................................86 
8 
Statistics ..............................................................................................86 
8.1.1 
Part 1, M8891 Single Agent, Solid Tumors .......................................86 
8.1.2 
Part 2, M8891 with Cabozantinib, mRCC ..........................................87 
8.2 
Randomization ....................................................................................87 
8.3 
Endpoints ............................................................................................88 
8.3.1 
Part 1, M8891 Single Agent, Solid Tumors .......................................88 
8.3.2 
Part 2, M8891 with Cabozantinib, mRCC ..........................................89 
8.4 
Analysis Sets .......................................................................................89 
8.5 
Description of Statistical Analyses .....................................................90 
8.5.1 
General Considerations .......................................................................90 
8.5.2 
Efficacy Analysis ................................................................................91 
8.5.3 
Safety Analysis ...................................................................................92 
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8.5.4 
Pharmacokinetics ................................................................................95 
8.5.5 
Analysis of Other Endpoints ...............................................................96 
8.6 
Interim and Additional Planned Analyses ..........................................97 
8.6.1 
Part 1, M8891 Single Agent, Solid Tumors .......................................97 
8.6.2 
Part 2, M8891 with Cabozantinib, mRCC ..........................................97 
9 
Ethical and Regulatory Aspects ..........................................................97 
9.1 
Responsibilities of the Investigator ....................................................97 
9.2 
Subject Information and Informed Consent .......................................97 
9.3 
Subject Identification and Privacy ......................................................98 
9.4 
Emergency Medical Support and Subject Card ..................................99 
9.5 
Clinical Trial Insurance and Compensation to Subjects .....................99 
9.6 
Independent Ethics Committee or Institutional Review Board ..........99 
9.7 
Health Authorities .............................................................................100 
10 
Trial Management .............................................................................100 
10.1 
Case Report Form Handling .............................................................100 
10.2 
Source Data and Subject Files ..........................................................100 
10.3 
Investigator Site File and Archiving .................................................101 
10.4 
Monitoring, Quality Assurance and Inspection by Health 
Authorities ........................................................................................101 
10.5 
Changes to the Clinical Trial Protocol ..............................................102 
10.6 
Clinical Trial Report and Publication Policy ....................................102 
10.6.1 
Clinical Trial Report .........................................................................102 
10.6.2 
Publication ........................................................................................102 
11 
References Cited in the Text .............................................................102 
12 
Appendices .......................................................................................105 
Appendix I 
Contraceptive Guidance and Woman of Childbearing Potential ......105 
Appendix II 
Drugs which are potent combined CYP2C9, CYP2C19 and 
CYP3A4 inhibitors ...........................................................................107 
Appendix III 
Laboratory Tests (Only for Part 2 of the study) ...............................108 
Appendix IV 
Protocol Amendment History ...........................................................109 
Appendix V 
Signature Pages and Responsible Persons for the Trial ....................115 
Sponsor Signature Page ...................................................................................................116 
Signature Page –Coordinating Investigator .....................................................................117 


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Signature Page – Principal Investigator ...........................................................................118 
Sponsor Responsible Persons Not Named on the Cover Page ........................................119 
Sponsor Responsible Persons Not Named on the Cover Page ........................................120 
Sponsor Responsible Persons not Named on the Cover Page .........................................121 
Table of In-Text Tables 
Table 1 
Schedule of Assessments for Part 1, M8891 Single Agent, Solid 
Tumors ................................................................................................22 
Table 2 
Schedule of Assessments for Part 2A, M8891 Combined with 
Cabozantinib, mRCC, Dose Escalation ..............................................25 
Table 3 
Schedule of Assessments for Part 2B, M8891 Combined with 
Cabozantinib, mRCC, Dose Expansion ..............................................28 
Table 4 
Schedule of Pharmacokinetic, Electrocardiogram Assessments 
and Food Guidance during Part 2A M8891 Combined with 
Cabozantinib, mRCC, Dose Escalation ..............................................30 
Table 5 
Schedule of Pharmacokinetic and Electrocardiogram Assessments 
during Part 2B M8891 Combined with Cabozantinib, mRCC, 
Expansion Cohort ...............................................................................32 
Table 6 
Part 2A Objectives and Endpoints ......................................................39 
Table 7 
Part 2B Objectives and Endpoints ......................................................41 
Table 8 
Recommendation to the Investigator for M8891 Dose Adjustment 
Based on Non-hematological Adverse Events ...................................53 
Table 9 
Dose Reductions of Cabozantinib ......................................................54 
Table 10 
Dose Modifications of Cabozantinib for Treatment Related AEs ......54 
Table 11 
First in Human Starting Dose Calculated from Results of 4-week 
Repeat-Dose Toxicity Studies in Rats and Dogs ................................56 
Table 12 
Management of Specific AEs with M8891 Combined with 
Cabozantinib .......................................................................................68 
Table 13 
Analysis Sets .......................................................................................90 
Table 14 
Combined Potent Inhibitors ..............................................................107 
Table of In-Text Figures 
Figure 1 
Study Design .......................................................................................44 
 


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List of Abbreviations 
AE 
Adverse Event  
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BED 
Biologically effective dose 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CR 
Complete response 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DDI 
Drug-drug interaction 
DLT 
Dose limiting toxicity 
DoR 
Duration of response 
DVT 
Deep vein thrombosis  
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
EOT 
End of treatment 
FBE 
Free-Base Equivalent 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
ICB 
Immune Checkpoint Blockade 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
LMWH 
Low-molecular-weight heparin  
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LSFD 
Last Subject First Dose  
LLOQ 
Lower limit of quantification 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoA 
Mode of Action 
mRCC 
Metastatic renal cell carcinoma 
MRI 
Magnetic resonance imaging 
ms 
milliseconds 
mTOR 
mammalian target of rapamycin 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network  
NCI-
CTCAE 
National Cancer Institute – Common Terminology Criteria for AEs 
NOAEL 
No observed adverse effect levels 
ORR 
Objective response rate 
PD 
Progressive disease 
PD-1 
Programmed death-1 
PD-L1 
Programmed death-ligand 1  
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
QD 
Once daily 
QTcF  
QT interval corrected for heart rate according to Fridericia 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RDE 
Recommended dose for expansion 
RP2D 
Recommended Phase II dose 
SAE 
Serious adverse event 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
SoA 
Schedule of Assessments 
SOC 
System Organ Class 
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SoC 
Standard of care 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitor  
ULN 
Upper limit of normal 
USPI 
US-Prescribing Information  
VEGF 
Vascular endothelial growth factor  
VEGFR 
Vascular endothelial growth factor receptor 
VTE 
Venous thromboembolism 
WBC 
White blood cells 
WOCBP 
Woman of childbearing potential 
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Objectives:  
Part 1, M8891 Single Agent, Solid Tumors 
Primary: 
x To determine the maximum tolerated dose (MTD) of M8891 as a single agent in 
subjects with solid tumors. 
Secondary: 
x To evaluate the safety profile and tolerability of M8891 as a single agent 
x To investigate the pharmacokinetic (PK) profile of M8891 as single agent 
x To assess the antitumor activity of M8891 as single agent according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 
x To determine the recommended Phase II dose (RP2D) as single agent. 
Part 2, M8891 Combined with Cabozantinib, Metastatic Renal Cell Carcinoma (mRCC) 
Part 2A, Dose Escalation 
Primary: 
x To determine the recommended dose for expansion (RDE) (MTD, if reached) of 
M8891 combined with cabozantinib in subjects with mRCC, based on safety, 
tolerability, and antitumor activity  
Secondary: 
x 
To characterize the PK profile of M8891 (single and multiple dose exposure) 
combined with cabozantinib in subjects with mRCC  
x 
To further assess antitumor activity of M8891 combined with cabozantinib in subjects 
with mRCC 
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Part 2B, Expansion Cohort 
Primary: 
x 
To determine recommended Phase II dose (RP2D) of M8891 combined with 
cabozantinib in subjects with mRCC based on antitumor activity and safety.  
Secondary: 
x 
To assess other measures of antitumor activity of M8891 combined with cabozantinib 
in subjects with mRCC.  
x 
To characterize the PK profile of M8891 (single and multiple dose exposure) in 
subjects with mRCC. 
Methodology:  
This is a 2-part, Phase I/Ib, first in human, multicenter, open-label trial of M8891 administered 
daily.  
Part 1 is a dose-escalation study designed to explore the safety, tolerability, PK and 
 profiles, 
and clinical activity of M8891 as a single agent across cycles of 21-day treatment, in subjects 
with advanced solid tumors with no surgical, radiation, or systemic anticancer therapies 
available. 
Part 2 is designed to determine the safety, tolerability, and anti-tumor activity of M8891 
combined with cabozantinib in subjects with mRCC. In Part 2A, a dose escalation (Part 2A) 
and an expansion cohort (Part 2B) design are planned. 
In Part 2A, escalating doses of M8891 will be combined with cabozantinib in subjects with 
mRCC who have progressed to 1 or more previous lines of systemic anticancer therapy, 
excluding treatment with cabozantinib. The Part 2A of the study allows subjects accrual in a 
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or worsen between start of study intervention and 30 days after end of study intervention 
will be considered TEAEs 
• Study clinically relevant abnormal changes in clinical laboratory measures from baseline, 
vital signs, ECOG performance status, and ECGs from start of study intervention to 30 days 
after end of study intervention 
• Objective Response according to RECIST v1.1 as assessed by Investigators 
Secondary endpoints:  
• Duration of Response (DoR) according to RECIST v1.1 criteria as assessed by 
Investigators  
• PFS time according to RECIST v1.1 criteria as assessed by Investigators 
Part 2B, Expansion Cohort 
Primary endpoints: 
• Occurrence of study serious AEs including deaths from first dose of study intervention to 
30 days after end of study intervention 
• Study clinically relevant abnormal changes in clinical laboratory measures from baseline, 
vital signs, ECOG PS, and ECGs from start of study intervention to 30 days after end of 
study intervention 
• Occurrence of TEAEs (including deaths) from start of the study intervention to 30 days 
after end of the study intervention 
• Objective response according to RECIST v1.1 criteria as assessed by Investigators  
Secondary endpoints:  
• DoR according to RECIST v1.1 criteria as assessed by Investigators  
• PFS time according to RECIST v1.1 criteria as assessed by Investigators 
Pharmacokinetics 
Part 1, M8891 Single Agent, Solid Tumors 
• PK parameters of M8891 after QD dosing, as applicable: Cmax, tmax, AUC0-t, AUC0-∞, 
AUC0-τ, t1/2, λz, CL/F, CLss/F, Vz/F, Racc(AUCτ) and Racc(Cmax)  
Part 2, M8891 Combined with Cabozantinib, mRCC 
Part 2A, Dose Escalation  
• PK parameters of M8891 in terms of Cmax, tmax, AUC0-t on Day 1 Cycle 1, (combined with 
cabozantinib, single dose)  
• PK parameters of M8891 in terms of Cmax, tmax, AUC0-t on Day 8 and Day 15 Cycle 1, and 
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• Histologically confirmed advanced solid tumors with no clear curative treatment options 
available after at least 1 prior systemic anticancer therapy  
• Tumor accessible for biopsies and agreement to conduct pre-dose and post-dose fresh 
tumor biopsies   
• Male or female subjects at least 18 years of age. 
Key exclusion: 
• ECOG PS ≥ 2 
• Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone 
marrow/stem cell transplantation within 5 years of study start 
• Severe bone marrow, renal or liver impairment 
Part 2, M8891 Combined with Cabozantinib, mRCC 
Key inclusion: 
• Histologic or cytologic evidence/proven of mRCC with clear cell component 
• Previous treatments: 
a. Part 2A: Subjects should have progressed to 1 or more previous lines of systemic 
anticancer therapy, excluding treatment with cabozantinib 
b. Part 2B: Subjects should have progressed to 1 or 2 previous lines of systemic 
anticancer therapy, excluding treatment with cabozantinib. Subjects should have 
failed to only 1 previous TKI for metastatic disease. Adjuvant therapy with sunitinib 
will be considered as 1 line of therapy for metastatic disease in the case that disease 
progression occurs during or within 3 months of the completion of the treatment. 
• At least 1 lesion that is measurable using RECIST v1.1.  
• Adequate organ function (i.e. liver, kidney, bone marrow), as evidenced by multiple 
laboratory value results within specific parameters  
Key exclusion: 
• Previous use of cabozantinib or a MetAP2 inhibitor 
• Thromboembolic 
events 
requiring 
therapeutic 
anticoagulation. 
Concomitant 
anticoagulation at therapeutic doses with oral anticoagulants (i.e., warfarin, direct thrombin 
and Factor Xa inhibitors) or platelet inhibitors (i.e., clopidogrel) started within the last 
6 months of screening 
Note: Low dose aspirin for cardio-protection and low dose low-molecular-weight heparin 
(LMWH) are permitted (in subjects who are on a stable dose of LMWH for at least 6 weeks 


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before the first dose of study treatment, and who have had no clinically significant 
hemorrhagic complications from the anticoagulation regimen or the tumor) 
• Current significant cardiac conduction abnormalities, QT corrected for heart rate according 
to Fridericia (QTcF) interval prolongation of > 450 ms for males and > 470 ms for females 
or cardiovascular disorders, including symptomatic congestive heart failure, unstable 
angina pectoris, and serious cardiac arrhythmias. 
Investigational Medicinal Product: dose/mode of administration/ dosing schedule:  
Part 1, M8891 Single Agent, Solid Tumors 
M8891 in capsule form will be administered orally QD, according to the dose escalation 
schedule and as determined by the safety monitoring committee (SMC). The starting dose of 
initial dose escalation cohort will be 7 mg QD. A Bayesian two-parameter logistic regression 
model with overdose control will be used to assist the SMC with dose selection during the dose 
escalation part. The model incorporates nonclinical toxicity and observed DLT information 
from all previously completed dose escalation cohorts to provide a recommended dose for the 
next cohort. 
Part 2, M8891 Combined with Cabozantinib, mRCC 
Part 2A, Dose Escalation  
M8891 in capsule form combined with cabozantinib will be administered orally QD in the 
morning in fasted conditions. Three pre-specified dose levels of M8891 are planned (20 mg, 
35 mg and 60 mg) combined with 60 mg of cabozantinib.  
A Bayesian two-parameter logistic regression model with overdose control will be used to 
assist the SMC with dose selection for the next cohort and to determine the MTD/RDE of 
M8891 combined with cabozantinib 60 mg QD for Part 2B.  Dose levels may be added or 
skipped for others that are not part of the pre-specified but they will never exceed the dose level 
of M8891 that has already been declared to be safe in Part 1. 
Cabozantinib will be used at the approved 60 mg-free-base equivalent (FBE) daily dosage with 
dosage adjustments to 40 mg FBE or 20 mg FBE permitted to manage AEs. 
Part 2B, Dose Expansion  
In Part 2B, subjects will receive M8891 at the dose level defined in the Part 2A and 
cabozantinib at 60 mg QD in 21-day cycles until disease progression, unacceptable toxicity, 
withdrawal of consent, or any criterion for withdrawal from the study.  
In part 2B, the SMC will continue to monitor the safety of M8891 combined with cabozantinib 
and may recommend on continuation on the same dose, change in dose (not higher than MTD 
defined in Part 2A), or stop of the expansion cohort. Unacceptable toxicity for the expansion 
(Part 2B) cohort will be AEs that fulfill the DLT criteria. The SMC will evaluate the safety and 
cumulated toxicity of the combination therapy after 10 and after 20 subjects, who have finished 


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their DLT period or dropped out. The SMC decisions in the expansion cohort will also be 
supported by a two-parameter Bayesian logistic regression model. Enrollment of subjects will 
not be suspended between SMCs. 
Reference therapy: dose/mode of administration/dosing schedule: 
Not applicable. 
Planned trial and treatment duration per subject:  
Study duration per subject is approximately 8 months for Part 1, and 12 months for Part 2 
including screening, treatment and follow up. Treatment is administered in consecutive 21-day 
cycles of continuous treatment. Subjects will receive study drug at the pre-specified dose level 
until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for 
withdrawal from the trial. 
Statistical methods:  
Part 1, M8891 Single Agent, Solid Tumors 
Analyses will be prepared by dose level. There is no formal significance level for this trial and 
all analyses are considered descriptive.  
Dose escalation will be aided by a Bayesian two-parameter logistic regression model. The SMC 
dedicated to dose escalation decisions will receive results of a Bayesian two-parameter logistic 
model with overdose control updated with the observed DLT data. Recommendation will be 
based on a loss function.  
Part 2, M8891 Combined with Cabozantinib, mRCC 
Part 2A, Dose escalation 
A Bayesian two-parameter logistic regression model with overdose control will be used to 
assist the SMC to select the next dose of M8891 from 3 pre-specified dose levels (20 mg, 
35 mg, and 60 mg QD). The SMC may add or skip a dose, as long as it does not exceed the 
dose level of M8891 that has already been declared to be safe in Part 1. 
Part 2B, Expansion cohort 
A 2-stage design with an interim analysis for futility will be used to evaluate response. 
 
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Table 1 
Schedule of Assessments for Part 1, M8891 Single Agent, Solid Tumors 
Activity / Assessment 
Screening 
On Treatment Visits 
EOT Safety 
F/U a 
 
–28 to -1 
Cycle 1 
Cycle 2 
Cycle 3  
and 
following 
 
 
Cycle Day 
 
1 2 
4 
8 15 16 
1 
8b 
15b 
1 
30 
 
Visit Window 
 
 
 
 
±1 ±1 
 
±2 
±2 
±2 
±2 
±3 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (beta 
hCG)d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X e 
X 
 
X X X 
 
X 
 
 
X 
X 
 
Vital signsf, weight, height (height 
at screening only) 
X 
X 
 
X X X 
 
X 
 
 
X 
X 
 
12-lead ECGg 
X 
X X 
 
X X 
X 
X 
 
 
X 
X 
 
ECOG PS 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
AE assessment  
X 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication  
X 
X X X X X 
X 
X 
X 
X 
X 
X 
 
Hematology, biochemistry, 
coagulationh 
Xe 
X 
 
X X X 
 
X 
 
 
X 
X 
 
Urine dipstick and pregnancy testi 
X 
X 
 
X X X 
 
X 
 
 
X 
 
 
Urine - PK urine samplesl 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Blood - PK blood samplesm 
 
X X 
 
X X 
X 
X 
 
 
X 
 
 
Tumor assessment   
(RECIST v1.1)  
Xr 
X 
 
 
 
 
 
 
 
 
Xs 
X 
 
Drug administration and 
dispensingt 
 
X X X X X 
X 
X 
X 
X 
X 
X 
 
AE: Adverse event; ALT: Alanine aminotransferase; AP: Alkaline phosphatase; aPTT: Activated partial 
thromboplastin time; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; CT: Computed tomography; ECG: 
Electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EOT: End of treatment; 
F/U: Follow up; FSH: Follicle-stimulating hormone; GGT: Gamma-glutamyl transferase; hCG: Human chorionic 
gonadotropin; MRI: Magnetic resonance imaging; INR: International Normalized Ratio; 
; 
 PK: Pharmacokinetic; PT: Prothrombin time; QD: Once daily; RECIST: 
Response Evaluation Criteria in Solid Tumors; SAE: Serious adverse event; SMC: Safety Monitoring Committee; 
WBC: White blood cells.  
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a. Safety follow up will be performed if SAE is not recovered at the EOT, and may be done by phone interview if 
clinical visit is not feasible.  
b. In Cycle 2 and subsequent cycles AE and concomitant medication assessment should be performed at clinic, but 
phone interview is acceptable if subjects have conflict schedule and can’t visit clinic.  
c. The tumor diagnosis must be proved by pathology report.  
d. If applicable additional assessments should be performed as required and if clinically indicated. FSH measured if 
needed to confirm postmenopausal status. 
e. Physical exam, hematology, biochemistry, and coagulation do not have to be repeated on Day 1 if performed 
within 48 hours as a screening/baseline assessment. 
f. Heart rate, diastolic and systolic blood pressure, respiratory rate, body temperature. 
g. 12-lead triplicate digital ECG will be performed with 2-minute intervals after at least 10 minutes rest in supine 
position.  On Cycle 1 Day 1 and Day 15 at pre-dose and 1, 2, 4, 5, 6, 8, 12 hours and 24 hours post-dose (± 15 
minutes) and on pre-dose on Day 8.  The SMC may decide that the Day 15/Day 16 assessment can be waived in 
case no relevant drug accumulation is being observed. ECG assessments at subsequent cycles will be performed 
pre-dose at time points as indicated in the table. ECGs should be performed directly before PK sampling time 
points on days where both assessments are performed.  
h. Hemoglobin, white blood cell count, differential, platelet count, creatinine, creatinine clearance AST, ALT, GGT, 
AP, lipase, amylase, BUN, total bilirubin, total protein, albumin, uric acid, sodium, chloride, bicarbonate, 
potassium, calcium, phosphorus, magnesium and glucose, PT, aPTT and INR.  
i. Standard urine test, and pregnancy test will be done at each visit after Cycle 2 (corresponds to women of 
childbearing potential). 
 
m. PK time points: 3 mL (2 aliquots of 1.5 mL) blood each at following time points: QD dosing: Cycle 1 Day 1: 0 hour 
(pre-dose within 60 minutes prior to each treatment administration) and 1 (± 10 minutes), 2 (± 10 minutes), 3 (± 10 
minutes), 4 (± 20 minutes), 5 (± 20 minutes), 6 (± 30 minutes), 8 (± 30 minutes), 12 hours post-dose (± 60 
minutes), on Day 2 at 24 hours post-dose (before next drug administration) (± 60 minutes). Cycle 1 Day 8: 0 hour 
(pre-dose within 60 minutes prior to treatment administration), Cycle 1 Day 15: 0 hour (pre-dose within 60 minutes 
prior to each treatment administration) and 1 (± 10 minutes), 2 (± 10 minutes), 3 (± 10 minutes), 4 (± 20 minutes), 
5 (± 20 minutes), 6 (± 30 minutes), 8 (± 30 minutes), 12 hours post-dose (± 120 minutes), on Day 16 at 24 hours 
post-dose (before next drug administration) (± 60 minutes), 63 mL blood in Cycle 1. &\FOH'D\KRXUSUH-
dose within 60 minutes prior to each treatment administration).  
p. Pre-dose; optional blood sample: collection will only be performed after an Informed Consent Form has been 
signed.  
r. Imaging (e.g. CT scan) do not have to be repeated on Day 1 if performed within 28 days as a screening/baseline 
assessment. 
s. Imaging analysis must be done with consistent modalities. ± 1 week time window is permitted. Tumor response 
will be assessed on Day 1 of Cycles 3, 5 and 7, and every 18 weeks (6 Cycles) thereafter. Subjects who 
discontinue treatment will undergo EOT visit procedures. 
t. Subjects will receive M8891 once a day, at same time in the morning, in fasted condition for at least 2 hours prior 
and 1 hour post dosing, M8891 will be dispensed on Day 1 of each Cycle. Subjects should be asked to return all 
of the unused trial medication, including the packaging (even if empty), at every dispensing visit.  
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Note: At visits where assessment time points coincide with each other, the following procedure should be followed: 
x 
Perform vital signs assessments slightly before the specific time point 
x 
Perform ECG assessments on time  
x 
PK blood sampling should be done directly after the ECG (e.g. within 10 minutes) 
x 
  
x 
Use of agreed upon time windows will be allowed. 
 
 
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Table 2 
Schedule of Assessments for Part 2A, M8891 Combined with 
Cabozantinib, mRCC, Dose Escalation 
Activity / 
Assessment 
Screening 
On Treatment Visits 
EOTa 
Safety  
F/Ub 
Notes 
 
M8891 
M8891 + Cabozantinib 
 
 
 
 
 
Cycle 
1 
Cycle 
2-4 
Cycle 
5 
Cycle 
7 and on 
 
 
After Cycle 7, 
visits on Day 1 of 
every third cycle 
Cycle Day 
-28 to -2 
-1 
 (-24h) 
c 
1 
8 15 
1 
15 
1 
1 of every 
third cycle 
Within 7 
days of last 
intervention 
30 days 
after last 
dose  
For rescreening 
see Section 5.1.1 
 
Visit Window 
 
 
 
±1 ±1 
±2 
±2 
±3 
±3 
+7 
±7 
 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(beta hCG)d 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs, weight, 
height (height at 
screening only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Heart rate, 
diastolic and 
systolic blood 
pressure, 
respiratory rate, 
body temperature 
12-lead ECG  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Table 4 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AE assessment  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE and 
concomitant 
medication 
assessment 
should be 
performed at 
every visit 
Concomitant 
medication  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Hematology, 
biochemistry, 
coagulation, thyroid 
functionf, urine 
chemistry, serologyg 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Appendix III 
Urine pregnancy test 
 
X 
 
 
 
X 
 
X 
X 
 
 
Appendix III 
Archival tumor biopsy 
(if available)h 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood – PK blood 
sample/s 
M8891 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Table 4 
PK samples will 
be collected only 
until Day 1 
Cycle 2 
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Activity / 
Assessment 
Screening 
On Treatment Visits 
EOTa 
Safety  
F/Ub 
Notes 
 
M8891 
M8891 + Cabozantinib 
 
 
 
 
 
Cycle 
1 
Cycle 
2-4 
Cycle 
5 
Cycle 
7 and on 
 
 
After Cycle 7, 
visits on Day 1 of 
every third cycle 
Cycle Day 
-28 to -2 
-1 
 (-24h) 
c 
1 
8 15 
1 
15 
1 
1 of every 
third cycle 
Within 7 
days of last 
intervention 
30 days 
after last 
dose  
For rescreening 
see Section 5.1.1 
 
Visit Window 
 
 
 
±1 ±1 
±2 
±2 
±3 
±3 
+7 
±7 
 
Blood – PK blood 
sample/s 
cabozantinib 
 
 
X 
X 
X 
X 
 
 
 
 
 
Table 4 
PK samples will 
be collected only 
 until Day 1 Cycle 
2 
Blood – ctDNAj 
 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
Tumor assessment   
(RECIST v1.1)  
Xk 
Xk 
 
 
 
Xl 
 
X l 
X l 
X 
 
 
Drug administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensing every Day 1 of each cycle until Cycle 5 and then on 
Cycle 7 and afterwards every third cycle 
 
 
M8891 
Administration 
 
X 
M8891 given in clinic on C1D1 and taken once daily at 
home thereafter until study treatment is discontinued 
 
Section 5.1.3.2 
Cabozantinib 
Administration 
 
 
Cabozantinib given in clinic on C1D1 and taken once daily 
at home thereafter until study treatment is discontinued 
 
Section 5.1.3.2  
AE: Adverse event; ctDNA: circulating tumor DNA; CT: Computed tomography; ECG: Electrocardiogram; ECOG PS: Eastern 
Cooperative Oncology Group Performance status; EOT: End of treatment; MRI: Magnetic resonance imaging; mRCC: Metastatic 
renal cell carcinoma; PK: Pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: Serious adverse event. 
a. Subjects who discontinue treatment will undergo EOT visit procedures. 
b. Safety follow up will be performed if SAE is not recovered at the EOT. 
d. For Contraception and postmenopausal status see Appendix 1. 
e. Physical exam, hematology, biochemistry, and coagulation do not have to be repeated on Day -1, Cycle 1 (predose) if 
performed within 48 hours as a screening/baseline assessment. 
f. 
Free T4 and TSH must be performed at screening, until Cycle 7 on Day 1 of each odd cycle (C1, 3, 5 , 7), after Cycle 7 on 
Day 1 of every third cycle (7,10, 13, etc), and at EOT (if not performed within the last 8 weeks). Thyroid Function test may be 
performed more frequently if clinically indicated. 
g. Serology should be done only at screening and do not have to be repeated on Day -1, Cycle 1 if performed within 28 days as a 
screening/baseline assessment. 
 
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j. 
Blood – ctDNA: at Day 1 pre-dose and during treatment pre-dose within 60 minutes prior to M8891 combined with cabozantinib 
treatment administration mandatory blood sampling (20 mL each) to assess mutant allele frequency of tumor-derived cell-free 
DNA. 
k. Imaging (e.g. CT scan) do not have to be repeated on Day -1, Cycle 1 if performed within 28 days as a screening/baseline 
assessment. 
l. 
Imaging analysis must be using the same technique during the study, e.g. it’s not allowed to use CT scan at baseline then 
change to MRI during the study. Tumor response will be assessed within 1 week prior to Day 1 of Cycles 3, 5, and 7, and every 
third cycle thereafter. Subjects who discontinue treatment will undergo EOT visit procedures. 
 
 
 


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Table 3 
Schedule of Assessments for Part 2B, M8891 Combined with 
Cabozantinib, mRCC, Dose Expansion 
Activity / 
Assessment 
Screening 
On Treatment Visits 
EOTa 
Safety  
F/Ub 
Notes 
 
 
M8891 + Cabozantinib 
 
 
 
 
 
Cycle  
1 
Cycle 
2-4 
Cycle 
5 
Cycle 
7 and on 
 
 
After Cycle 7, 
visits on Day 1 of 
every third cycle 
Cycle Day 
-28 to -1 
1 
8 
15 
1 
15 
1 
1 of every third 
cycle 
Within 7 
days of last 
intervention 
30 days 
after last 
dose  
For rescreening 
see Section 5.1.1 
Visit Window 
 
 
±1 
±1 
±2 ±2 
±3 
±3 
+7 
±7 
 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(beta hCG)c 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X d 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs, weight, 
height (height at 
screening only) 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Heart rate, 
diastolic and 
systolic blood 
pressure, 
respiratory rate, 
body temperature 
12-lead ECG  
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Table 5 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AE assessment  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE and 
concomitant 
medication 
assessment 
should be 
performed at 
every visit 
Concomitant 
medication  
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology, 
biochemistry, 
coagulation, thyroid 
functione, urine 
chemistry, serologyf 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
 
Appendix III 
Urine pregnancy test 
 
X 
 
 
X 
 
X 
X 
 
 
Appendix III 
Archival tumor biopsy 
(if available)g 
X 
 
 
 
 
 
 
 
 
 
 
Blood – PK blood 
sample/s M8891 
 
X 
X 
X 
 
 
 
 
 
 
Table 5 PK 
samples will be 
collected only until 
Day 15 Cycle 1 
Blood – PK blood 
sample/s 
cabozantinib 
 
X 
X 
X 
 
 
 
 
 
 
Table 5 PK 
samples will be 
collected only until 
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Activity / 
Assessment 
Screening 
On Treatment Visits 
EOTa 
Safety  
F/Ub 
Notes 
 
 
M8891 + Cabozantinib 
 
 
 
 
 
Cycle  
1 
Cycle 
2-4 
Cycle 
5 
Cycle 
7 and on 
 
 
After Cycle 7, 
visits on Day 1 of 
every third cycle 
Cycle Day 
-28 to -1 
1 
8 
15 
1 
15 
1 
1 of every third 
cycle 
Within 7 
days of last 
intervention 
30 days 
after last 
dose  
For rescreening 
see Section 5.1.1 
Visit Window 
 
 
±1 
±1 
±2 ±2 
±3 
±3 
+7 
±7 
 
Tumor assessment   
(RECIST v1.1)  
X 
Xj 
 
 
Xk 
 
Xk 
Xk 
X 
 
 
Drug administration 
 
Dispensing every Day 1 of each cycle until Cycle 5 and then on 
Cycle 7 and afterwards every third cycle 
 
 
M8891 
Administration 
 
M8891 given in clinic on C1D1 and taken once daily at home 
thereafter until study treatment is discontinued 
 
Section 5.1.3.2 
Cabozantinib 
Administration 
 
Cabozantinib given in clinic on C1D1 and taken once daily at 
home thereafter until study treatment is discontinued 
 
Section 5.1.3.2  
AE: Adverse event; 
; CT: Computed tomography; ECG: Electrocardiogram; ECOG PS: Eastern 
Cooperative Oncology Group Performance status; EOT: End of treatment; mRCC: Metastatic renal cell carcinoma; MRI: Magnetic 
resonance imaging; PK: Pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: Serious adverse event.  
a. Subjects who discontinue treatment will undergo EOT visit procedures. 
b. Safety follow up will be performed if SAE is not recovered at the EOT.   
c. For contraception and postmenopausal status see Appendix I. 
d. Physical exam, hematology, biochemistry, and coagulation do not have to be repeated on Day 1 if performed within 48 hours as 
a screening/baseline assessment. 
e. Free T4 and TSH must be performed at screening, until Cycle 7 on Day 1 of each odd cycle (C1, 3, 5), after Cycle 7 on Day 1 of 
every third cycle (Cycle 7, 10, 13 etc), and at EOT (if not performed within the last 8 weeks). Thyroid Function test may be 
performed more frequently if clinically indicated. 
f. 
Serology should be done only at screening and do not have to be repeated on Day -1, Cycle 1 if performed within 28 days as a 
screening/baseline assessment. 
g. Archival tumor tissue (paraffin block) or 15 tumor slides to explore alterations in MetAP2 expression and other biologically 
related markers in correlation with tumor response to M8891 treatment (optional, but strongly recommended). 
j. 
Imaging (e.g. CT scan) do not have to be repeated on Day 1, Cycle 1 if performed within 28 days as a screening/baseline 
assessment. 
k. Imaging analysis must be using the same technique during the study, e.g. it’s not allowed to use CT scan at baseline then 
change to MRI during the study. Tumor response will be assessed, within 1 week prior to Day 1 of Cycles 3, 5, and 7, and every 
third cycle thereafter. Subjects who discontinue treatment will undergo EOT visit procedures. 
 
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Table 4 
Schedule of Pharmacokinetic, Electrocardiogram Assessments and Food 
Guidance during Part 2A M8891 Combined with Cabozantinib, mRCC, 
Dose Escalation 
Treatment Day  
Time 
h (± min)a,b 
ECGc 
PK M8891 
PK 
Cabozantinib 
Day -1, C1 
Pre-dose (-60 min) 
X 
Xd 
 
1 (± 5) 
 
Xd 
 
2 (± 10) 
X 
Xd 
 
3 (± 15) 
 
Xd 
 
4 (± 15) 
 
Xd 
 
6 (± 15) 
X 
Xd 
 
8 (± 15) 
 
Xd 
 
D1 C1 
Pre-dose (-60 min) 
X 
X 
X 
1 (± 5) 
 
X 
 
2 (± 10) 
X 
X 
X 
3 (± 15) 
 
X 
4 (± 15) 
 
X 
 
6 (± 15) 
X 
X 
X 
D8 C1 
Pre-dose (-60 min) 
X  
X 
X 
2 (± 5) 
X 
X 
X 
D15 C1 
Pre-dose (-60 min) 
X 
X 
X 
1 (± 5) 
 
X 
 
2 (± 10) 
X 
X 
X 
3 (± 15) 
 
X 
 
4 (± 15) 
 
X 
 
6 (± 15) 
X 
X 
X 
D1C2 
Pre-dose (-60 min) 
X 
X 
X 
2 (± 10) 
X 
X 
X 
D1C3-5 
Pre-dose (-60 min) 
X 
 
 
1 (± 5) 
X 
 
 
D1C7 (and Day 1 of every third cycle) 
Pre-dose (-60 min) 
X 
 
 
1 (± 5) 
X 
 
 
C: Cycle; D: Day; ECG: Electrocardiogram; eCRF: Electronic case report form; mRCC: Metastatic renal cell carcinoma; PK: 
Pharmacokinetics. 
a. 
At visits where assessment time points (ECG and PK) coincide with each other  
1) 
Perform vital signs assessments at first  
2) 
ECG assessments slightly before the specific collection time point 
  
3) 
PK assessments at scheduled collection time point. 
b. 
Actual collection times should be documented in the eCRF. 


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c. 
Standard triplicate (within 2 min) 12-lead ECG will be obtained after the subject has been rested in semi-recumbent position for 
at least 5 min at the indicated times. ECGs will be also performed during the End of Treatment and Safety Follow-up Visit (30 ± 
7 days). Triplicate ECGs will be read locally. The calculated QTcF interval average of the three 12-lead ECGs must be ≤ 450 
ms for males and ≤ 470 ms for females for elig bility. Subjects, in which the calculated QTcF interval average increases to 
> 500 ms or > 60 ms change over baseline during treatment, must interrupt study treatment until further clinical evaluations 
(See Section 7.4.5). 
d. 
All subjects in Part 2A will receive on Day -1, Cycle 1 a single dose of M8891 with a high calorie, high-fat breakfast. PK data 
collected at the indicated times will be compared with those obtained at the same dose-levels in Part 1 where subjects have 
received M8891 under fasted conditions. 
 
 


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Table 5 
Schedule of Pharmacokinetic and Electrocardiogram Assessments 
during Part 2B M8891 Combined with Cabozantinib, mRCC, Expansion 
Cohort 
Treatment Day  
Time 
h (± min)a,b 
ECGc 
PK M8891 
PK Cabozantinib 
D1 C1 
Pre-dose (-60 min) 
X 
X 
X 
 
2 (± 10) 
X 
X 
 
 
6 (± 15) 
X 
X 
X 
D8 C1 
Pre-dose (-60 min) 
X 
X 
X 
 
2 (± 5) 
X 
X 
X 
D15 C1 
Pre-dose (-60 min) 
X 
X 
X 
 
2 (± 10) 
X 
X 
 
 
6 (± 15) 
X 
X 
X 
D1C2 
Pre-dose (-60 min) 
X 
 
 
 
2 (± 5) 
X 
 
 
D1C3-5 
Pre-dose (-60 min) 
X 
 
 
 
1 (± 5) 
X 
 
 
D1C7 (and Day 1 of every third cycle) Pre-dose (-60 min) 
X 
 
 
 
1 (± 5) 
X 
 
 
C: Cycle; D: Day; ECG: Electrocardiogram; eCRF: Electronic case report form; mRCC: Metastatic renal cell carcinoma; 
PK: Pharmacokinetics. 
a. 
At visits where assessment time points (ECG, and PK) coincide with each other  
1) 
Perform vital signs assessments at first  
2) 
ECG assessments slightly before the specific collection time point 
  
3) 
PK assessments at scheduled collection time point  
b. 
Actual collection times should be documented in the eCRF. 
c. 
Standard triplicate (within 2 min) 12-lead ECG will be obtained after the subject has been rested in semi-recumbent position for 
at least 5 min at the indicated times. ECGs will be also performed during the End of Treatment and Safety Follow-up Visit (30 ± 
7 days). Triplicate ECGs will be read locally. The calculated QTcF interval average of the three 12-lead ECGs must be ≤ 450 ms 
for males and ≤ 470 ms for females for eligibility. Subjects, in which the calculated QTcF interval average increases to > 500 ms 
or > 60 ms change over baseline during treatment, must interrupt study treatment until further clinical evaluations (See 
Section 7.4.5). 
 




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3 
Background Information 
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3.2 
Background 
The discovery of fumagillin with potent anti-angiogenic and anti-proliferative activities promoted 
the development of MetAP2 antagonists as a novel class of anticancer agents. MetAP2 plays an 
important role in the development of different types of cancer. MetAP2 inhibition induces 
cytostasis by cell cycle arrest at the G1 phase selectively in endothelial cells and in a subset of 
tumor cells. MetAP2 inhibitors block neo-angiogenesis both in vitro and in vivo and show potent 
antitumor efficacy in a variety of tumor types in murine models.  
In clinical trials fumagillin proved unsuitable as an anticancer agent due to its pronounced 
neurotoxicity. The reversible MetAP2 inhibitor M8891 is not chemically related to fumagillin and 
has not shown signs of neurotoxicity in toxicology studies. In comparison to irreversible MetAP2 
inhibitors it has the promise of an improved safety and tolerability profile, which is the prerequisite 
for administration over extended periods.   
RCC represents a heterogeneous group of cancers that arise from the kidney. The most common 
histological variant of RCC is clear cell RCC, which comprises about 70% of RCC and has the 
highest metastatic potential (Moch 2016). The genetic basis of clear cell RCC is via a biallelic 
inactivation of the VHL tumor suppressor gene (present in 70% of clear cell cancers) located on 
the short arm of chromosome 3 (3p25.3), which encodes for the degradation of HI)Į (Kim 2004).  
Medical treatment for mRCC has expanded considerably from a nonspecific immune approach to 
targeted therapies against VEGFR and mammalian target of rapamycin (mTOR). Today the 
salvage approach has evolved, to include immune checkpoint blockade (ICB) targeting 
programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) (Salgia 2019). VEGFR 
TKIs alone, ICB, or VEGFR TKIs combined with ICB are preferred options for first-line treatment 
of mRCC. Cabozantinib, nivolumab, and axitinib are preferred subsequent therapy options. Given 
that cabozantinib appears to be active following earlier ICB and TKI regimens (as monotherapy 
or as combinations) (Barata 2018; Powles 2018.) and the MoA of MetAP2 inhibition is 
independent of the ICB MoA, a combination that synergizes with cabozantinib would still be 
expected to show efficacy.  
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3.3 
Benefit/Risk Assessment 
Based on the nonclinical data on M8891 showing evidence of tumor stasis and prolonged survival 
after single-agent use in xenograft models, and after combination with cabozantinib in RCC 
patient-derived xenograft models, the conduct of this trial is considered justifiable using the 
dose(s) and dosage regimen(s) of the investigational drug as specified in this clinical trial protocol. 
Refer to the M8891 Investigator’s Brochure (IB) for further information about the nonclinical 
program. Based on the clinical data to date from the ongoing single agent study with M8891 (Part 
1) and the known safety profile of cabozantinib, the safety measures such as stringent eligibility, 
routine safety monitoring along with AE reporting for the proposed study are considered adequate. 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP and 
any additional applicable regulatory requirements. 
3.3.1 
M8891 
More detailed information about the anticipated benefits and risks based on nonclinical data of 
M8891 is presented in Section 3.1 and the M8891 IB. 
Based on the currently available data, M8891 (parent drug) is predicted to exhibit a low drug-drug 
interaction (DDI) potential as perpetrator of CYP3A4 sensitive substrates at doses at the upper 
range of the estimated BED (60 mg QD). The DDI potential as victim of strong CYP3A4, 2C19 
and 2C9 inhibitors is predicted to be weak, and as victim of a combined CYP3A4, 2C19 and 2C9 
inhibitor to be only in the moderate range. 
No relevant effects on cardiovascular, respiratory, or central nervous system function are 
anticipated from the in vitro and in vivo safety pharmacology studies for the expected clinically 
relevant exposures. 
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The lymphatic and hematopoietic system including the bone marrow, the spermatogenetic 
epithelium and epithelia of the gastrointestinal tract were the main toxicity target organs of M8891 
in pivotal 4-week oral repeat-dose toxicity studies in rats and dogs with no observed adverse effect 
levels (NOAELs) of 3 mg/kg/day and 0.75 mg/kg/day, respectively. M8891 was devoid of 
genotoxic, phototoxic and skin irritating potential. 
Since the start of Part 1, until the 16 Mar 2019 data cut, a total of 17 subjects with various solid 
tumors have received M8891 in doses ranging from 7 mg to 60 mg with a minimum of 3 subjects 
per dose level.  Preliminary data from this ongoing Part 1 of the study have shown that the oral 
exposure of M8891 increased reasonably in direct proportion to the dose up to 35 mg QD, whereas 
at dose of 60 mg QD exposure seems to increase less than in direct proportion to the dose. No 
safety concerns have been raised (refer to M8891 IB). QT corrected for heart rate according to 
Fridericia (QTcF) interval prolongation is currently investigated in the ongoing Part 1 of the study 
using 12-lead triplicate digital ECGs. There is no preclinical or preliminary clinical evidence that 
M8891 is leading to QTcF interval prolongation.  
3.3.2 
Cabozantinib 
Cabozantinib is indicated for the treatment of patients with mRCC. The recommended dosage of 
cabozantinib in mRCC is 60 mg once daily without food until the patient no longer experiences 
clinical benefit or experiences unacceptable toxicity (Cabometyx USPI 2019). 
3.3.3 
M8891 combined with cabozantinib 
Promising signals for the activity of M8891 combined with cabozantinib have been observed in 
nonclinical studies (Refer to the M8891 IB).  
Thromboembolic events have been reported with the use of cabozantinib or MetAP2 inhibitors 
and specific exclusion criteria have been defined to reduce the risk for this overlapping toxicity. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of M8891 and cabozantinib may be found in Sections 3.1 and 6.5.5, the M8891 IB, 
as well as the cabozantinib US-Prescribing Information (USPI). 
Risks for potential DDIs of M8891 with cabozantinib are predicted to be small. This is based on 
mechanistic static modeling approaches using reported data for cabozantinib, i.e. an observed AUC 
increase of 38% when combined with the strong CYP3A4 inhibitor ketoconazole and a total 
fraction metabolized of 0.7 (worst case scenario considering 27.3% renal elimination), respectively 
(Nguyen 2015; Lacy 2015).  Combining with nonclinical DDI and human exposure data of M8891 
(Refer to the M8891 IB) a small AUC ratio of only 1.2 (maximal 1.2-fold increase in cabozantinib 
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exposure) based on time dependent inhibition (TDI) of CYP3A4 by M8891 was estimated. 
Because labeling information recommends a dose adaption of cabozantinib when used in 
combination with strong inducers or inhibitors of CYP3A4 only, it is sufficient to monitor 
cabozantinib exposure when combined with M8891. Based on information reported for 
cabozantinib, the victim potential of M8891 - when combined with cabozantinib - is considered as 
very low. 
Overall, the available clinical data generated to date indicate a positive benefit risk profile for this 
new combination and therefore it is considered justifiable to conduct the study, as specified in this 
protocol. 
4 
Trial Objectives 
4.1 
Part 1, M8891 Single Agent, Solid Tumors 
In the Part 1 of this study, M8891 will be administered as single agent in subjects with advanced 
solid tumors. 
4.1.1 
Primary Objectives 
The primary objective is: 
x To determine the maximum tolerated dose (MTD) of M8891 as a single agent in subjects with 
solid tumors. 
4.1.2 
Secondary Objectives 
Secondary objectives are: 
x To evaluate the safety profile and tolerability of M8891 as a single agent 
x To investigate the PK profile of M8891 as single agent 
x To assess the antitumor activity of M8891 as single agent according to Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 
x To determine the recommend Phase II dose (RP2D) as single agent. 
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AE: Adverse event; DoR: Duration of response; DLT Dose limiting toxicity; ECG: Electrocardiogram; ECOG PS: 
Eastern Cooperative Oncology Group Performance Status; 
; mRCC: Metastatic 
renal cell carcinoma; MTD: Maximum tolerated dose; PFS: Progression-free survival; PK: Pharmacokinetic; RECIST: 
Response Evaluation Criteria in Solid Tumors; RP2D: Recommended Phase II dose; TEAE-Treatment emergent 
adverse event; 
; 
 
5 
Investigational Plan 
5.1 
Overall Trial Design and Plan 
This is a 2-part, Phase I/Ib, first in human, multicenter, open-label trial of M8891 administered 
daily.  
Part 1 is a dose-escalation study designed to explore the safety, tolerability, PK and 
 profiles, 
and clinical activity of M8891 as a single agent in subjects with advanced solid tumors with no 
surgical, radiation, or systemic anticancer therapies available. 
Part 2 is designed to determine the safety, tolerability, PK and antitumor activity of M8891 
combined with cabozantinib in subjects with mRCC. Part 2 will be conducted in subjects with 
mRCC with clear cell component who have progressed to 1 or more prior therapy (Part 2A) or 
who have progressed to 1 or 2 lines of prior therapy (Part 2B) (Section 5.3.1.2). Part 2 of the study 
will be performed with a dose escalation (Part 2A) and a dose expansion (Part 2B) design. Part 2A 
is aimed at determining the MTD/RDE of M8891 combined with cabozantinib based on safety, 
tolerability, PK, and initial efficacy data.  
The Part 2A of the study allows subject accrual in a staggered manner. Thus, enrollment in Part 
2A can occur while Part 1 is still ongoing; however, enrollment will only be at a dose level of 
M8891 that has already been determined safe in Part 1 of the study. 
Following Part 2A, the safety and tolerability of M8891 (at the MTD/RDE defined in Part 2A) 
combined with cabozantinib will be investigated in an expansion cohort (Part 2B) of approximately 
30 evaluable for response subjects with mRCC for assessment of early clinical activity.  
In Part 2 (Part 2A and 2B) cabozantinib will be given at the approved 60 mg FBE daily dosage 
with dosage adjustments to 40 or 20 mg FBE permitted to manage AEs. In Part 2A, 3 prespecified 
dose levels of M8891 are planned (20 mg, 35 mg and 60 mg), although the SMC may add or skip 
a dose, as long as it does not exceed the dose level of M8891 that has already been declared to be 
safe in Part 1 (Section 5.1.3.2.1) . 
Each part of the study will include a Screening period of up to 28 days, a study intervention period 
consisting of 21-day cycles of M8891 single agent (Part 1) and M8891 combined with cabozantinib 
(Part 2), an End of Study Intervention visit (within 7 days), and a Safety Follow-up period of 
30 (± 7) days. Subjects who discontinue study intervention for any reason will complete the End 
of Study Intervention and Safety Follow-up visits. In Part 2A, before Cycle 1 of all dose levels, 
subjects will receive a single dose of M8891 in the morning in fed conditions (Day -1, Cycle 1) 
and the PK profile of M8891 will be evaluated pre-dose, 1, 2, 3, 4, 6, 8 and 24h (Day 1, Cycle 1) 
after administration (Section 5.1.3.2.1). Subsequently on Day 1 Cycle 1, subjects will initiate 
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treatment with M8891 combined with cabozantinib QD orally every morning under fasted 
conditions.  
Study duration per subject is approximately 8 months for Part 1, and 12 months for Part 2 including 
screening, treatment and follow up. 
The design of this study is presented in  
Figure 1 and a detailed Schedule of Assessments (SoAs) is provided in Table 1, Table 2, Table 3, 
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AE: Adverse event; DL: Dose level; FBE Free-base equivalent; MTD: Maximum tolerated dose; QD: Once daily; SMC: Safety Monitoring Committee; RP2D: 
Recommended Phase 2 Dose; mRCC: metastatic renal cell carcinoma; 
. 
a. 
The MTD of M8891 single agent will be defined, and RP2D of M8891 single agent suggested, by the SMC. 
b. 
Subjects should have progressed to 1 or more previous lines of systemic anticancer therapy, excluding treatment with cabozantinib. 
c. 
Cabozantinib will be given at the approved 60 mg FBE daily dosage with dosage adjustments to 40 mg or 20 mg permitted to manage AEs. 
f. 
30 subjects evaluable for response. 
g. 
The DLT assessment period for Part 2A is the Cycle 1 (= 22 days, 21 days of M8891 combined with cabozantinib, preceded by 1 day of M8891 alone) of study 
treatment. The rest of the Cycles in Part 2A are 21-day cycles of M8891 combined with cabozantinib. 
h. 
See Section 8.5.1 for the Bayesian two-parameter logistic regression model.  
 
 
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5.1.1 
Screening Period 
Screening will be performed within 28 days prior to first M8891 administration (Part 1 and Part 2). 
If there are no clinically significant findings based upon the Investigator’s assessment, other than 
underlying tumor disease at Screening and the subject meets all the protocol-defined inclusion and 
none of the exclusion criteria, the subject will be considered as eligible. For dose-escalation Part 1 
and Part 2A, eligible subjects screened for the next cohort will only be treated pending decision 
by the SMC. Subjects who fail to meet the protocol-specified criteria or who withdraw their 
consent during the screening period will be considered screening failures. 
Subjects in Part 2 who do not meet the laboratory criteria (see Section 5.3.1) or for any reason 
exceed the screening period time for participation in this study (screen failure) may be rescreened 
once. Rescreened subjects will be assigned a new subject number. 
5.1.2 
Doppler Ultrasonography: 
Version 2.0, including amendment 1.0, of this protocol excluded subjects with the presence of 
deep vein thrombosis (DVT) based on screening lower extremity Doppler ultrasonography but not 
on D-dimer levels.  D-dimer has low specificity in the oncology setting (Carrier 2008) and 
therefore adds little value to the screening. Lower extremity Doppler ultrasonography was 
performed at screening, the D1, D8, and D15 of Cycle 1, and the D1 of each subsequent cycle (21 
days) and withdraw subjects with a positive finding on lower extremity Doppler ultrasonography.  
Multiple guidelines recommend clinical prediction rules to estimate pretest probability of DVT 
before ultrasound or other imaging tests ordering. Lower extremity Doppler ultrasonography is the 
standard imaging test for patients suspected of having lower extremity DVT. A venous ultrasound 
does not exclude the presence of a pulmonary embolism or portal vein thrombosis, neither predicts 
their development in the future. After an unlikely clinical pretest probability of DVT based on a 
clinical decision rule assessment, a venous ultrasound is not appropriate for those individuals 
(Needleman 2018). 
In the current Version 4.0 of this protocol, Part 1 has been revised such that D-dimer will no longer 
be monitored and the related exclusion criteria altered (See Table 1 and Section 5.3.2). In the 
remainder of the ongoing Part 1 and in Part 2, of this study, all subjects will have physical 
examination for the occurrence of venous thromboembolism (VTE), and imaging tests (e.g. lower 
extremity Doppler ultrasonography, chest computed tomography (CT) angiography, liver 
ultrasonography, or others) will be performed accordingly. Subjects with thromboembolic events 
in the last 6 months, requiring therapeutic anticoagulation will be excluded. Low dose aspirin for 
cardioprotection and low dose LMWH will be permitted (in subjects who are on a stable dose of 
LMWH for at least 6 months before the first dose of M8891 combined with cabozantinib, and who 
have had no clinically significant hemorrhagic complications from the anticoagulation regimen or 
the tumor).  
The current clinical trial protocol (Version 4.0) has taken into consideration the updated clinical 
practice guidelines for VTE risk assessment in cancer patients. The NCCN guidelines describe that 
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antiangiogenic agents are associated with increased VTE risk. The Khorana Predictive model for 
chemotherapy-associated VTE is the one recommended (Khorana 2008) for identifying cancer 
patients receiving chemotherapy who are at high risk for VTE. The risk factors identified by 
Khorana et al (Khorana 2008), which formed the basis for the risk assessment models, set the stage 
for prospective, confirmatory randomized clinical trials evaluating the risks and benefits of risk-
targeted prophylaxis in ambulatory cancer patients receiving chemotherapy. Doppler 
ultrasonography is not included in the VTE Clinical Risk. American Society of Clinical Oncology 
(ASCO) recommends that outpatient candidates for chemotherapy should be scored according to 
the Khorana model or other validated scores at the time of chemotherapy initiation and periodically 
thereafter (Lyman 2015). The use of the Khorana Predictive model is a 2A level recommendation 
(moderate benefit-risk) in the NCCN guidelines. The European Society of Medical Oncology 
(ESMO) (Mandala 2011), and the National Institute of Health and Care Excellence guidelines 
(NICE) (Howard 2013) also include the Khorana Score along with other validated scores as an 
option to guide the decision-making regarding prophylaxis of patients receiving chemotherapy.  
5.1.3 
Treatment Period: 
5.1.3.1 
Part 1, M8891 Single Agent, Solid Tumors 
The treatment period will begin at the first dose of M8891 in Cycle 1 Day 1 and consist of 
consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions.  
Subjects will receive M8891 at the pre-specified dose level until disease progression, unacceptable 
toxicity, withdrawal of consent, or any criterion for withdrawal from the study (Section 5.5.2).  
If the subject tumor evaluation indicates that the disease is slowly progressing according to the CT 
scan as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria (a growth of the 
target lesions of less than 35% from baseline and no new lesions, or new lesion(s) smaller than 
1 cm; bone metastatic lesions or lesions treatable with local radiotherapy would also fall in the 
same category), but the subject performance status is the same as baseline and there are no safety 
concerns, i.e. no ongoing symptomatic events Grade 2 or higher in severity, treatment may be 
continued for another 2 cycles to the next tumor evaluation, upon evaluation by the treating 
physician and after the continuation of therapy has been discussed with the Sponsor.  
In principle, dose escalation of M8891 will proceed according to the decision of the SMC to the 
MTD, or the SMC may decide ceasing further dose escalation following review of safety, 
tolerability, PK and 
results.   
The selection of the recommended dose for the expansion cohort of M8891 is based on the 
following criteria derived from the PK/
 model:  
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The MS100015-0019 trial employs a Bayesian two-parameter logistic regression model with 
overdose control to assist the SMC with dose selection (Babb 1998; Neuenschwander 2008). The 
model incorporates nonclinical toxicity and observed DLT information from all previously 
completed dose escalation cohorts to provide a dose recommendation for the next dose cohort. The 
SMC will decide on the next dose level based on the Bayesian model, safety, PK analyses 
 
 'RVH escalation will start at 7 mg 
administered once daily. 
A preselected set of doses (8 projected escalation steps with doses of 7, 12, 20, 35, 60, 100, 150 
and 210 mg QD) are considered by the model, although doses may be skipped and/or others that 
are not part of the pre-specified set may be chosen as well. Sequential cohorts of 3 subjects at the 
same dose level will be used. 
At each dose level, and following initiation of dosing, the first subject in each cohort will be 
observed for DLTs for at least 7 days before commencing dosing of 2 subsequent subjects. The 
SMC may choose to reduce or extend 7-day intra-patient observation interval up to ± 7 days based 
upon safety observations. The DLT assessment period is Cycle 1 (= 21 days). Subjects who missed 
more than 4 cumulative days of treatment in the first cycle for any reason other than a DLT will 
not be considered in the Bayesian model. An SMC meeting with selection of dose for next cohort 
will also be held if only data from 2 subjects of a 3 subject cohort are available (e.g. if a subject 
missed more than 4 cumulative days of treatment in the first cycle for any reason other than a 
DLT). Subject replacement will be considered based on reason for withdrawal and safety 
evaluation of cumulative data i.e. current and previous cohort data if applicable.   
5.1.3.2 
Part 2, M8891 combined with Cabozantinib, mRCC 
5.1.3.2.1 
Part 2A, Dose Escalation 
In Part 2A, before Cycle 1 Day 1 of all dose levels, subjects will receive a single dose of M8891 
in the morning in fed conditions (Day -1, Cycle 1) and the PK profile of M8891 will be evaluated. 
Subsequently on Day 1 Cycle 1, subjects will initiate treatment with M8891 combined with 
cabozantinib QD orally every morning under fasted conditions.  Following Cycle 1, all other cycles 
will start with Day 1 and will include only the 21 days of M8891 combined with cabozantinib. 
Subjects will accrue in cohorts of 3 subjects for evaluation of M8891 combined with cabozantinib 
60 mg QD (with dosage adjustments to 40 or 20 mg FBE permitted to manage AEs as described 
in Section 6.5.5). Both drugs will be taken in the morning in fasted conditions. A Bayesian 
2-parameter logistic regression model with overdose control will be used to assist the SMC with 
dose selection for the next cohort and to determine the MTD/RDE of M8891 combined with 
cabozantinib 60 mg QD for Part 2B.  
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Three pre-specified dose levels of M8891 are planned (20 mg, 35 mg and 60 mg) combined with 
60 mg of cabozantinib. Dose levels may be added or skipped for others that are not part of the pre-
specified set but they will never exceed the dose level of M8891 that has already been declared to 
be safe in Part 1. The dose levels have been chosen based on preliminary data from the ongoing 
Part 1 of the study. At the time of Amendment 2, M8891 single agent was being investigated at 60 
mg QD in subjects with solid tumors. PK
 studies have shown that the 20, 35 and 60 mg QD 
regimens reached pre-VHOHFWHGH[SRVXUHQJP/DWVWHDG\VWDWHZKLOH
 
. Three and 5 GUDGH 3 
TEAEs have been seen at 20 and 35 mg QD regimen, respectively. One DLT (Grade 4 
thrombocytopenia) has been observed in the ongoing 60 mg QD cohort (Refer to the M8891 IB).  
Dose escalation of the combination will proceed until the RDE of M8891 is reached in combination 
with a fixed dose of cabozantinib or dose escalation ends due to occurrence of an MTD, or the 
SMC decides ending dose escalation following review of safety, tolerability, and PK results, 
whatever occurs first. The maximum dose of M8891 combined with cabozantinib will not exceed 
the MTD of M8891 in monotherapy determined in Part 1 of the study.  
Subjects will receive M8891 at the assigned dose level and cabozantinib at 60 mg QD until disease 
progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from 
the study (Section 5.5). Unacceptable toxicity in Part 2A is defined as AEs that meet the DLT 
criteria (Section 5.1.3.3) regardless of when they occur during treatment. An SMC meeting will 
be held after every cohort to evaluate the safety and tolerability of the combination and to decide 
on the dose of M8891 for the next cohort.  
During Part 2A the selection of the dose will only influence the dose of M8891. Cabozantinib will 
be given at the approved dose of 60 mg QD. Subjects who develop a DLT during the DLT period, 
will discontinue treatment with M8891 and will be withdrawn from the study. It will at the 
Investigator’s discretion to continue treatment with cabozantinib or not. The SMC will meet after 
the completion of each cohort, evaluate the safety of M8891 (combined with cabozantinib), and 
decide on the recommended dose of M8891. During the treatment phase of the study, guidance for 
M8891 dose reduction for safety and tolerability is provided in Section 5.1.3.5. Reduction of 
cabozantinib dose in accordance with the USPI (Refer also to Section 5.1.3.5) will be at the 
Investigator’s discretion based on clinical judgement for safety and tolerability. 
At each dose level, the first subject will be observed for DLTs for at least 48 h before commencing 
dosing of 2 subsequent subjects. The DLT assessment period for Part 2A is the first Cycle 
(= 22 days, 21 days of M8891 combined with cabozantinib, preceded by 1 day of M8891 alone) 
of study treatment. Subjects who do not receive at least 80% of the planned cumulative dose of 
both treatments in Cycle 1 for any reason other than a DLT will not be considered in the DLT 
evaluation per Bayesian model. Subjects will be replaced to reach a minimum of 2 evaluable 
subjects per cohort. 
In cases where enrollment of the 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 the DLT period. For this subject, the SMC will consider all available 
data (and any subsequent emerging data) at a subsequent meeting. An ad-hoc meeting will be 
convened if this subject experiences a DLT. 
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5.1.3.2.2 
Part 2B, Expansion Cohort 
In Part 2B, subjects will receive M8891 at the dose level defined in the Part 2A and cabozantinib 
at 60 mg QD in 21-day-cycles until disease progression, unacceptable toxicity, withdrawal of 
consent, or any criterion for withdrawal from the study (see Section 5.5). Both drugs will be taken 
in the morning under fasted conditions.  
In Part 2B, the SMC will continue to monitor the safety, cumulative and unacceptable toxicity of 
M8891 combined with cabozantinib and may decide by consensus on continuation on the same 
dose, change in dose (not higher than MTD in Part 2A), or stop of expansion cohort. Unacceptable 
toxicity in Part 2B is defined as an AE that meet the DLT criteria (as defined in Section 5.1.3.3) 
regardless of when they occur while on treatment. Once an MTD or RDE of M8891 combined 
with cabozantinib has been defined in Part 2A (Section 5.1.3.2.1), enrollment into part 2B may 
proceed.  If less than 6 subjects have been treated at the MTD / RDE selected in Part 2A, there will 
be an SMC meeting after the first 3 subjects have been treated in Part 2B at the MTD / RDE once 
these subjects have finished their DLT period or have dropped out, in order to additionally evaluate 
safety and tolerability at this dose. Enrollment will be suspended for this SMC. The SMC will also 
meet to evaluate the safety and tolerability of the combination therapy after 10 and 20 subjects 
have finished their DLT period or dropped out for cumulative and unacceptable toxicity. 
Enrollment will continue during preparation of these SMCs.  
The SMC decisions in the expansion cohort will also be supported by a 2-parameter Bayesian 
logistic regression model. For details on the model, see Section 8.5. 
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Dose management of cabozantinib in Part 2B will be at the Investigator’s discretion based on 
clinical judgement. The Investigator must refer to study protocol or M8891 dose modification and 
to USPI for cabozantinib (see also Section 5.1.3.5). 
5.1.3.3 
Dose-Limiting Toxicities 
DLTs will be used to determine dose escalation and de-escalation as well as determination of 
MTD. A DLT is any Grade ≥ 3 non-hematologic AE or any Grade ≥ 4 hematologic AE according 
to the National Cancer Institute – Common Terminology Criteria for AEs (NCI-CTCAE) version 
4.03, occurring during the DLT observation period (Cycle 1) that is judged not to be related to the 
underlying disease or any previous or concomitant medication. DLTs, along with other safety 
information (including AEs assessed as not related to the underlying disease or other concomitant 
medications), will also be used to determine RP2D for M8891 as single agent (Part 1) and the 
RDE/MTD for M8891 combined with 60 mg of cabozantinib QD (Part 2A). 
• DLTs are defined as any of the following pre-defined set of AEs observed in the first treatment 
cycle for Part 1 (21 days) and Part 2A (22 days; 21 days of M8891 combined with cabozantinib, 
preceded by 1 day of M8891 single agent) based on predefined set of AEs and judged to be 
M8891 (or M8891 combined with cabozantinib) related or clinically relevant, (excluding 
events to be related to underlying disease, medical history or concomitant medications/ 
procedures in the opinion of the SMC). 
• Any death not clearly due to the underlying disease or extraneous causes 
• A treatment-emergent AE (TEAE) attributable to study drug that in the opinion of the SMC is 
of potential clinical significance such that further dose escalation would expose subjects to 
unacceptable risk 
• Evidence of treatment related hepatocellular injury, e.g. alanine aminotransferase or aspartate 
aminotransferase (ALT/AST) > 3 × upper limit of normal (ULN) with elevation of serum total 
bilirubin to > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) or other apparent clinical causality, including liver metastasis  
• Any Grade 4 liver enzyme elevation that is possibly drug related should be considered a DLT. 
In case of Grade 3 or 4 values, the subject must be monitored until recovery to ≤ Grade 2 
• Grade 4 neutropenia lasting >5 days or Grade ≥ 3 neutropenia with fever (temperature of 
> 38.3°C) 
• Grade 4 thrombocytopenia lasting > 5 days or Grade ≥3 thrombocytopenia with clinically 
significant bleeding 
• Any treatment interruption > 7 days or > 30% of total dose in Cycle 1 due to AEs not related to 
the underlying disease or concomitant medication 
• Any Grade ≥3 non-hematologic toxicity excluding: 
• Grade 3 nausea or vomiting that lasts < 48 hours, and resolves to ≤ Grade 1 either 
spontaneously or with conventional medical intervention 
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x Grade 3 hypertension in the absence of maximal medical therapy 
x Grade 3 rash GD\V 
x Grade 3 electrolyte abnormality that lasts < 72 hours, is not clinically complicated, and 
resolves spontaneously or responds to conventional medical intervention 
x *UDGHVLQJOHODEYDOXHLQFUHDVHZLWKRXWFOLQLFDOFRUUHODWH. 
In addition, any TEAE that impairs daily function or considered clinically significant abnormality 
involving a study subject receiving M8891 (monotherapy or combined with cabozantinib) 
occurring any time during the study, may be assessed as a DLT.  
Subjects screened and eligible for the subsequent cohort will be treated with M8891 (or M8891 
combined with cabozantinib) only after a formal SMC decision to proceed to the next dose level 
has been documented. 
5.1.3.4 
Maximum Tolerated Dose / Recommended Phase II dose 
(MTD /RP2D) 
In Part 1, the MTD for M8891 as single agent will be investigated and the RP2D for M8891 as 
single agent will be decided by the SMC. At least 6 subjects need to have been treated at the 
MTD / RP2D. This might necessitate enrolling additional subjects to fulfill this criterion. In Part 
2, the MTD/ RDE and the RP2D for M8891 combined with cabozantinib will be defined. The 
target toxicity level of the Bayesian 2-parameter model is 30%. The-dose-toxicity model will be 
used to assist the SMC in selecting the MTD by showing the estimated DLT rate per dose and 
associated variability of the estimates. In Part 2A, at least 3 subjects need to have been treated at 
the MTD / RDE. If MTD cannot be determined, the SMC may decide to end dose escalation based 
on safety, PK and/or 
 data (Part 1) or based on safety and/or PK data (Part 2A), and 
recommended dose for expansion (RDE) will be determined. Once the MTD/RDE of M8891 
combined with cabozantinib (see Section 5.1.3.2.1) for a cohort has been identified in Part 2A, 
enrollment into Part 2B, dose expansion may proceed (Figure 1). 
5.1.3.5 
Dose Modification 
5.1.3.5.1 
M8891 
In Cycle 1 dose escalation Part 1 and Part 2A, dose modification is not allowed. After completion 
of the DLT period in subsequent cycles of Part 1 and Part 2A and in all cycles of Part 2B, if  Grade 
 3 non-hematological AEs (for exceptions see 5.1.3.3 Section) or Grade 4 hematological AEs 
occur but they recover to Grade 1 in  14 days of treatment interruption, and in the absence of 
disease progression, the subject may continue treatment at a lower dose i.e., 1 level below the 
current dose or a dose defined by the SMC. If indicated, a further dose und reduction is possible.  
In Part 1, if a subject does not tolerate the lower dose, the subject will be withdrawn from the trial, 
In Part 2A, if a subject does not tolerate the dose of 20 mg M8891, the subject will be withdrawn 
from the trial (see Section 5.5). AEs assessed by the Investigator to be exclusively related to the 
C
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subject’s underlying disease or medical condition/concomitant treatment are not applicable to the 
guidelines for dose modification. 
The following dose modification guideline in Cycle 2 and subsequent cycles is recommended 
(Table 8). 
Table 8 
Recommendation to the Investigator for M8891 Dose Adjustment Based 
on Non-hematological Adverse Events 
CTCAE v. 4.03 Grade 
Guideline for Management 
Dose Adjustment 
1 
No intervention 
None 
2 
Treatment as appropriate 
according to PI’s judgment 
Dose reduction can be considered 
after discussion with the medical 
monitor or SMC decision. 
≥ 3 
Treatment as appropriate 
according to PI’s judgment 
Treatment held until Grade 1 after 
≤14 days, then the subject may 
continue treatment at a lower dose 
i.e., 1 level below the current dose 
or defined by SMC.  
PI: Principal Investigator. 
Guidelines for the management of specific AEs are provided in Section 6.5.5.  
In the case of M8891 dose modifications, the SMC might modify the SoA based on emergent data 
(e.g. PK sampling, if the dose must be adjusted). 
5.1.3.5.2 
Cabozantinib  
The approved dosage of cabozantinib in mRCC is 60 mg once daily without food until the subject 
no longer experiences clinical benefit or experiences unacceptable toxicity. In Part 2A, 
cabozantinib will be used at the approved 60 mg free-base equivalent (FBE) daily dosage. After 
completion of the DLT period in Part 2A and in all cycles of Part 2B, the dose of cabozantinib can 
be adjusted to 40 mg and then 20 mg to manage AEs (Section 6.5.5). Subjects unable to tolerate a 
daily dose of 20 mg should discontinue study treatment. 
The following should be taken into consideration in decisions regarding cabozantinib dose 
modifications (reductions or interruption): 
• As a general approach all AEs should be managed with supportive care at the earliest signs of 
toxicity (Table 9 and Table 10). Should this be ineffective, dose reductions or interruptions 
should be considered to prevent worsening of toxicity. 
• The assigned dose for cabozantinib is 60 mg QD. Two dose reduction levels of cabozantinib 
are permitted (Table 9) if appropriate. 
• Dose modification criteria for cabozantinib are shown in Table 10. Dose reductions and/or 
interruptions should be implemented for unacceptable toxicity. Doses may be modified at any 
time while on study. 


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• Dose modifications or interruptions may also occur in the setting of lower grade toxicity than 
defined in Table 10, if the Investigator feels it is in the interest of a subject’s safety and will 
optimize drug tolerability. 
• Interruption of cabozantinib treatment for AEs may occur at any time (except from Cycle 1 in 
Part 2A) per Investigator discretion. If treatment is interrupted due to AEs for more than 
6 weeks, cabozantinib should be discontinued. 
• Dose interruptions for reason(s) other than AEs (e.g. surgical procedures) can be longer than 6 
weeks but require Sponsor approval. The acceptable length of interruption will depend on 
agreement between Investigator and the Sponsor. 
Table 9 
Dose Reductions of Cabozantinib 
Assigned dose 
First Dose Level Reduction 
Second Dose Level Reduction 
60 mg cabozantinib oral QD 
40 mg cabozantinib oral QD 
20 mg cabozantinib oral QD 
QD: Once daily.  
Cabozantinib should be discontinued if a QD dose of 20-mg cabozantinib (minimum dose) is not tolerated. 
 
Table 10 
Dose Modifications of Cabozantinib for Treatment Related AEs 
CTCAE v. 4.03 Grade 
Recommended Guidelines for Managementa 
1 
Add 
supportive 
care 
as 
indicated. 
Continue 
cabozantinib treatment at the current dose level if AE 
is manageable and tolerable. 
2, tolerable and are easily managed) 
 
 
2, intolerable and cannot be adequately managed 
 
Continue cabozantinib treatment at the current dose 
level with supportive care. 
 
At the discretion of the Investigator, cabozantinib 
should be dose reduced or interruptedb.  
3 
(except 
clinically 
non-relevant 
laboratory 
abnormalities) 
 
Cabozantib should be interrupted unless the toxicity 
can be easily managed with a dose reduction and 
optimal medical careb. 
Grade 4 AEs (except clinically non-relevant laboratory 
abnormalities) 
 
Subjects 
should 
have 
cabozantinib 
interrupted 
immediately. 
Discontinue cabozantinib unless the following criteria 
are met: 
• 
Subject is deriving clear clinical benefit as 
determined by the Investigator and agreed by the 
Sponsor 
• 
Toxicity can be managed with a dose reduction 
following recovery to Grade 1 (or baseline) and 
optimal medical care 
AE: Adverse event. 
 a Study treatment dose adjustment is only needed if the toxicity was deemed related to cabozantinib treatment or had 
an unclear relationship to cabozantinib treatment. 
 b It is recommended that dose holds be as brief as possible. 
Guidelines for the management of specific AEs are provided in Section 6.5.5. 


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5.1.3.5.3 
Cabozantinib or M8891 Dose Reinstitution  
If the subject recovers from his/ her toxicities to CTCAE version 4.03 Grade ≤ 1 or to the baseline 
value (or lower) and the toxicity was unrelated to study treatment, then study treatment may be 
restarted with no change in dose.  
 
If the subject recovers from his or her toxicities to Grade ≤ 1 or to the baseline value (or lower) 
within 2 weeks and the AE was deemed possibly related to study treatment, then study treatment 
may be restarted at a reduced dose (see Section 5.1.3.5). 
In case of dose reduction, re-escalation of cabozantinib or M8891 to the previous dose is not 
allowed. 
5.1.4 
Follow-up  
For Part 1, all subjects will complete an End of Treatment (EOT) Visit 30 (± 3) days after the last 
dose of study drug. For Part 2, all subjects will complete an EOT visit within 7 days after the last 
dose of study drug.  For both Part 1 and Part 2, subjects with serious AEs (SAEs) ongoing at EOT 
Visit must be followed during the safety follow-up by the Investigator until stabilization or until 
the outcome is known, unless the subject is documented as “lost to follow-up”. 
Subjects who tolerate M8891 (or M8891 combined with cabozantinib) without significant 
clinically relevant toxicities may continue to receive trial treatment, at the Investigator’s discretion 
or after consultation with the Sponsor’s physician, as long as there is no evidence of disease 
progression. 
5.2 
Discussion of Trial Design 
This is a 2-part, Phase I/Ib, first in human, multicenter, open-label trial of M8891 single agent in 
solid tumors and M8891 combined with cabozantinib in mRCC, administered daily. 
5.2.1 
Dose Selection 
5.2.1.1 
Part 1, M8891 Single Agent, Solid Tumors 
ICH guideline S9 has been considered as the reference guideline for the determination of the first-
in-human starting dose, i.e., a dose that is expected to have pharmacologic effects and reasonably 
safe to use.  
Based on the toxicity profile of M8891 administered to rats and dogs in the 2 pivotal 4-week 
repeat-dose oral toxicity studies, defining NOAELs of 3 mg/kg in rats and 0.75 mg/kg in dogs, the 
dog was identified to be the most sensitive species (Table 11). The NOAEL of 0.75 mg/kg dose in 
dogs also corresponded to the highest non-severely toxic dose (HNSTD). According to ICH 
guideline S9, when the non-rodent is the most appropriate species, 1/6 of the HNSTD is considered 
an appropriate starting dose. Hence, the proposed first-in-human starting dose for Part 1 of the 


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study was calculated to be 7.5 mg (rounded to 7 mg)/subject/day. In the first cohorts of subjects 
with late stage advanced malignancies, this dose will be given as a once daily oral administration. 
Table 11 
First in Human Starting Dose Calculated from Results of 4-week Repeat-
Dose Toxicity Studies in Rats and Dogs 
Species 
Treatment 
regimen 
NOAEL 
(mg/kg/day) 
Safety 
factor 
Starting dose based on NOAEL 
(mg per subject)a 
Rat 
Daily, oral  
3 
1/10 
18 
Dog 
Daily, oral 
0.75b 
1/6 
7.5 
NOAEL: No observed adverse effect level. 
a Based on the assumption of 60 kg patient.  
b Corresponds to the highest non-severely toxic dose. 
This dose is at the lower end of the predicted BED (20 mg QD /subject) and is therefore considered 
to be pharmacologically active as well as being safe. 
A Bayesian two-parameter logistic regression model with overdose control will be used to assist 
the SMC with dose selection. The model incorporates nonclinical toxicity and observed DLT 
information from all previously completed dose escalation cohorts to provide a recommended dose 
for the next cohort. A preselected set of doses are considered by the model, although doses that are 
not part of the pre-specified set may be chosen as well. Overdose control will be implemented, 
thus only doses with an estimated probability of less than 25% that the true DLT rate is more than 
33% will be recommended by the model. The decision on the next dose is made by the SMC. 
5.2.1.2 
Part 2, M8891 combined with Cabozantinib, mRCC 
5.2.1.2.1 
Part 2A, Dose Escalation 
In Part 2A, M8891 will be combined with cabozantinib for subjects with mRCC who have 
progressed to 1 or more previous lines of therapy for metastatic disease. The starting dose of 
M8891 will be 20 mg QD (See Section 5.1.3.2.1). Three pre-specified dose levels of M8891 are 
planned (20 mg, 35 mg and 60 mg) although the SMC may add or skip a dose, as long as it does 
not exceed the dose level of M8891 that has already been declared to be safe in Part 1 (See Section 
5.1.3.2.1).  
Similar to Part 1, a Bayesian two-parameter logistic regression model with overdose control will 
be used to assist the SMC with dose selection for the next cohort and to determine the MTD/RDE 
of M8891 combined with cabozantinib 60 mg QD for Part 2B. For the implemented overdose 
control, overdose is defined as a DLT rate of > 33%. For each dose level the risk of overdose will 
be calculated, and only dose levels for which this risk is lower than 25% will be recommended by 
the model. The decision on the next dose is made by the SMC. 
In Part 2A, cabozantinib will be used at the approved 60 mg FBE daily dosage with dosage 
adjustments to 40 or 20 mg permitted to manage AEs (Section 5.1.3.5). The cabozantinib tablet 
formulation (Cabometyx™) is approved in USA and in the European Union (EU) at a 60 mg FBE 
daily dosage for the treatment of patients with advanced RCC. While simulations showed that the 


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20, 40, and 60 mg cabozantinib starting dosages were all predicted to reduce tumor growth, the 
60 mg dose resulted in the greatest reduction in tumor growth, best objective response rate (ORR), 
and lowest rate of disease progression. In the review of the New Drug Application for cabozantinib 
for the treatment of patients with RCC, FDA addressed the issue regarding the appropriateness of 
dose selection given the high percentage of dose reductions in the METEOR study (A Study of 
Cabozantinib vs Everolimus in Subjects with Metastatic Renal Cell Carcinoma). Based on their 
review, FDA concluded that: (1) most adverse reactions were successfully managed with dose 
interruptions and supportive measures; (2) Exposure-Response modeling indicated that lower 
starting doses could possibly compromise activity of the drug with decreased response rates; and 
(3) the dose selection of 60 mg daily was adequate based on Exposure-Response analyses and a 
safety profile that is acceptable for the patient population (Lacy 2018).  
5.2.1.2.2 
Part 2B, Dose Expansion 
Following Part 2A, the safety and tolerability of M8891 combined with cabozantinib will be 
investigated in an expansion cohort of 30 evaluable for response subjects with mRCC, for 
assessment of early clinical activity with an interim analysis after 15 subjects. The dose of M8891 
in Part 2B will be determined by Part 2A and cabozantinib will be given at 60 mg QD (See Section 
5.1.3.2.1).  
5.2.2 
Endpoint Selection 
5.2.2.1 
Part 1, M8891 Single Agent, Solid Tumors 
The study endpoints are standard Phase I endpoints, namely to define the safety and PK of the drug 
in humans, and activity in terms of tumor growth control (using RECIST v1.1 guidelines) for solid 
tumors in subjects with advanced disease with no other therapeutic options, and toxicity. 
5.2.2.2 
Part 2, M8891 Combined with Cabozantinib, mRCC 
The study endpoints are standard Phase Ib endpoints, namely to define that the combination of 
M8891 and cabozantinib is safe and tolerable in subjects with mRCC who have progressed to one 
or more previous lines of therapies (See Section 5.1). The efficacy of the combination therapy will 
be determined by the ORR with response including complete and partial response rate/proportion 
as assessed by RECIST v1.1 criteria. 
5.2.3 
Inclusion of Special Populations 
Not applicable. 
CCI


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5.3 
Selection of Trial Population 
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial 
as subjects. Prior to performing any trial 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 
5.3.1.1 
Part 1, M8891 Single Agent, Solid Tumors 
Subjects are eligible to be included in the study only if all the following criteria apply: 
1. Subjects must be refractory to or intolerant of existing cancer therapy(ies) known to provide 
clinical benefit. 
2. Histologically confirmed advanced solid tumors with no clear curative treatment options 
available after at least 1 prior systemic anticancer therapy  
3. Male and female subjects age 18 years and older who are able and willing to give written 
informed consent 
4. 
A male subject must agree to use and to have their female partners 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 before first dose of study treatment (as appropriate), during the 
treatment period and for at least 92 days (3 months) after the last dose of study treatment 
and refrain from donating sperm during this period. 
5. A female subject 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 in Appendix I of this protocol 
before start of first dose of study treatment (as appropriate), during the treatment 
period and for at least  92 days (3 months) after the last dose of study treatment. 
6. 
Tumor accessible for biopsies and agreement to conduct pre-dose and post-dose fresh 
tumor biopsies. Archival tumor tissue is not mandatory for the inclusion in the study but is 
strongly recommended. 
5.3.1.2 
Part 2, M8891 combined with Cabozantinib, mRCC  
Subjects are eligible to be included in the Part 2 of the study only if all the following criteria apply: 


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1. Male and female subjects age 18 years and older who are able and willing to give written 
informed consent before the performance of any study-specific procedures. 
2. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening. 
3. Histologic or cytologic evidence/proven of mRCC with clear cell component. 
4. Previous treatments: 
a. Part 2A: Subjects should have progressed to 1 or more previous lines of systemic 
anticancer therapy, excluding treatment with cabozantinib. 
b. Part 2B: Subjects should have progressed to 1 or 2 previous lines of systemic 
anticancer therapy, excluding treatment with cabozantinib. Subjects should have failed 
to only 1 previous TKI for metastatic disease. Adjuvant therapy with sunitinib will be 
considered as 1 line of therapy for metastatic disease in the case that disease 
progression occurs during or within 3 months of the completion of the treatment. 
5. At least 1 lesion that is measurable using RECIST v1.1. 
6. Ability to swallow capsules and tablets. 
7. Recovery from any acute toxicities from the previous therapy to Grade 1. 
8. Predicted life expectancy of > 3 months (according to the opinion of the Investigator). 
9. Adequate organ function (i.e. liver, kidney, bone marrow), as evidenced by multiple laboratory 
value results within specific parameters. Specifically: 
- Hemoglobin ≥ 9.0 g/dL (no transfusion in the past 2 weeks before first dose); 
neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L (no transfusion in the past 
2 weeks before first dose).  
- Glomerular filtration rate ≥30 mL/min (according to the Cockcroft-Gault formula)   
- Total bilirubin ≤1.5 x ULN, AST/ALT ≤ 2.5 x ULN. For documented Gilbert's 
syndrome a total bilirubin < 3 x ULN is accepted. 
 
10. Patients with central nervous system (CNS) metastases must have received surgical and/or 
radiation treatment and be neurologically stable no evidence of CNS disease progression as 
determined by CT or MRI within 21 days prior to the first dose of study drug. 
11. Subjects on bisphosphonates may continue receiving bisphosphonates therapy during study 
treatment. 
12. A male subject 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 before first dose of study treatment (as appropriate), during the treatment 


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period and for at least 92 days (3 months) after the last dose of study treatment and refrain from 
donating sperm during this period. 
13. A female subject 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 in Appendix I of this protocol before start of first 
dose of study treatment (as appropriate), during the treatment period and for at least 
92 days (3 months) after the last dose of study treatment. 
- Who has a negative serum pregnancy test at the Screening Visit and a negative urine 
pregnancy test on Day 1 before dosing, as required by local regulations, within 
24 hours before the first dose of study intervention.  
5.3.2 
Exclusion Criteria 
5.3.2.1 
Part 1, M8891 Single Agent, Solid Tumors 
For Part 1, subjects are excluded from the study if any of the following criteria apply: 
1. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2 
2. 
Bone marrow impairment as evidenced by hemoglobin < 9.0 g/dL, neutrophil count 
< 1.5 x 109/L, platelets < 100 x 109/L. Transfusion is not allowed within 3 weeks before 
first dose 
3. 
Renal impairment as evidenced by calculated creatinine clearance < 60 mL/min (according 
to the Cockcroft-Gault formula) 
4. 
Liver function abnormality as defined by total bilirubin > 1.5 x ULN, or AST/ALT 
> 2.5 x ULN, for subjects with liver involvement AST/ALT > 5 x ULN 
5. 
Extensive prior radiotherapy to more than 30% of bone marrow reserves, or prior bone 
marrow/stem cell transplantation within 5 years of study start  
6. 
Clinically significant cardiac conduction abnormalities, including QTcF interval 
prolongation of > 480 ms and/or pacemaker or impaired cardiovascular function such as 
New York Heart Association classification score > 2 
7. 
Thromboembolic 
events 
requiring 
therapeutic 
anticoagulation. 
Concomitant 
anticoagulation at therapeutic doses with oral anticoagulants (i.e., warfarin, direct thrombin 


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and Factor Xa inhibitors) or platelet inhibitors (i.e., clopidogrel) started within the last 
6 months of screening. 
Note: Low dose aspirin for cardio-protection and low dose LMWH are permitted (in subjects 
who are on a stable dose of LMWH for at least 6 weeks before the first dose of study treatment, 
and who have had no clinically significant hemorrhagic complications from the anticoagulation 
regimen or the tumor). 
8. 
Pregnant or nursing female subject  
9. 
Any other severe clinical condition that in the opinion of the treating physician may 
compromise the trial participation  
10. 
Subjects used any investigational agents 14-28 days or 5-half-lives (whichever is shorter) 
of the initiating study treatment 
11. 
History of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease 
or conditions that may hamper compliance and/or absorption of the investigational drugs 
12. 
Life expectancy < 3 months 
13. 
Known hypersensitivity to the trial treatment or to one or more of the excipients used 
14. 
Legal incapacity or limited legal capacity. 
 
5.3.2.2 
Part 2, M8891 combined with Cabozantinib, mRCC 
For both Part 2A and Part 2B, subjects are excluded from the study if any of the following criteria 
apply: 
1. Previous use of cabozantinib or a MetAP2 inhibitor. 
2. Receipt of other anticancer therapy within 2-4 weeks (wash-out period of 5 half-lives) or 
radiotherapy within 1 week prior to first dose of study treatment or patients who have not 
recovered from the side effects of such therapy to Baseline or Grade 1 (except for alopecia or 
potentially neuropathy).  
3. Subjects used any investigational agents 14-28 days or 5-half-lives (whichever is shorter) of 
the initiating study treatment. 
4. Tumor in contact with, invading or encasing major blood vessels or radiographic evidence of 
significant cavitary pulmonary lesions. 
5. Pathologic evidence of tumor invading the gastrointestinal tract, or any evidence of 
endotracheal or endobronchial tumor within 28 days before the first dose of study treatment. 


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6. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 mL) of 
red blood, or other history of significant bleeding (e.g. pulmonary hemorrhage) within 3 
months before the first dose of study treatment. 
7. Major surgery within 12 weeks before the first dose of study treatment. Complete wound 
healing from major surgery must have occurred 1 month before the first dose of study 
treatment. Minor surgery within 28 days before the first dose of study treatment. Complete 
wound healing from minor surgery must have occurred at least 10 days before the first dose of 
study treatment. 
8. Active symptomatic fungal, bacterial (requiring IV antibiotics) and/or viral infection. 
Individuals with known or seropositive testing for human immunodeficiency virus (HIV) or 
actively infected viral hepatitis (B or C) are excluded. However, individual with Hepatitis C 
treated with curative therapy are not considered actively infected. 
9. Uncontrolled hypertension defined as sustained Blood Pressure (BP) > 150 mm Hg systolic or 
> 100 mm Hg diastolic despite optimal antihypertensive treatment. 
10. Current significant cardiac conduction abnormalities, including QTcF interval prolongation of 
> 450 ms for males and > 470 ms for females or cardiovascular disorders, including 
symptomatic congestive heart failure, unstable angina pectoris, and serious cardiac 
arrhythmias. 
11. The subject is pregnant or breastfeeding. 
12. Cerebrovascular accident/stroke (< 6 months prior enrollment) or neurologic instability per 
clinical evaluation due to tumor involvement of the CNS. 
13. Thromboembolic events requiring therapeutic anticoagulation. Concomitant anticoagulation at 
therapeutic doses with oral anticoagulants (i.e., warfarin, direct thrombin and Factor Xa 
inhibitors) or platelet inhibitors (i.e., clopidogrel) started within the last 6 months of screening. 
Note: Low dose aspirin for cardio-protection and low dose LMWH are permitted (in subjects 
who are on a stable dose of LMWH for at least 6 weeks before the first dose of study treatment, 
and who have had no clinically significant hemorrhagic complications from the anticoagulation 
regimen or the tumor). 
14. Presence of clinically significant cardiac, respiratory, or other medical or psychiatric condition 
that might interfere with participation in the trial or interfere with the interpretation of trial 
results.  
15. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to cabozantinib or M8891. 
16. An active second malignancy or evidence of disease of cancer (other than RCC) before the 
date of enrollment (exceptions are squamous and basal cell carcinomas of the skin and 
carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator, with 


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concurrence with the Sponsor's medical monitor, is considered cured with minimal risk of 
recurrence within 3 years). 
5.4 
Criteria for Initiation of Trial Treatment 
Not applicable. 
5.5 
Criteria for Subject Withdrawal 
5.5.1 
Withdrawal from Trial Therapy  
A subject must be withdrawn from M8891 if any of the following occur:  
• Subject withdrew consent 
• Subject lost to follow up 
• Participation in another clinical trial   
• Any events that unacceptably endanger the safety of the subject 
• Discontinuation is considered necessary by the Investigator and/or Sponsor due to occurrence 
of an exclusion criterion or AE which is clinically relevant and affects the subject’s safety 
• Discontinuation of M8891 (or M8891 combined with cabozantinib) is desired or considered 
necessary by the Investigator and/or the subject (if applicable) due to occurrence of > Grade 2 
AEs for more than 6 days 
• If at any time on study the average QTcF interval from the 3 ECGs is > 500 ms and  
- Cardiac evaluation confirms that symptoms are the consequence of QT interval 
prolongation or 
- Recurrence of QTcF interval prolongation after reinitiation of study treatment at a 
reduced dose (see Section 6.5.5 for cabozantinib) 
• Any DLTs as described in Section 5.1. 
• Stroke (including transient ischemic attack, TIA), myocardial infarction, or other ischemic 
event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) 
• Occurrence of pregnancy  
• Noncompliance that is deemed by the Investigator or the Sponsor to compromise the subject’s 
safety or trial integrity. 
5.5.2 
Withdrawal from the Trial 
A subject may withdraw from the study at any time, at his/her own request without giving a reason 
or may be withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons.  
A subject must be withdrawn if any of the following occur during the trial: 


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• Subject withdrew consent 
• Documented disease progression (see Section 5.3.1.1 for exception) 
• Lost to follow-up 
• Noncompliance that is deemed by the Investigator or the Sponsor to compromise the subject’s 
safety or trial integrity 
• Occurrence of AEs for which discontinuation is desired or considered necessary by the 
Investigator and/or the subject 
• Participation in any other interventional trial during the duration of treatment in this trial. 
At the time of discontinuing from the study, an EOT visit will be conducted, as listed in the SoAs. 
The SoAs specifies the data to collect at EOT and follow-up, and any additional evaluations that 
need to be completed. 
If the subject withdraws consent for future involvement in the study, any data collected up to that 
point may still be used, but no future data can be generated, and any biological samples collected 
after consent withdrawal will be destroyed. 
A subject has the right at any time to request destruction of any biological samples taken. The 
Investigator must document this in the site study records. 
If a subject has failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible. 
During dose escalation (Part 1 and Part 2A), subjects who prematurely discontinue treatment 
during Cycle 1 for any other than DLT reason, will be replaced to reach a minimum of 2 evaluable 
subjects in each cohort.  Subjects discontinuing due to DLT in Cycle 1 are not replaced. 
5.6 
Premature Termination of the Trial 
The clinical trial may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk benefit judgment for any 
Investigational Medicinal Product (IMP). The Sponsor may discontinue the trial if it becomes 
unjustifiable for 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. 
The whole trial may be discontinued prematurely in the event of any of the following: 
• New information leading to unfavorable risk-benefit judgment of M8891 (or M8891 combined 
with cabozantinib), e.g., due to: 
• Evidence of inefficacy of M8891 (or M8891 combined with cabozantinib) 
• Occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions 
• Other unfavorable safety findings. 


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(Note: evidence of inefficacy may arise from this trial or from other trials; unfavorable safety 
findings may arise from examinations within clinical or nonclinical studies, e.g., toxicology.) 
• Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons 
• Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely 
• Discontinuation of development of M8891. 
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
will be informed about the discontinuation of the trial in accordance with applicable regulations. 
5.7 
Definition of End of Trial 
A clinical trial protocol may not be considered closed as long as: 
• Any subject is still receiving any IMP 
• Visits specified by the protocol are still taking place 
• Procedures or interventions according to the protocol are still being undertaken in any subject  
• The post-treatment follow-up period, defined in the clinical trial protocol as being part of the 
trial, has not yet been completed for any subject. 
If the trial is not prematurely discontinued for a reason given in Section 5.6, the end of the trial is 
defined as the last subject enrolled in the trial having treatment up to 2 years or either stopped 
M8891 (or M8891 combined with cabozantinib), i.e., having withdrawn because of disease 
progression, death, unacceptable toxicity, or Investigator/subject decision, or having completed 
the EOT visit and Safety Follow-up visit if applicable. Subjects who are on ongoing treatment at 
this time may be offered continued treatment outside of the study under observation of local 
regulations. 
6 
Investigational Medicinal Product and Other Drugs Used in 
the Trial 
The term “Investigational Medicinal Product” (IMP) refers to an active substance or a placebo 
being tested or used as a reference therapy in a clinical trial, 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.  The IMP for this study is M8891. 
6.1 
Description of the Investigational Medicinal Product 
6.1.1 
M8891 
The chemical name of M8891 drug substance is (S)-3-Hydroxy-1-(1H-indol-5-yl)-2-oxo-
pyrrolidine-3-carboxylic acid 3,5-difluoro-benzylamide. 


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M8891 is formulated as 1 mg (size “3”, color white), 5 mg (size “3”, color white) and 30 mg 
(size 0, color Swedish orange) hard gelatin capsules for oral administration. No other excipients 
are used. 
6.1.2 
Cabozantinib (Cabometyx) 
Cabozantinib is indicated for the treatment of patients with mRCC, metastatic medullary thyroid 
cancer and hepatocellular carcinoma. The approved dosage of cabozantinib in mRCC is 60 mg 
once daily without food until the patient no longer experiences clinical benefit or experiences 
unacceptable toxicity. Cabozantinib malate is the (S)-malate salt of cabozantinib, a kinase 
inhibitor. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-
yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(2S)-hydroxybutanedioate. 
The commercial cabozantinib drug product tablet formulation (Cabometyx; Exelixis, Inc.) is 
marketed in three strengths (20, 40, and 60 mg). Complete information for cabozantinib may be 
found in the USPI (Cabometyx USPI 2019). 
6.2 
Dosage and Administration 
6.2.1 
Part 1, M8891 Single Agent, Solid Tumors 
M8891 will be administered orally as single agent continuously in 21-day cycles at the starting 
dose of 7 mg QD. In subsequent cohorts subjects will take the total assigned dose of M8891 once 
daily in the morning with a full glass of water (approximately 240 mL/8 fluid ounces). The subjects 
should be instructed to swallow the capsules whole and not to bite into the capsules, break or open 
them, or attempt to dissolve the contents in water prior to taking their assigned dose.  
M8891 will be taken under fasted conditions in the morning before breakfast (i.e. at least 2 hours 
fasted) and subjects will be instructed to continue to fast for 1 hour post-dosing. 
Except for water consumed with M8891 administration, water will be withheld for 1 hour before 
and 1 hour after dose administration.  
Dose escalation is described in Section 5.1.3.1 
6.2.2 
Part 2, M8891 with Cabozantinib, mRCC  
In Part 2A M8891 will be administered orally at a starting dose of 20 mg QD combined with 
cabozantinib continuously in 21-day cycles. 
Dose escalation is described in Section 5.1.3.2.1.  
Cabozantinib will be used at the approved 60 mg FBE daily dosage with dosage adjustments to 40 
or 20 mg permitted to manage AEs (Section 5.1.3.5).  
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When the MTD/RDE has been defined in Part 2A (Section 5.1.3.4), the Part 2B expansion cohort 
with M8891 combined with cabozantinib will be initiated.  
In Part 2 
, M8891 
combined with cabozantinib will be taken under fasted conditions in the morning before breakfast 
(i.e. at least 2 hours fasted) and subjects will be instructed to continue to fast for 1 hour post-
dosing. Except for water consumed with M8891 and cabozantinib administration, water will be 
withheld for 1 hour before and 1 hour after dose administration.  
6.3 
Assignment to Treatment Groups 
Not applicable.  This is a single-arm open-label study. 
6.4 
Non-investigational Medicinal Products to be Used 
Not applicable. 
6.5 
Concomitant Medications and Therapies 
All concomitant medications taken by the subject during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the electronic case report form 
(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 that are considered necessary to protect subject welfare and will not interfere 
with the trial medication may be given at the Investigator’s discretion, e.g. hormone therapy is 
allowed for subjects with prostate cancer. 
Rescue medications may be administered to address ineffective treatment, anticipated adverse 
reactions or anticipated emergency situations. 
6.5.2 
Prohibited Medicines 
6.5.2.1 
Part 1, M8891 Single Agent, Solid Tumors 
Not applicable for Part 1. 
6.5.2.2 
Part 2, M8891 with Cabozantinib, mRCC 
For cabozantinib the investigators should refer to Section 7 of the cabozantinib USPI (Cabometyx 
USPI 2019). 
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6.5.3 
Other Interventions 
Not applicable. 
6.5.4 
Special Precautions 
Subjects will be instructed to avoid or to replace medications that are potent combined inhibitors 
of CYP3A4, CYP2C9 and CYP2C19 (i.e. fluconazole and voriconazole) during treatment of 
M8891. (See Appendix II for details).  
6.5.5 
Management of Specific Adverse Events or Adverse Drug 
Reactions 
Based on nonclinical data, the main anticipated toxicity for M8891 may include anemia, 
neutropenia, leukopenia, thrombocytopenia, opportunistic infections, nausea, diarrhea, 
gastrointestinal (GI) hemorrhage and osteoporosis (see Section 3.3.1). Cabozantinib safety profile 
has been established (Cabometyx USPI 2019). 
Potential occurring AEs that study subjects are likely to encounter during the study period and 
guidance on the management is presented in the Table 12. 
Table 12 
Management of Specific AEs with M8891 Combined with Cabozantinib 
Adverse Event 
Management Recommendationa 
Diarrhea 
• 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements.  
• 
Administration of antidiarrheal/ antimotility agents is recommended at the first sign of 
diarrhea as initial management.  
• 
Some subjects may require concomitant treatment with more than one antidiarrheal agent. 
When therapy with antidiarrheal agents does not control the diarrhea to tolerable levels, 
study treatment should be temporarily interrupted, or dose reduced (Section 5.1.3.5).  
• 
When the diarrhea is controlled, retreatment with study treatment may be acceptable per 
Investigator decision. 
• 
In addition, general supportive measures should be implemented including continuous oral 
hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and 
stopping lactose-containing products, high fat meals, and alcohol. 
Nausea and Vomiting 
 
• 
Antiemetic agents are recommended as clinically appropriate at the first sign of nausea and 
vomiting or as prophylaxis to prevent emesis, along with supportive care according to 
clinical practice guidelines.  
• 
In the case of cabozantinib, the 5-HT3 receptor antagonists are recommended over chronic 
use of NK-1 receptor antagonists and dexamethasone (NK-1 receptor antagonists can 
induce or inhibit CYP3A4, and glucocorticoids induce CYP3A4 and thus could lower 
cabozantinib exposure (see Section 7 in cabozantinib USPI (Cabometyx USPI 2019).  
• 
For cabozantinib, caution is also recommended with the use of nabilone, which is a weak 
inhibitor of CYP3A4. 
Stomatitis and Mucositis 
 
• 
Preventive measures may include a comprehensive dental examination to identify any 
potential complications before study treatment is initiated. Removal of local factors should 
be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of 
gingivitis (dental examination/procedures before study initiation will be recommended but 
not covered by the study). 
• 
During treatment good oral hygiene and standard local treatments such as nontraumatic 
cleansing and oral rinses (e.g., with a weak solution of salt and baking soda) should be 


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Adverse Event 
Management Recommendationa 
maintained. The oral cavity should be rinsed and wiped after meals, and dentures should be 
cleaned and brushed often to remove plaque.  
• 
Local treatment should be instituted at the earliest onset of symptoms.  
• 
Obtain bacterial/viral culture if oral infection is suspected and treat infection as indicated by 
local guidelines.  
• 
When stomatitis interferes with adequate nutrition and local therapy is not adequately 
effective, dose reduction or temporary withholding of study treatment should be considered. 
Hepatobiliary Disorders 
 
• 
It is recommended that subjects with elevation of ALT, AST, and/or bilirubin have more 
frequent laboratory monitoring of these parameters. 
• 
If possible, hepatotoxic concomitant medications should be discontinued in subjects who 
develop increased values of ALT, AST, or bilirubin. 
• 
Dose reductions of study treatment should be considered in any subject who develops 
drug-related Grade 2 elevated ALT, AST, or bilirubin lasting longer than 1 week.  
• 
A subject who develops Grade ≥ 3 elevated ALT, AST, or bilirubin should have study 
treatment held and restarted at a reduced dose (Section 5.1.3.5) after ALT, AST, and 
bilirubin levels resolve to at least Grade ≤ 1 or baseline.  
• 
In subjects with recurrence of drug-related Grade ≥ 3 elevated ALT, AST, or bilirubin at 
the lowest dose level, study treatment should be discontinued.  
• 
In subjects who develop ALT/AST elevations > 3 × ULN in combination with a bilirubin 
elevation > 2 × ULN without reasonable other explanation, drug-induced liver injury 
should be suspected and study treatment should be interrupted.  
• 
Reinstitution of study treatment after recovery of ALT, AST, and bilirubin to Grade 1 or 
baseline level must be discussed and approved with the Sponsor. 
Hematological Disorders 
 
• 
Hematological toxicities (i.e., neutropenia and thrombocytopenia) and associated 
complications may be managed with dose interruptions and/or dose reductions. Use of 
granulocyte colony-stimulating factor support for neutrophil recovery is allowed per 
Investigator discretion and in accordance with accepted guidelines after the first incidence 
of clinically relevant cytopenia. 
• 
Complete blood counts with differentials and platelets should be performed regularly. 
Subjects with hematologic toxicities may require additional or more frequent laboratory 
tests according to institutional guidelines. 
• 
Febrile neutropenia or evidence of infection associated with neutropenia must be assessed 
immediately and treated appropriately and in a timely manner according to institutional 
guidelines. 
• 
Dose reductions or dose interruptions for anemia are not mandated but can be applied as 
clinically indicated. Supportive care such as red blood cell transfusions may be managed 
according to institutional guidelines. 
Fatigue, Anorexia, and 
Weight Loss 
 
 
• 
Common causes of fatigue such as anemia, deconditioning, emotional distress (depression 
and/or anxiety), nutrition, sleep disturbance, and hypothyroidism should be ruled out 
and/or these causes treated according to standard of care. Individual non-pharmacological 
and/or pharmacologic interventions directed to the contributing and treatable factors 
should be given.  
• 
Pharmacological management with psychostimulants such as methylphenidate should be 
considered after disease specific morbidities have been excluded. Note: Chronic use of 
modafinil should be avoided because of its potential to reduce cabozantinib exposure (see 
Section 7 in cabozantinib USPI (Cabometyx USPI 2019). 
• 
Dose reduction of study treatment should be considered when general or pharmacological 
measures have not been successful in reducing symptoms.  
• 
Dose interruption may be considered for Grade ≥ 3 fatigue despite optimal management, at 
the Investigator’s discretion. 
• 
Anorexia and weight loss should be managed according to local standard of care including 
nutritional support. Pharmacologic therapy such as megestrol acetate should be considered 
for appetite enhancement. Should these interventions prove ineffective, dose hold and 
reductions may be considered for Grade ≥ 3 anorexia or weight loss.  
Skin Disorders 
  
• 
All subjects on study should be advised on prophylactic skin care. This includes the use of 
hypoallergenic moisturizing creams, ointment for dry skin, and sunscreen with sun 
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Adverse Event 
Management Recommendationa 
pressure sensitive areas of hands and feet, and use of thick cotton gloves and socks to 
prevent injury and to keep the palms and soles dry. 
• 
Subjects with skin disorders should be carefully monitored for signs of infection (e.g., 
abscess, cellulitis, or impetigo). 
• 
Early signs of hand-foot syndrome could be tingling, numbness, and slight redness or mild 
hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on 
the palms and soles. The lateral sides of the fingers or peri-ungual zones may also be 
affected. 
• 
Adequate interventions are required to prevent worsening of skin symptoms such as 
blisters, desquamations, ulcerations, or necrosis of affected areas. Aggressive management 
of symptoms is recommended, including early dermatology referral. 
• 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
Investigator may request that additional assessments be conducted with the subject’s 
consent. These assessments may include digital photographs of the skin changes and/or a 
biopsy of the affected skin and may be repeated until the skin changes resolve 
• 
VEGF inhibitors can cause wound healing complications and wound dehiscence which 
may occur even long after a wound has been considered healed. Therefore, surgical and 
traumatic wounds must have completely healed prior to starting study treatment and be 
monitored for wound dehiscence or wound infection while the subject is being treated with 
M8891 with cabozantinib. 
Hypertension 
 
• 
Hypertension is a common class effect of drugs that inhibit VEGF pathways  
• 
Blood pressure should be monitored in a constant position at each visit (either sitting or 
supine). 
• 
In general, subjects with known hypertension should be optimally managed prior to study 
entry. 
• 
Decisions to decrease or hold the dose of study treatment must be based on blood pressure 
readings taken by a medical professional and must be confirmed with a second 
measurement at least 5 minutes following the first measurement.  
• 
Other than for hypertension requiring immediate therapy, the presence of new or worsened 
hypertension should be confirmed at a second visit before taking therapeutic action. It is 
recommended that this second visit occurs within 1 week. 
• 
In the case of hypertensive crisis or hypertensive encephalopathy, study treatment should 
be discontinued. 
Thromboembolic Events 
 
• 
Study treatment should be discontinued in subjects who develop PE or DVT, an acute 
myocardial infarction or any other clinically relevant arterial thromboembolic complication 
(Section 5.5). 
Proteinuria 
 
• 
During each safety assessment visit, proteinuria will be quantified by measuring the urine 
protein-to-creatinine (UPCR) ratio. In addition, urine dipstick analysis will be performed 
(see Table 2 and Table 3). 
 
  
Severity of Proteinuria 
(UPCR) 
Action To Be Taken 
1 mg/mg (≤ 113.1 
mg/mmol) 
• 
No change in study treatment or monitoring 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
 
• 
No change in study treatment required 
• 
Consider confirming with a 24-hour protein assessment 
within 7 days 
• 
Repeat UPCR within 7 days and once per week. If UPCR 
< 1 on 2 consecutive readings, UPCR monitoring can revert 
to protocol-specific times. (Second reading is confirmatory 
and can be done within 1 week of first reading.) 
≥ 3.5 mg/mg (≥ 395.9 
mg/mmol) 
 
• 
Hold study treatment pending repeat UPCR within 7 days 
and/or 24-hour urine protein. 
• 
If ≥ 3.5 on repeat UPCR, continue to hold study treatment 
and check UPCR every 7 days. If UPCR decreases to < 2, 


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Adverse Event 
Management Recommendationa 
restart study treatment at a reduced dose and monitoring of 
urine protein/creatinine should continue weekly until the 
UPCR decreases to < 1. 
Nephrotic syndrome 
• 
Discontinue study treatment 
 
 
Corrected QTcF interval 
Prolongation 
 
 
If at any time on study the average QTcF interval from the 3 ECGs is > 500 ms, the following 
actions should be taken: 
• 
Withhold study treatment 
• 
Immediately notify the Sponsor 
• 
Hospitalize symptomatic subjects (e.g., with palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology 
evaluation and management 
• 
Consider cardiology consultation for asymptomatic subjects for evaluation and 
management 
• 
Check electrolytes, especially magnesium, calcium, and potassium; correct abnormalities 
as clinically indicated 
• 
Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (refer to 
http://www.qtdrugs.org) 
• 
Repeat ECG triplicates hourly until the average QTcF interval is ≤ 500 ms 
• 
Subjects with QTcF interval prolongation and symptoms must be monitored closely until 
the QTcF interval prolongation and symptoms have resolved.  
 
Study treatment may be restarted at a reduced dose level if ALL the following conditions are 
met: 
• 
Symptoms are determined to be unrelated to the QT interval prolongation 
• 
The QTcF interval value returns to ≤ 500 ms 
• 
Study treatment has been interrupted through a minimum of 1 week following the return of 
the QTcF interval to ≤ 500 ms 
• 
QT prolongation can be unequivocally associated with an event other than study treatment 
administration and is treatable/has been resolved 
• 
Sponsor has reviewed all available information and has agreed to the continuation of study 
treatment 
 
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 
2 weeks for 1 month, then according to the protocol-defined time points. 
 
Study treatment must be permanently discontinued if either of the following applies: 
• 
Cardiac evaluation confirms that symptoms are the consequence of QT interval 
prolongation 
• 
Recurrence of QTcF interval prolongation after reinitiation of study treatment at a reduced 
dose 
Hypophosphatemia 
 
• 
Serum phosphorus should be monitored frequently while receiving study treatment.  
• 
Mild hypophosphatemia is usually asymptomatic or symptoms can be non-specific such as 
weakness, bone pain, rhabdomyolysis, or altered mental status.  
• 
Other causes of hypophosphatemia such as poor nutrition, chronic alcoholism, 
malabsorption, excessive antacid use, glucocorticoids use, kidney dysfunction, respiratory 
alkalosis, vitamin D deficiency should be ruled out and/or these causes treated according 
to standard of care.  
• 
Mild to moderate hypophosphatemia should be managed by oral replacement including 
food that are high in phosphate (diary items, meats, beans) and/or oral phosphate 
supplements according to standard clinical practice guidelines  
• 
Clinically relevant hypophosphatemia should be managed according to the dose 
modification guidelines as outlined in Section 5.1.3.5 or as clinically indicated 
Thyroid 
Function 
Disorders 
Management of thyr.oid dysfunction (e.g., symptomatic hypothyroidism) should follow accepted 
clinical practice guidelines and dose modification guidelines as outlined in Table 10. 


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a Subjects with pre-existing conditions who are at greater risk of experiencing serious toxicities should be monitored 
carefully throughout the study. For cabozantinib, Investigators are encouraged to refer to local product label; dose 
modification of any study treatment should always be considered in consultation with the Sponsor’s Medical 
Responsible.  
6.6 
Packaging and Labeling of the Investigational Medicinal 
Product 
M8891 will be packed in wallets containing 3 blisters with 6 capsules each for the dose strengths 
1 mg (only for Part 1, M8891 single agent) and 5 mg and with 5 capsules each blister for the 30 
mg dose strength. 
M8891 will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines. 
6.7 
Preparation, Handling, and Storage of the Investigational 
Medicinal Product 
M8891 must be stored at the recommended temperature 
 until use and must not be 
frozen. Any deviations from the recommended storage conditions should be immediately reported 
and the trial drug should not be used until authorization has been received from the Sponsor.  
The Investigator or a trained designee will dispense M8891 to subjects according to their dose 
level. 
At the end of the trial drug will not be returned to depot for destruction and will be destroyed on 
site by either site followed process or designated study drug destruction process. 
6.8 
Investigational Medicinal Product Accountability 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
x Upon receipt of the study intervention(s), the Investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported 
and resolved before use. Also, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate document and returning 
it to the location specified. A copy will be archived for the Investigator Site File. 
x Only subjects enrolled in the study may receive study intervention(s) and only authorized site 
staff may supply it. All study intervention(s) must be stored in a secure, environmentally-
controlled, and monitored (manual or automated) area, in accordance with the labeled storage 
conditions, and with access limited to the Investigator and authorized site staff. 
x Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit. 
x Study intervention(s) accountability records at the study site will include the following: 
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• Confirmation of receipt, in good condition and in the defined temperature range. 
• The inventory provided for the clinical study and prepared at the site. 
• The dose(s) each subject used during the study. 
• The disposition (including return, if applicable) of any unused study intervention(s). 
• Dates, quantities, batch numbers, kit numbers, expiry dates, and the subject numbers. 
• The Investigator site will maintain records, which adequately documents that subjects were 
provided the doses specified in this protocol, and all study intervention(s) provided were fully 
reconciled. 
• Unused study intervention(s) must not be discarded or used for any purpose other than the 
present study. No study intervention that is dispensed to a subject may be re-dispensed to a 
different subject. 
• A Study Monitor will periodically collect the study intervention(s) accountability forms. 
• Further guidance and information for the final disposition of unused study intervention(s) are 
provided in the Operations Manual. 
6.9 
Assessment of Investigational Medicinal Product Compliance 
The information of each IMP administration including the date, time, and dose of IMP will be 
recorded on the eCRF. The Investigator will make sure that the information entered into the eCRF 
regarding IMP administration is accurate for each subject. Any reason for noncompliance should 
be documented. 
6.10 
Blinding 
This is a single-arm study, blinding procedures are not applicable.  
6.11 
Emergency Unblinding 
Not applicable. This is an open-label trial without randomization. 
6.12 
Treatment of Overdose 
An overdose is defined as any dose greater than the highest daily dose included in a clinical trial 
protocol or planned for an individual subject enrolled in the trial. Even if it does not meet other 
criteria for an SAE, any overdose must be recorded in the trial medication section of the eCRF and 
reported to Drug Safety in an expedited manner using the SAE Report Form, and following the 
procedure in Section 7.4.  
6.13 
Medical Care of Subjects after End of Trial 
After a subject has completed the trial or has withdrawn early, usual treatment on Investigator’s 
choice will be administered, if required, in accordance with the trial site’s generally accepted 


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medical practice and depending on the subject’s individual medical needs. The Sponsor will not 
provide any additional care to subjects after they leave the trial because such care should not differ 
from what is normally expected for the patients. 
7 
Trial Procedures and Assessments 
7.1 
Schedule of Assessments 
Prior to performing any trial 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. 
Complete SoAs for Part 1, Part 2A, and Part 2B of the trial is provided in Table 1 (Part 1), Table 
2 (Part 2A) and Table 3 (Part 2B). Sample collection for PK, and ECG safety evaluations are 
provided in Table 4 and Table 5. 
7.2 
Demographic and Other Baseline Characteristics 
At screening, demographic and other baseline characteristic data will be collected, e.g., age, sex 
(gender), race, ECOG PS, and complete medical history should be undertaken.  
7.3 
Efficacy Assessments 
No more than 28 days before the first dose of study medication, CT scan or magnetic resonance 
imaging (MRI) in regions where disease is located, and metastases may be expected (based on the 
tumor type) will be performed to document the baseline status using the most appropriate criteria 
for the malignancy type. The target and non-target lesions will be selected based on the initial scan 
and all subsequent scans should use the same methodology. 
Clinical efficacy will be assessed by the Investigators according to RECIST v1.1 at the time points 
defined in the SoAs in Table 1 (Part 1), Table 2 (Part 2A) and Table 3 (Part 2B). Specifically, in 
Part 1 tumor response will be assessed on Day 1 of Cycles 3, 5 and 7, and every 18 weeks (6 
Cycles) thereafter. In Part 2 tumor response will be assessed on Day 1 of Cycles, 3, 5, 7 and every 
third cycle thereafter. PFS, defined as time from first dose to objective disease progression or 
death, whichever occurs first, by Investigator will also be considered. 
7.4 
Assessment of Safety 
The safety profile of M8891 single agent and M8891 combined with cabozantinib will be assessed 
through the recording, reporting and analysis of baseline medical conditions, AEs, physical 
examination findings, vital signs and laboratory tests at specified times during the study. 
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the trial. The Investigator will report any 
AEs, 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. 


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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, version 4.03, 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. 
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 IMP/study treatment 
(including any other non-IMPs, radiation therapy, etc.) using the following definitions. Decisive 


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factors for the assessment of causal relationship of an AE to the IMP include, but may not be 
limited to, temporal relationship between the AE and the IMP, known side effects of study 
treatment, medical history, concomitant medication, course of the underlying disease, trial 
procedures. 
Unrelated: Not reasonably related to the IMP/study treatment. AE could not medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under study 
in this clinical trial protocol. Only events clearly not related (disease progression, 
environmental, unrelated trauma, etc.) should be categorized as unrelated to the 
study treatment.  
Related: 
Reasonably related (ie, any toxicities considered related, probably related, or 
possibly 
related) 
to 
the 
IMP/study 
treatment. 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under study 
in this clinical trial 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. 
Serious Adverse Events 
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.) 


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For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered an SAE, as described in Section 7.4.1.4. 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an overnight stay to facilitate chemotherapy 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 trial visit that do not worsen in severity or frequency during 
the trial 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 AE/SAE, 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). 
7.4.1.2 
Methods of Recording and Assessing Adverse Events 
At each trial 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 Report Form as 
described in Section 7.4.1.4. 
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 trial treatment, 
any other potential causal factors, any treatment given or other action taken, including dose 
modification or discontinuation of the IMP, and its outcome. In addition, serious cases should be 
identified, and the appropriate seriousness criteria documented. If an AE constitutes a DLT, this 
must be documented accordingly. 
Specific guidance can be found in the eCRF Completion and Monitoring Conventions provided 
by the Sponsor. 


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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 
trial (date of first signature of first informed consent) and continues until the EOT visit and through 
the safety follow-up period for SAEs. Subjects with SAEs ongoing at EOT Visit must be followed 
during the safety follow-up. 
Any SAE assessed as related to M8891 must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of M8891.  
7.4.1.4 
Procedure for Reporting Serious Adverse Events, Adverse 
Events of Special Interest and Dose Limiting Toxicities 
Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee in writing. All written reports should be transmitted using the SAE Report 
Form, which must be completed by the Investigator following specific completion instructions. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, 
addresses, and telephone and fax numbers for SAE reporting will be included in the trial-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). In all cases, the information provided 
on the SAE Report Form must be consistent with the data about the event recorded in the eCRF. 
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 Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 
Dose Limiting Toxicities  
Each event meeting the criteria of a DLT (see Section 5.1.3.3) must be recorded in the eCRF within 
24 HOURS after becoming aware of the event. Serious DLTs must be reported in an expedited 
manner as SAEs as outlined above. 


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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 trial subjects to the IEC/IRB that approved the 
trial. 
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 trial or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the trial.” In particular and in line with 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 trials 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 
AEs are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) and are 
assessed for final outcome at the EOT Visit. All SAEs ongoing at EOT Visit must be followed 
during the safety follow-up period. The safety follow-up 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.  


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7.4.2 
Pregnancy and In Utero Drug Exposure  
Only pregnancies considered by the Investigator to be related to trial 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 eCRF. 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 Pregnancy Report Form, which must be transmitted according to the same 
process as described for SAE reporting in Section 7.4.1.4.  
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial. 
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form 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 7.4.1.4, 
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 trial, the subject must 
be discontinued from trial medication immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above. 
7.4.3 
Clinical Laboratory Assessments 
Blood and urine samples will be collected for the following clinical laboratory tests, following the 
timing noted in the SoAs (Table 1 for Part 1 and Table 2 and Table 3 for Part 2). For maximal 
blood volumes refer to the Laboratory Manual. 
All samples should be clearly identified.   
The Sponsor should receive a list of laboratory normal ranges before shipment of trial drug. Any 
change in laboratory normal ranges during the trial should be forwarded to the CRO. 
For Part 1 of the study, clinical laboratory assessments include hemoglobin, WBC count, 
differential, platelet count, PT, aPTT, creatinine, creatinine clearance, AST, ALT, GGT, AP, 
lipase, amylase, BUN, total bilirubin, total protein, albumin, uric acid, sodium, chloride, 
bicarbonate, potassium, calcium, phosphorus, magnesium and glucose. 
For Part 2 of the study, clinical laboratory assessments include hematology, serum chemistry, 
coagulation, urine chemistry, serology and thyroid function tests (See Appendix III
 
Laboratory Tests (Only for Part 2 of the study).  


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Additional details regarding laboratory assessments (e.g., sampling methods, processing, and 
storage) will be included in the Laboratory Manual. 
7.4.4 
Vital Signs, Physical Examinations, and Other Assessments 
Vital sign, physical exam, and other assessments include: heart rate, diastolic blood pressure 
systolic blood pressure, weight, temperature, and additional assessments as included in Table 1, 
Table 2, and Table 3. 
For timings of assessments, see the SoAs (Table 1, Table 2, and Table 3). For detailed procedures 
refer to the Manual of Operations.  
7.4.5 
Electrocardiograms 
ECG will be performed throughout the study at specified time points (during Part 1 and Part 2) as 
indicated in the SoAs (Table 1 for Part 1, and Table 4 and Table 5 for Part 2).  
The Fridericia formula is depicted below for calculation of the corrected QT (QTcF) interval. 
QTcF interval = QT/RR1/3, where QT = measured QT interval in milliseconds; RR = measured R 
to R interval (which can be derived from the heart rate as 60/heart rate). 
7.4.5.1 
Part 1 M8891 Single Agent, Solid Tumors 
ECGs for QT/QTc Evaluation  
At screening, 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 using standard 12-lead 
equipment to determine the QTcF interval. If the average of these three consecutive results for 
QTcF interval is > 480 ms the subject does not meet eligibility in this regard.  
12-lead triplicate digital ECG will be performed within 2-minutes after at least 10 minutes rest in 
supine position, on Cycle 1 Day 1 and Day 15 at pre-dose and 1, 2, 4, 5, 6, 8, 12 hours and 24 
hours post-dose (± 15 minutes) and on pre-dose on Day 8. The SMC may decide that the Day 
15/Day 16 assessment can be waived in case no relevant drug accumulation is being observed. 
ECG assessments at subsequent cycles will be performed pre-dose at time points as indicated in 
Table 1. ECGs should be performed directly before PK sampling time-points on days where both 
assessments are performed. 
Digital ECGs will be stored for a later independent analysis: ECG extractions will be made by the 
central ECG laboratory and over-read of interval measurements will be provided by experienced, 
qualified, and certified cardiac safety specialists. The readers will be blinded to subject details, 
treatment, visit day, and time points of the ECG recording, and a single reader will read all ECGs 
of a given subject. Time-matched, replicate ECGs and PK samples collected will be used to 
analyze for QTcF interval responses using slope analysis of exposure/response. This analysis may 
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7.4.5.2 
Part 2 M8891 with cabozantinib, mRCC 
Safety ECGs  
Safety ECGs are standard triplicate 12-lead ECGs obtained for safety monitoring according to the 
SoAs (Table 4 for Part 2A and Table 5 for Part 2B). Subjects will rest in semi-recumbent position 
for at least 5 minutes. Safety ECGs will be read locally, and all ECGs should be assessed on the 
day of collection to determine continued eligibility. The calculated QTcF interval average of 3 
12-lead ECGs must be ≤ 450 ms for males and ≤ 470 ms for female participants’ eligibility. To 
confirm suitability for treatment after screening, ECGs must be repeated on Day -1, Cycle 1, prior 
to administering the first dose of study treatment unless the screening tests were performed within 
14 days prior to first dose.  
During the scheduled safety visits, subjects, in whom the calculated QTcF interval average 
increases to > 500 ms or > 60 ms change over baseline during treatment with M8891 combined 
with cabozantinib, must interrupt study treatment until further clinical evaluation. ECGs should be 
repeated if QTcF interval is outside the range until resolution (Table 12, Section 6.5.5). To assess 
the safety and tolerability of the study intervention, an ECG can be repeated at the Investigator’s 
discretion at unscheduled visits. Start and end of resting time and ECG time will be recorded in 
the eCRF.  
Abnormalities in the ECG that lead to a change in subject management (e.g., dose reduced or 
withheld, treatment discontinued, requirement for additional medication or monitoring as 
described in Table 12, Section 6.5.5) or result in clinical signs and symptoms are considered 
clinically significant for the purposes of this study and will be deemed adverse events. If values 
meet criteria defining them as serious, they must be reported as SAEs. 
7.5 
Pharmacokinetics 
7.5.1 
Part 1, M8891 Single Agent, Solid Tumors 
For the PK analysis, the plasma level of M8891 will be analyzed by the analytical laboratory 
selected under responsibility of the Sponsor, using an appropriate validated bioanalytical method. 
Urine level of M8891 will be analyzed using an appropriate qualified method.  
Full details of the bioanalytical method used will be described in a separate bioanalytical report. 
Plasma concentrations of M8891 and its metabolites will be analyzed as indicated in Table 1. 
At each time point, 3 mL (2 aliquots of 1.5 mL) blood will be collected. The exact blood volume 
will be indicated in the Laboratory Manual. For all clinical and research studies, the total blood 
volume (mL) drawn in a 30-day period will never exceed the 280 mL. 
Actual date and time of M8891 administration and PK actual sampling date and time will be 
recorded in the eCRF. 


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The PK sampling (and corresponding
 sampling) schedule may be modified based upon 
emerging PK information collected during the study with the provision that the overall amount of 
blood to be collected for PK sampling is not increased. 
List of PK parameters: 
x Cmax: Observed maximum plasma concentration  
x tmax: Time to reach maximum observed plasma concentration  
x AUC0-: Area under the concentration-time curve from time zero extrapolated to infinity, based 
on the predicted value for the concentration at tlast  
x AUC0-t: Area under the concentration-time curve from time zero to the last sampling time at 
which the concentration is at or above the lower limit of quantification (LLOQ) 
x AUC0-Ĳ Area under the plasma concentration versus time curve within one dosing interval 
x t1/2: Apparent terminal half-life  
x Ȝz: Apparent terminal rate constant 
x CL/F: Apparent body clearance of drug following extravascular administration 
x CLss/F: Apparent body clearance of drug following extravascular administration at steady state 
x Vz/F: Apparent volume of distribution during the terminal phase following extravascular 
administration 
x Racc(AUCĲ): Accumulation ratio for AUCĲ 
x Racc(Cmax): Accumulation ratio for Cmax. 
In dose level 4 and dose level 5, urine samples for exploratory determination of M8891 and its 
metabolites will be taken from the total pooled urine sample provided during the 12-hour collection 
period on Day 1 and Day 15. The start and stop date/time of each pooled urine collection should 
be recorded in the eCRF. The volume of each urine collection will also be recorded. 
Additional analyses may be conducted on the plasma and/or urine samples to further investigate 
the presence and/or identity of drug metabolites. Any results from such analyses on plasma and/or 
urine may be reported separately from the clinical trial report. 
Details on sample shipment and handling will be provided in the Laboratory Manual. 
7.5.2 
Part 2, M8891 with Cabozantinib, mRCC  
Sampling time schedules for determination of M8891 and cabozantinib can be found in the SoAs 
(Table 4 for Part 2A and Table 5 for Part 2B). 
For the PK analysis, the plasma level of M8891 and cabozantinib will be analyzed by the analytical 
laboratory selected under responsibility of the Sponsor, using an appropriate validated 
bioanalytical method. Full details of the bioanalytical method used will be described in the 
Laboratory Manual. 
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7.7 
Other Assessments 
Not applicable. 
8 
Statistics 
Statistical methodology is generally described within this Section 8. Additional details will be 
provided in an Integrated Analysis Plan. 
8.1 
Sample Size 
8.1.1 
Part 1, M8891 Single Agent, Solid Tumors 
A Bayesian model is applied to assist the SMC in dosing decisions. For details on the model see 
Section 8.5.3.1  
As this is the dose escalation part of the trial, with M8891 single agent, sample size cannot be 
exactly prespecified, but depends among other things on the number of DLTs seen. 
The sample size for Part 1 dose escalation (QD) is capped at a maximum of 42 subjects.   
At least 6 subjects need to have been treated at the suggested MTD or RP2D. That might 
necessitate the enrollment of additional subjects after dose escalation was stopped. For this sample 
size assessment, it is assumed that it is not necessary to enroll additional subjects to fulfill this 
criterion. 
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It is anticipated that 36 evaluable subjects (8 dose levels with 3 to 12 subjects, e.g. assuming a 
scenario with 5 dose levels with 3 subjects, 2 dose levels with 6 subjects (2 cohorts) and one dose 
level with 9 subjects (3 cohorts) may be needed in order to determine the MTD of QD dosing of 
M8891. 
The anticipated total number of evaluable subjects is approximately 36 (42 if the maximal sample 
size stopping criterion is reached).   
8.1.2 
Part 2, M8891 with Cabozantinib, mRCC 
8.1.2.1 
Part 2A, Dose Escalation 
In Part 2A, a Bayesian model is applied to assist the SMC in dosing decisions. For details on the 
model see Section 8.5.3. Like Part 1, the sample size for the dose escalation in Part 2A cannot be 
exactly prespecified but depends among other things on the number of DLTs seen. The planned 
cohort size is 3 subjects. The SMC may decide to change the planned cohort size. The total sample 
size will depend on the number of cohorts to be evaluated. It is anticipated that 6 to 15 subjects 
maximum will be needed. The following scenario is possible: 2 dose levels with 3 subjects each 
and 1 dose level with 6 subjects, resulting in 12 subjects. 
8.1.2.2 
Part 2B, Expansion Cohort 
In the Part 2B expansion cohort, a 2-stage design with a total of 30 subjects evaluable for response 
will be applied. If 11/30 responses are seen at the final analysis, the posterior probability that the 
ORR ≥ 30% is 81%.  
An interim analysis for futility will occur after enrollment of 15 subjects treated at the same dose 
who are evaluable for response. The cut-off for the interim analysis for futility was chosen to 
balance sufficient information for decision with the potential of sparing subjects an additional 
treatment from the standard of care cabozantinib. The boundary and operational characteristics are 
described in Section 8.5.2 
In case the SMC decides to decrease the M8891 dose during the expansion phase, then only 
subjects treated at the same dose will be considered in the 2-stage design. Therefore, the number 
of subjects in the expansion cohort might increase to reach the required number of 30 subjects 
treated on the same dose who are evaluable for response. The increase in sample size is limited to 
maximally 40 subjects in Part 2B. 
8.2 
Randomization 
Not applicable. 


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8.3 
Endpoints 
8.3.1 
Part 1, M8891 Single Agent, Solid Tumors 
8.3.1.1 
Primary Endpoints 
The primary endpoint of the Part 1 of this trial is DLTs during the first 21-day treatment cycle, 
based on a predefined set of AEs, to determine the MTD.  
8.3.1.2 
Secondary Endpoints 
Secondary endpoints include: 
• Occurrence and severity of TEAEs, and deaths, including cause of death, from screening up to 
the End of Treatment Visit 
• Changes in clinical laboratory measures, ECG measures, vital signs, ECOG PS 
• PK parameters of M8891 after QD dosing: 
• Cmax, tmax 
• AUC0-t,  
• AUC0-∞,  
• AUC0-τ, 
• t1/2,  
• λz,  
• CL/F,  
• CLss/F,  
• Vz/F,  
• Racc(AUCτ)  
• Racc(Cmax) 
Time points for PK assessments for QD dosing: Cycle 1 Day 1: 0 hour (pre-dose within 60 
minutes prior to each treatment administration) and 1 (± 10 minutes), 2 (± 10 minutes), 3 (± 10 
minutes), 4 (± 20 minutes), 5 (± 20 minutes), 6 (± 30 minutes), 8 (± 30 minutes), 12 hours post-
dose (± 60 minutes), on Day 2 at 24 hours post-dose (before next drug administration) (± 60 
minutes). Cycle 1 Day 8: 0 hour (pre-dose within 60 minutes prior to treatment administration), 
Cycle 1 Day 15: 0 hour (pre-dose within 60 minutes prior to each treatment administration) and 
1 (± 10 minutes), 2 (± 10 minutes), 3 (± 10 minutes), 4 (± 20 minutes), 5 (± 20 minutes), 
6 (± 30 minutes), 8 (± 30 minutes), 12 hours post-dose (± 120 minutes), on Day 16 at 24 hours 
post-dose (before next drug administration) (± 60 minutes), 63 mL blood in Cycle 1. Cycle ≥2 
Day 1: 0 hour (pre-dose within 60 minutes prior to each treatment administration). 


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x Best overall response (BOR: CR, PR, SD, or PD) according to RECIST v 1.1. criteria as 
assessed by Investigators  
x Clinical benefit defined as CR, PR, or SD for  12 weeks 
x PFS is defined as the time from first study drug administration to either first observation of PD 
(as assessed by RECIST v 1.1) or occurrence of death due to any cause, whichever occurs first.  
8.3.1.3 
Other Endpoints 
8.3.2 
Part 2, M8891 with Cabozantinib, mRCC 
Endpoints for Part 2A are provided in Table 6 and endpoints for Part 2B are provided in Table 7. 
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 subjects who sign informed consent 
Dose Escalation  
All subjects treated in dose escalation cohorts who either 
Part 1: 
x 
did not miss > 4 cumulative days of planned doses of M8891 in the first cycle 
of the dose escalation part or 
x 
who experienced a DLT  
Part 2A and 2B:  
x 
Received at least 80% of the planned cumulative dose of each treatment in 
the first cycle of the dose escalation part or 
x 
who experienced a DLT 
  
Safety 
The Safety Analysis Set will include all subjects who receive at least one dose of trial 
treatment. 
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 M8891, and M8891 combined with cabozantinib and have sufficient 
M8891/cabozantinib plasma concentration data to enable the calculation of at least one 
PK parameter. Sufficient concentration data is defined as at least 3 valid, post-dose 
concentration points in the PK profile to obtain any PK parameter.  
Pharmacodynamics in 
WBCs 
All subjects who received at least one dose of M8891 and provide the pre-dose and at 
least one post-dose WBC assessment. (Only for Part 1 of the study.) 
PK: Pharmacokinetic; WBC: White blood cell. 
8.5 
Description of Statistical Analyses 
8.5.1 
General Considerations 
The following summary statistics will be used to summarize the trial data per Part and dose level 
unless otherwise specified: 
x Continuous variables: number of not missing observations, mean, standard deviation, median, 
minimum, and maximum 
x Categorical variables: frequencies and percentages. 
All summary statistics will be described in detail in the respective Integrated Analysis Plan. There 
is no formal significance level for this trial and all analyses are considered descriptive. 
The cutoff for the analysis will be as follows: 
For the analysis after the end of Part 1, the cutoff will be Last Subject Last Visit (LSLV), or 
4 months after the last subject enrolled into the monotherapy dose escalation cohort has finished 
their DLT period, whichever comes first. 
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For both dose escalation parts, the analysis will focus on the number of subjects experiencing a 
DLT. The SMC will receive results of a Bayesian two-parameter logistic model with overdose 
control updated with the observed DLT data for SMCs dedicated to dose escalation decisions 
(Babb 1998; Neuenschwander 2008). Recommendation is based on a loss function (probabilities 
of being in one of the four toxicity probability intervals will be multiplied with a loss term as 
follows: 
0 * P(target dosing (0.17-0.33]) + 1 * P(for over (0.33-0.67] or under dosing [0-0.17]) + 2 * 
P(excessive dosing (0.67-1]). 
Glossary:  
 
(x.xx-y.yy] = lower limit excluded, upper limit included in the penalties 
 
[x.xx-y.yy]  =  lower limit included, upper limit included in the penalties 
In addition, only doses that have a corresponding probability of less than 25% that the true DLT 
rate is more than 33% (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. 
• MTD definition 
The target DLT rate for the MTD definition is 30%. The MTD suggested by the model (if reached) 
will be defined as follows: 
Highest tested dose with estimated DLT rate ≤ 30%. Additionally, the following needs to be 
fulfilled: 
- The upper bound of the 95% credible interval of a potential MTD is not more than 40% 
and 
- The estimated DLT probability for the suggested MTD is above or equal to 17%. 
The SMC will be notified of a potential MTD if a tested dose fulfills the above last 2 criteria. The 
SMC defines the MTD and can deviate from the suggestion of the model. 
 
8.5.2 
Efficacy Analysis 
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 and, additionally for Part 2 posterior 
probabilities (2.5%, 25%, 50%, 75%, and 97.5% quantiles), for clinical benefit will 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-, 18-, 24-month survival rate 
estimates and estimates for every 6 months thereafter if applicable) including the corresponding 
two-sided 95% confidence intervals. The confidence intervals for the median will be calculated 
according to Brookmeyer and Crowley (1982) and confidence intervals for the survival function 




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Posterior probabilities (2.5%, 25%, 50%, 75%, and 97.5% quantiles) for DLT probabilities at 
selected doses will be estimated from the Bayesian logistic regression model. The Dose Escalation 
Analysis Set will be used for this analysis.  
The Bayesian escalation approach will be used to assist the SMC to select the next dose from a 
predicted set of acceptable doses (e.g. 7, 12, 20, 35, 60, 100, 150, and 210 mg QD). The SMC may 
choose a different dose than suggested by the Bayesian escalation approach.  
Subjects who miss > 4 cumulative days of planned doses of M8891 in the first cycle of the dose 
escalation part for other reasons than a DLT are not eligible for DLT assessment and will not be 
considered in the Bayesian model. Subject replacement will be considered based on reason for 
withdrawal and safety evaluation of cumulative data i.e. current and previous cohort data if 
applicable. If a subject out of a cohort of 3 is not eligible for the Bayesian model, the Bayesian 
model will be updated with the data from the evaluable subjects only and the SMC can decide 
upon next dose level. 
The target probability for the MTD will be 30%. 
The two-parameter logistic regression model will be set up as follows: 
The relationship between dose and toxicity rate is defined by  
ܲ൫ܦܮܶห݀௝, ߙ, ߚ൯=
exp ൬ߙ+ exp(ߚ) כ log ൬݀௝
݀௥௘௙൰൰
1 + exp ൬ߙ+ exp(ߚ) כ log ൬݀௝
݀௥௘௙൰൰
 
Where dj ( 7 mg, 12 mg, 20 mg, 35 mg, 60 mg, 100 mg, 150 mg, 210 mg) (QD dosing) DQGĮȕ
are bivariate normally distributed and the reference dose (dref) is 340 mg.  
 the following could 
be derived: 
E(Į)=log(0.8/0.2)=1.386 
E(ȕ)=log((log(0.33/0.67)-log(0.8/0.2))/log(210/340))=1.469 
9DULDQFHVDUHFKRVHQDVIROORZV9DUĮ 2ð9DUȕ 2ð&RYĮȕ 2  
Posterior distribution and the recommended next dose level will be calculated using 
R version 3.1.2 or higher with library packages bcrm (Sweeting 2013) or crmPack (Bove 2019), 
or SAS Software version 9.3 or higher, or EAST version 6.4 or higher. 
In Part 1, dose escalation will stop as soon as one of the following rules applies:  
x A maximum number of 42 subjects are evaluable in dosing escalation LHPLVVHGSODQQHG
doses in Cycle 1 except subject was qualified to have had a DLT) 
CCI


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• More than 4 cohorts are assigned to the same dose level,  
• Or the estimate for DLT probability of the MTD reaches sufficient precision.  
At least 6 subjects need to have been treated at the suggested MTD. That might necessitate the 
enrollment of additional subjects after dose escalation was stopped. 
8.5.3.2 
Part 2A M8891 with cabozantinib, mRCC 
The Bayesian escalation approach will be used to assist the SMC to select the next dose from a 
predicted set of acceptable doses (e.g. 20, 35, and 60 mg QD) (See Section 5.1.3.2.1). The SMC 
may add or skip dose levels for others that are not part of the pre-specified set, but they will never 
exceed the dose level of M8891 that has already been declared to be safe in Part 1 
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) for DLT probabilities at 
selected doses will be estimated from the Bayesian logistic regression model. The same type of 
two-parameter logistic regression model will be used as described in Section 8.5.3.1 for Part 1. 
The Dose Escalation Analysis Set will be used for this analysis.  
If a subject out of a cohort of 3 is not eligible for the Bayesian model, the Bayesian model will be 
updated with the data from the evaluable subjects only and the SMC can decide upon next dose 
level. 
The target probability for the MTD will be 30%. 
The two-parameter logistic regression model will be set up using data from Part 1 and will be 
specified in the SMC charter prior to dosing of the first subject. 
8.5.3.3 
Part 2B M8891 with cabozantinib, mRCC 
The SMC will continue to monitor the safety of M8891 combined with cabozantinib and may 
decide on continuation on the same dose, change in dose (not higher than MTD in Part 2A), 
modifications of the study protocol, or stop of expansion cohort. The same DLT criteria as for the 
monotherapy dose escalation will apply. If less than 6 subjects have been treated at the MTD / 
RDE selected in Part 2A, there will be an SMC meeting after the first 3 subjects have been treated 
in Part 2B at the MTD / RDE once these subjects have finished their DLT period or have dropped 
out, in order to additionally evaluate safety and tolerability at this dose. Enrollment will be 
suspended for this SMC. The SMC will also meet to evaluate the safety and tolerability 
(cumulative and unacceptable toxicity) of the combination therapy after 10 and 20 subjects have 
finished their DLT period or dropped out. Enrollment of subjects will not be interrupted between 
these SMCs. 
The SMC decisions in the expansion cohort will also be supported by a two-parameter Bayesian 
logistic regression model, as described in Section 8.5.3.1 for Part 1. This model will either use the 


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same prior as Part 2A, or, if the data seen in Part 2A conflict with the prior, a new prior will be set 
up and will be specified in the SMC charter.  
8.5.4 
Pharmacokinetics 
8.5.4.1 
Descriptive Statistics 
The PK variables will be analyzed descriptively for each dose level and day, separately. 
Descriptive statistics for PK concentrations are: number of non-missing observations (N), 
arithmetic mean (Mean), standard deviation, coefficient of variation (CV%), minimum, median 
and maximum. Descriptive statistics of PK Parameters should additionally show the geometric 
mean, the geometric coefficient of variation and the 95% confidence interval for the geometric 
mean. The drug concentration in plasma at each sampling time will be presented on the original 
scale for all subjects in the PK analysis set. Values below the LLOQ will be taken as zero for 
descriptive statistics of concentrations. 
Individual plasma concentration-time profiles (linear and semi-logarithmic scale) will be plotted. 
Mean plasma concentrations per dose level and day will be plotted with standard deviation using 
scheduled time points. If evidence is given that the weight affects the PK parameters, the analyses 
will also be performed for weight normalized PK parameters. 
All statistical tests will be performed in an exploratory way.  
All analyses will be based on the PK data set.  
Details of the statistical analyses will be described in the Integrated Analysis Plan. 
8.5.4.2 
Analysis of dose proportionality 
For the assessment of dose proportionality, the PK endpoints, AUC0-τ (or AUC0-∞ if appropriate), 
and Cmax of M8891 will be compared between dose levels for Day 1 and Day 15 separately. 
The PK parameters will be dose normalized. The dose normalized parameters and the overall mean 
will be plotted. Modeling on the log transformed scale will be applied to the dose normalized 
parameters including dose as covariate. Dose proportionality will also be checked using the power 
model, if appropriate. The relationship between the PK parameter y and the actual total dose is 
defined as follows: 
y = α doseβ 
On the log transformed scale this becomes a linear relationship to which a linear regression 
approach can be applied: 
log(y) = log (α) + β*log (dose) 


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7KHHVWLPDWHRIȕDQGFRQILGHQFHLQWHUYDOVZLOOEHFRPSXWHGWRquantify dose proportionality. 
,IGRVHSURSRUWLRQDOLW\LVJLYHQȕin theory is equal to 0 and the estimate of the model should not 
deviate strongly from 0. 
8.5.5 
Analysis of Other Endpoints 
Laboratory variables 
Laboratory results will be classified by Grade according to NCI-CTCAE. The worst on-trial 
Grades after the first trial treatment will be summarized. Shifts in toxicity grading from first 
treatment to highest Grade will be displayed. Results for variables that are not part of NCI-CTCAE 
will be presented as below, within, or above normal limits. Only subjects with post-baseline 
laboratory values will be included in these analyses. 
Physical examination (including vital signs) 
Physical examination, vital signs (body temperature, respiratory rate, heart rate, and blood 
pressure) and ECG recorded at baseline and after drug administration will be presented. For Part 1 
of the study, the ECG parameter will be summarized by descriptive statistics per time point, 
changes from baseline will be calculated. Data will be further analyzed using concentration effect 
modeling for baseline corrected QTcF interval values. 
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8.6 
Interim and Additional Planned Analyses 
8.6.1 
Part 1, M8891 Single Agent, Solid Tumors 
The cutoff for dose escalation assessments by the SMC will be triggered by the completion of the 
DLT period (or drop-out) of the last subject in the respective cohort. 
For the analysis after the end of dose escalation for monotherapy, the cutoff will be LSLV, or 4 
months after the last subject enrolled into the monotherapy dose escalation cohort has finished 
their DLT period, whichever comes first. 
Additional analyses during the study might be conducted, e.g. for publication purposes.  
8.6.2 
Part 2, M8891 with Cabozantinib, mRCC 
In part 2A, the cutoff for dose escalation assessments by the SMC will be triggered by the 
completion of the DLT period (or drop-out) of the last subject in the respective cohort. 
In Part 2B, there will be an interim analysis for futility after 15 subjects evaluable for response are 
included, as described in Section 8.5.2.  
Additional analyses during the study might be conducted, e.g. for publication and decision-making 
purposes. Analyses for decision-making purposes will include analyses to assess whether the 
criterion for the 2-stage design of 11 responses (see Section 8.5.2.) has already been reached at an 
early read out. 
9 
Ethical and Regulatory Aspects 
9.1 
Responsibilities of the Investigator 
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
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 trial. 
According to United States Code of Federal Regulations Part 54.2 (e), for trials conducted in any 
country that could result in a product submission to the United States Food and Drug 
Administration for marketing approval and could contribute significantly to the demonstration of 
efficacy and safety of an IMP (which are considered “covered clinical trials” 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 trial and for 12 months following completion of the trial. 
9.2 
Subject Information and Informed Consent 
An unconditional prerequisite for each subject prior to participation in the trial is written informed 
consent, which must be given before any trial-related activities are carried out. Adequate 


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information must therefore be given to the subject by the Investigator or an 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 trial, 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 trial and sign the Informed Consent Form, as above. 
After the information is provided by the Investigator, the Informed Consent Form 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 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 Informed Consent Form 
should be provided to the subject prior to participation. 
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the subject information sheet and any other written information to be 
provided to the subjects and submit them to the IRB for review and opinion. Using the approved 
revised subject information sheet and other written information, the Investigator will explain the 
changes to the previous version to each trial subject and obtain new written consent for continued 
participation in the trial. 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 trial as well as in the clinical trial 
database. All subject data collected in the trial will be stored under the appropriate subject number. 
Only the Investigator will be able to link trial 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 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. 
The Investigator will complete the subject registration form and fax it to the subject registration 
center. If the subject meets all inclusion criteria and does not meet any of the exclusion criteria, 


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the subject registration center will receive confirmation, register the subject and inform the 
Investigator and the Sponsor of the registration number by fax. If the subject is ineligible for the 
trial, a subject number will be allocated and documented. 
9.4 
Emergency Medical Support and Subject Card 
Generally, each subject will receive a card that includes certain minimum information pertaining 
to the trial, their participation, Investigator contact details and the appropriate Call Center Vendor 
or Phase I Unit for emergency medical support.  
Subjects will be provided with Emergency Medical Support cards supplied by the CRO for use 
during trial participation in order to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial 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 trial 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 provides the appropriate means to 
contact a Sponsor physician. This includes the provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor physician 
to assist with the medical emergency. 
9.5 
Clinical Trial Insurance and Compensation to Subjects 
Insurance coverage will be provided and conditions shall meet good local standards, as applicable. 
9.6 
Independent Ethics Committee or Institutional Review Board 
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents 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 trial, the clinical trial protocol version and 
the Subject Information and Informed Consent Form version reviewed should be provided. Where 
possible, copies of the meeting minutes should be obtained. 
Amendments to this clinical trial protocol will also be submitted to the concerned IEC or IRB, 
before implementation of substantial changes (see Section 10.5). Relevant safety information will 


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be submitted to the IEC or IRB during the course of the trial in accordance with national 
regulations and requirements. 
9.7 
Health Authorities 
The clinical trial protocol and any applicable documentation (for example, Investigational 
Medicinal Product Dossier, Subject Information and Informed Consent Form) will be submitted 
or notified to the Health Authorities in accordance with all local and national regulations for each 
site. 
10 
Trial Management 
10.1 
Case Report Form Handling 
Refer to the Manual of Operations for eCRF completion guidelines. 
The main purpose of the eCRF is to obtain data required by the clinical trial 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 
trial 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. The CRO will follow the standards of the Sponsor in the database design and 
data structure.  The CRO will be responsible for data review and processing, in accordance with 
the CRO’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 trial. 
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 trial. 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 trial) 
• Trial identification, that is, the Sponsor trial number for this clinical trial, and subject number 
• Dates for entry into the trial (informed consent) and visits to the site 


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• Any medical examinations and clinical findings predefined in this clinical trial protocol 
• All AEs 
• Date that the subject left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable). 
All documents containing source data must be filed, including, but not limited to CT or MRI scan 
images, echosonography and ECG recordings, diary, 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 trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial 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 trial 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 trial. The documents to be archived include the Subject Identification List and the signed 
subject Informed Consent Forms. 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 trial will be monitored in accordance with the ICH GCP and any other applicable regulations. 
The site Monitor will perform visits to the trial site at regular intervals. 
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial 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 trial documents and 
other materials at the site, including the Investigator Site File, the completed eCRFs, all IMP and 
IMP accountability records, and the original medical records or files for each subject. 


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10.5 
Changes to the Clinical Trial Protocol 
Changes to the clinical trial 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 trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2. 
10.6 
Clinical Trial Report and Publication Policy 
10.6.1 
Clinical Trial Report 
After completion of the trial, a clinical trial 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 trial sites that provided evaluable data. The Investigator will inform the 
Sponsor in advance about any plans to publish or present data from the trial. 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. 
11 
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12 
Appendices 
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 subject’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 hormone replacement therapy (HRT) and whose menopausal status is in doubt 
will be required to use one of the non-hormonal highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 


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Contraceptive Guidance 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of < 1% per year when used consistently and correctly.  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
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  
• 
Intrauterine hormone-releasing system  
• 
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 subject.)  
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 subjects 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 two highly effective methods of contraception should be utilized during the 
treatment period and for at least 92 days (3 months) after the last dose of study treatment. 


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Appendix II 
Drugs which are potent combined CYP2C9, CYP2C19 and 
CYP3A4 inhibitors 
Table 14 contains a list of drugs which are combined potent inhibitors of CYP2C9, CYP2C19 and 
CYP3A4 (moderate and/or potent inhibitors for at least 2 of the CYP enzymes).  
Table 14 
Combined Potent Inhibitors 
 
Strong inhibitors 
Moderate inhibitors 
Weak inhibitors 
CYP2C9 
- 
amiodarone, felbamate, 
fluconazole(a), 
miconazole, piperine 
diosmin, disulfiram, 
fluvastatin, 
fluvoxamine(b), 
voriconazole 
CYP2C19 
Fluconazole(a), 
fluoxetine(c), 
fluvoxamine(b), ticlopidine 
- 
omeprazole, 
voriconazole 
CYP3 
boceprevir, cobicistat(d), 
conivaptand), danoprevir, 
ritonavir(e), elvitegravir, 
grapefruit juice(f), 
indinavir, itraconazole(d), 
ketoconazole, lopinavir, 
paritaprevir, ombitasvir, 
dasabuvir(e), 
posaconazole, 
saquinavir, telaprevir(d), 
tipranavir, 
troleandomycin, 
voriconazole, 
clarithromycin(d), 
diltiazem(d), idelalisib, 
nefazodone, nelfinavir(d) 
aprepitant, cimetidine, 
ciprofloxacin, 
clotrimazole, crizotinib, 
cyclosporine, 
dronedarone(d), 
erythromycin, 
fluconazole(a), 
fluvoxamine(a), imatinib, 
tofisopam, verapamil(d) 
chlorzoxazone, 
cilostazol, fosaprepitant, 
istradefylline, ivacaftor(d), 
lomitapide, ranitidine, 
ranolazine(d), tacrolimus, 
ticagrelor(d) 
a) 
Strong inh bitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A.  
b) 
Strong inh bitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A. Strong inhibitor of CYP2C8, weak 
inh bitor of CYP2B6, and inh bitor of OATP1B1. 
c) 
Strong inh bitors of CYP2C19 and CYP2D6. 
d) 
Inhibitor of P-gp (defined as those increasing AUC of digoxin to ≥1.25-fold). 
e) 
Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution should be used 
when extrapolating the observed effect of ritonavir alone to the effect of combination regimens on CYP3A activities. 
f) 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies 
have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, 
double strength) or as a “moderate CYP3A inh bitor” when another preparation was used (e.g., low dose, single strength). 
 
Note: Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic 
pathway ≥5-fold, ≥2 to < 5-fold, and ≥1.25 to < 2-fold, respectively. This table is prepared to provide examples of clinical inhibitors 
and is not intended to be an exhaustive list. Data are based on a search of the University of Washington Metabolism and Transport 
Drug Interaction Database (Hachad 2010). Additional information can be found in the Drug Interaction Flockhart Table. For further 
details and update refer to the websites: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers#table3-2; https://drug-interactions.medicine.iu.edu/Main-Table.aspx. 
 




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Appendix IV 
Protocol Amendment History 
The information for the current amendment is on the title page.  
Amendment #1, 02 January 2018 (Global, Substantial), Protocol Version 2.0 
This amendment was initiated by the Sponsor. 
Major Scientific Changes 
This amendment:  
• Clarifies the procedure related to screening and dosing subjects for a next cohort during dose 
escalation  
• Adds a recommendation for dose modification 
• Removes the screening level of D-dimer from Exclusion Criterion #8 
• Increases monitoring of lower extremity by Doppler ultrasonography and adds a stopping 
criterion related to this monitoring 
• Removes potential inconsistencies between Section 7.6 and Section 9.3 regarding handling of 
samples after completion of the study 
• Clarification of schedule for ECG. 
Administrative and Editorial Changes 
The following generally describes administrative and editorial changes included in this 
amendment: 
• Window for PK sampling for Cycle 1 Day 15 increased from 60 min to 120 min. 
• Table numbers adjusted. 
• Typos on Schedule of Assessment (drug administration) corrected. 
• The protocol version number and date were updated. 
• Personnel were updated. 
• Correction of errant punctuation.  
• The Table of Contents was updated 
Amendment #2, 27 August 2019 (Global, Substantial), Protocol Version 3.0 
This amendment was initiated by the Sponsor. 
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 


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Overall Rationale for the Amendment 
The primary purpose of this amendment is to introduce investigation of M8891 combined with 
cabozantinib in subjects with metastatic renal cell carcinoma (mRCC) with clear cell component. 
This is referred to as Part 2, and the original investigation (dose escalation of M8891 single agent) 
is referred to as Part 1.  This amendment additionally makes some changes to improve the study 
design and clarity of Part 1. Important changes from the previous protocol (Version 2.0) are 
included in the table below.  Changes that do not meaningfully affect the design, conduct, or 
rationale for Part 1 are not included in the table below. Examples of revisions not included are 
those related to navigating or distinguishing the 2 parts of the study, minor edits to improve clarity, 
abbreviations, table/figure numbering, and formatting. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
Added Part 2 for combination with 
cabozantinib.  Part 2A for dose 
escalation and Part 2B for expansion 
cohort 
Expand study to investigate M8891 
combination therapy with cabozantinib. 
Title page, 
Synopsis 
Change in Coordinating Investigator 
Change in Medical Responsible 
Administrative change and alignment with the 
clinical needs of the Part 2 of the study 
Synopsis 
More detailed specification of Part 1 
population  
Clarification 
Synopsis 
Revised Part 1 exclusion criteria 
related to thrombosis and Doppler 
ultrasonography 
Updated guidelines regarding the mitigation of 
the risk for a thromboembolic event 
Synopsis 
Section 2 (Sponsor, 
investigators, and 
trial administrative 
structure) 
Section 3.1 (Study 
rationale) 
Section 5.1.3 
(Treatment period) 
Section 6.2.(Dosage 
and administration) 
Section 8.1 (Sample 
size) 
Section 8.3.1.2 
(Secondary 
endpoints) 
Section 8.5.1 
(General 
considerations) 
Removed the potential for twice daily 
dosing of M8891 in Part 1 
 
Initial findings from Part 1 have led to a focus 
on QD dosing only 
Synopsis / Schedule 
of Assessments 
Schedule of Assessments for Part 2, 
including detailed Table 4 and 5 for PK 
and safety ECGs assessments 
Clarity 
Schedule of 
Assessments for 
Part 1 
Revised monitoring related to 
coagulation and Doppler 
Updated guidelines regarding the mitigation of 
the risk for a thromboembolic event 
Schedule of 
Assessments for 
Part 1 
Footnote on imaging analysis has 
been updated 
Consistency with Schedule of Assessments for 
Part 2 
Schedule of 
Assessments for 
Part 1 
Footnote on detailed neurological 
examination has been deleted 
No longer considered relevant for the study 
Section 3 
(Background 
information) 
Reorganized into 3 subsections (study 
rationale, background, benefit risk) 
disperse original Part 1 text into these 
subsections and integrate with Part 2 
information. 
Clarity 
Section 3.3 
(Benefit/risk 
assessment)  
Updated information regarding M8891 
PK based on preliminary results of 
Part 1, including new estimated 
biologically effective dose. 
New clinical PK data available. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 3.3 
(Benefit/risk 
assessment) 
Updated discussion of potential 
M8891 safety concerns based on 
preliminary results from Part 1 
New clinical safety data available. 
Section 5.1 
Additional detail on Part 1 population 
Clarification 
Figure 1 
New study design figure incorporation 
Part 2 
Clearly represent Part 1, Part 2A and Part 2B 
of the study in a schematic. 
Section 5.1.2 
(Doppler 
Ultrasonography) 
New discussion of monitoring with 
Doppler ultrasonography in Part 1 and 
new approach for Part 2 
Updated guidelines and information on other 
MetAP2 inhibitors. 
Section 5.1.3.1 (Part 
1 M8891 single 
agent, solid tumors) 
Explanation of the criteria for the dose 
escalation 
Clarification 
Section 5.1.3.1 
(Treatment Period, 
M8891 single agent, 
Solid Tumors) 
Clarification of actions that may be 
taken by Safety Monitoring Committee 
Clarification 
Section 5.1.3.3 
(Dose-limiting 
Toxicities) 
Clarification of the roles of dose 
limiting toxicity data in this study 
Clarification 
Section 5.1.3.3 
(Dose-limiting 
Toxicities) 
Revisions to criteria for some dose 
limiting toxicities 
Clinical judgement for the safety of the subjects 
Section 5.1.3.5 
(Dose Modification) 
Revisions to criteria for M8891 dose 
modification. 
Clarification for dose modification of M8891 as 
single agent and combined with cabozantinib 
outside of the DLT period 
Section 5.2 
(Discussion of Trial 
Design) 
Reduced discussion of general trial 
design. 
Extensive discussion in Section 3 (Study 
Rationale, Background and Benefit/Risk 
assessment) 
Section 5.3.2 
(Exclusion Criteria) 
Modified Part 1 exclusion related to 
participation in another clinical study / 
other investigational agents 
Corrected wording 
Section 5.3.2.1 
(Exclusion Criteria) 
Modified Part 1 exclusion related to 
deep vein thrombosis / 
thromboembolic events. 
Accuracy on the clinical utility of doppler 
ultrasonography and safety of the patients 
Section 5.3.2.1 
(Exclusion Criteria) 
Modified Part 1 exclusion related to 
stroke, heart attack, thrombosis (e.g. 
deep vein thrombosis and pulmonary 
embolism) or genetically-determined 
hypercoagulopathy 
Accuracy and clarification. Thromboembolic 
events are included as exclusion criteria 
number 7.  
 
Section 5.5.1 
(Withdrawal from 
trial therapy) 
Added criteria related to ECG findings 
and to stroke 
Relevant to therapy with cabozantinib 
Section 5.5.2 
(Withdrawal from the 
trial) 
Additional criteria for withdrawal and 
clarification of subsequent activities 
Administrative 
Section 5.5.2 
(Withdrawal from the 
trial) 
Explanation of replacement of subjects 
Clarification 
Section 5.7 
(Definition of end of 
trial) 
Clarification of disposition of subjects 
on ongoing treatment. 
Clarification 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.2.1 
(Dosage and 
administration) 
Added instruction on withholding water 
around dosing 
Clarification 
Section 6.5.5 
(Management of 
specific adverse 
events…) 
List anticipated M8891 toxicities based 
on nonclinical data. 
Clarification 
Section 6.8 (IMP 
Accountability) 
Clarification to collection of 
accountability forms 
Clarification 
Section 7.3 (Efficacy 
assessments) 
Time points for efficacy assessments 
have been accurately defined 
Clarification 
Section 7.4.1.3 
(Definition of the 
Adverse Event 
Reporting Period) 
The window period of the EOT visit 
and the safety follow-up period has 
been updated 
Clarification 
Section 7.4.3 
(Clinical laboratory 
assessments) 
Section 7.5. 
(Pharmacokinetics) 
 
Reference to blood volumes in 
Laboratory Manual 
Clarification 
Section 7.4.4 (Vital 
signs, physical 
examinations, and 
other assessments); 
Section 8.5.5 
(Analysis of other 
endpoints) 
Physical exam no longer includes a 
complete neurological exam 
Medical evaluation that this is no longer 
warranted. 
Section 7.4.5 
(Electrocardiograms) 
New Section 7.4.5 that includes an 
updated explanation of ECG 
evaluations.   
Clarity: Part 1 ECGs for QTcF interval 
evaluation; Part 2 Safety ECGs 
Section 8.4 
Revised dose limiting toxicity as 
included in Dose Escalation analysis 
set. 
Clarification and consistency with the ongoing 
data analysis 
Section 8.5 
(Statistics) 
Subsections reordered 
Improve flow of text. 
Section 8.5.1 
(General 
considerations) 
Updated to include the new timing for 
the Part 1 analysis and the definition 
of MTD 
Clarification 
Section 8.5.2 
(Efficacy analysis) 
Added information on confidence 
intervals for all the study and posterior 
probabilities for Part 2 
Clarification on the statistical analysis plan for 
efficacy 
Section 8.5.3 (Safety 
analysis)  
Safety analysis for Part 1 has been 
updated to include when subject 
replacement will be considered 
Clarification 
Section 8.5.3. 
(Safety analysis) 
Addition of posterior probabilities for 
DLT analysis in Part 1 
Clarification on the statistical analysis plan for 
safety  
Section 8.6 (Interim 
and additional 
planned analyses) 
Updated to include the new timing for 
the Part 1 analysis  
Clarification 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 11 
(References cited) 
References added 
To support new text, primarily related to Part 2 
Appendix II 
Updated to include more details on 
pan-inhibitors that simultaneously 
inhibit CYP2C9, 2C19 and 3A4 
Clarity and relevant to therapy with 
cabozantinib 
Previous Appendix 
III (Blood Volumes) 
An appendix on blood volumes is no 
longer included in the protocol 
The exact blood volume will be indicated in the 
Laboratory Manual 
The limit on total blood volume has been added 
in the protocol at the respective sections related 
with blood collection 
Previous Appendix V 
(Protocol 
Amendments and 
List of Changes) 
Replaced by current Appendix IV 
(Protocol Amendment History) and this 
Summary of Changes 
Details of changes from Version 1.0 to 2.0 no 
longer relevant, and only summary now 
provided.  
Summary of current changes from Version 2.0 
to 3.0 provided in a more succinct and clearer 
format. 
Previous Appendix V 
table “Comparison 
with Clinical Trial 
Protocol Version 1.0, 
28 March 2017)” 
Deleted 
No longer relevant with this amendment from 
Version 2.0 to 3.0. 
Signature pages 
Updated for Sponsor’s signatory, 
Coordinating Investigator, and other 
Sponsor Responsible Persons 
New personnel 
 
 


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Appendix V 
Signature Pages and Responsible Persons for the Trial 
 


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Sponsor Signature Page 
 
Study Title: 
An Open-label, Phase I, Dose Escalation Trial of 
Methionine Aminopeptidase 2 Inhibitor M8891 in 
Subjects with Advanced Solid Tumors 
IND Number: 
 
Clinical Study Protocol Version: 
11 March 2020 / Version 4.0 
I approve the design of the clinical study: 
____ 
Date of Signature 
 
Name, academic degree: 
Function/Title: 
Medical Responsible 
Institution: 
Merck Healthcare KGaA.  
Address: 
Frankfurter Str. 250, 64293 Darmstadt, Germany  
Telephone number: 
Fax number: 
E-mail address: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Signature Page –Coordinating Investigator   
 
Trial Title 
An Open-label, Phase I, Dose Escalation Trial of 
Methionine Aminopeptidase 2 Inhibitor M8891 in 
Subjects with Advanced Solid Tumors 
IND Number 
Clinical Trial Protocol Date / 
Version 
11 March 2020 / Version 4.0  
 
I approve the design of the clinical trial and I understand and will conduct the trial according to 
the clinical trial protocol, any approved protocol amendments, International Council for 
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws. 
__ 
_____ 
Signature 
Date of Signature 
Name, academic degree:  
 
Function / Title: 
Institution: 
Address: 
Telephone number: 
Fax number: 
 
E-mail address: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Signature Page – Principal Investigator 
Trial Title 
An Open-label, Phase I, Dose Escalation Trial of 
Methionine Aminopeptidase 2 Inhibitor M8891 in 
Subjects with Advanced Solid Tumors 
IND Number 
 
Clinical Trial Protocol Date / 
Version 
11 March 2020 / Version 4.0 
Center Number 
 
Principal Investigator 
 
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, International Council for Harmonisation 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 trials 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: 
 
PPD


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Sponsor Responsible Persons Not Named on the Cover Page 
Name, academic degree: 
Function / Title: 
Institution: 
Merck Healthcare KGaA. 
Address: 
Frankfurter Str. 250, 64293, Darmstadt, Germany 
Telephone number: 
Fax number: 
E-mail address: 
 
PPD
PPD
PPD
PPD
PPD


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Sponsor Responsible Persons Not Named on the Cover Page 
 
Name, academic degree: 
Function / Title: 
Institution: 
Merck Healthcare KGaA  
Address: 
Frankfurter Str. 250, Darmstadt, Germany 
Telephone number: 
Fax number: 
NA 
E-mail address: 
PPD
PPD
PPD
PPD


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Sponsor Responsible Persons not Named on the Cover Page 
Name, academic degree: 
Function / Title: 
 
Institution: 
Merck Healthcare KGaA 
Address: 
Frankfurter Strasse 250, 64293 Darmstadt, Germany 
Telephone number: 
Fax number: 
NA 
E-mail address: 
 
PPD
PPD
PPD
PPD

SAP_001.pdf: 




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Merck KGaA
Frankfurter Strasse 250
64239 Darmstadt
Germany
Merck KGaA
Frankfurter Strasse 250
64239 Darmstadt
Germany
Merck KGaA
Frankfurter Strasse 250
64239 Darmstadt
Germany
Merck KGaA
Frankfurter Strasse 250
64239 Darmstadt
Germany
Document No. 
 
Object No. 
 


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1
Table of Contents
Integrated Analysis Plan ......................................................................................................1
Signature Page
..............................................................................................................2
1
Table of Contents..................................................................................4
2
List of Abbreviations and Definition of Terms ....................................6
3
Modification History ............................................................................9
4
Purpose of the Integrated Analysis Plan...............................................9
5
Objectives and Endpoints .....................................................................9
6
Overview of Planned Analyses...........................................................10
7
Changes to the Planned Analyses in the Clinical Trial Protocol........11
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........................................11
9
General Specifications for Data Analyses ..........................................12
9.1
Listings ...............................................................................................13
9.2
Tables..................................................................................................14
9.3
Software..............................................................................................15
10
Trial 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.............................18
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
Analysis of Best Overall Response, Clinical Benefit and 
Progression-free Survival Time..........................................................22
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2
List of Abbreviations and Definition of Terms
AE
Adverse Event
Ae!
Cumulative amount excreted during a complete dose interval at steady 
state
Ae0-t
Cumulative percentage of dose excreted from time zero (= dosing time) 
to the end of the current collection interval after dosing
Ae0-∀
Cumulative amount excreted from time zero (dosing time) to infinity
ATC
Anatomical Therapeutic Chemical
AUC0-t
Area under the concentration-time curve from time zero to last sampling 
time
AUC0-τ
Area under the concentration-time curve from zero to τ
AUC0-∞
Area under the concentration-time curve from zero extrapolated to 
infinity
AUCextra%
AUC from time tlast extrapolated to infinity given as percentage of 
AUC0-∀
BID
Twice Daily
BLM
Bayesian Logistic Model
BMI
Body Mass Index
BOR
Best Overall Reponse
CI
Confidence Interval
cIPD
Clinically Important Protocol Deviation
Cmax
Maximum observed concentration
CL/f
Apparent total body clearance of drug following extravascular 
administration
CLss/f
Apparent body clearance of drug following extravascular administration 
at steady state
CR
Complete Response
CRF
Case Report Form
cs
Clinically significant
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for AEs
CTP
Clinical Trial Protocol
CV%
Coefficient of Variation
DLT
Dose Limiting Toxicity
DRM
Data Review Meeting
DVT
Deep Vein Thrombosis
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
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EOT
End of Treatment
FU
Follow-up
GCP
Good Clinical Practice
GeoCV%
Geometric Coefficient of Variation
GeoMean
Geometric Mean
IAP
Integrated Analysis Plan
ICARS
International Cooperative Ataxia Rating Scale
ICH
International Conference on Harmonization
IMP
Investigational Medicinal Product
IPD
Important Protocol Deviation
λz
Terminal first order (elimination) constant
LCI
Lower limit of confidence interval
LLOQ
Lower limit of quantification
Max
Maximum
Mean
Arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MMSE
Mini-Mental State Examination
MTD
Maximum Tolerated Dose
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse 
Events
nc
Non-clinically relevant
ORR
Objective Response Rate
PCSA
Potentially Clinically Significant Abnormalities
PD
Progressive Disease
PFS
Progression-free Survival
PK
Pharmacokinetics
PopPK
Population Pharmacokinetics
PR
Partial Response
PT
Preferred Term
QCD
Quantitative Clinical Development
QD
Once daily
QTcF
QT interval corrected for heart rate according to Fridericia
Racc(AUC!)
Accumulation factor to assess increase in exposure until steady state is 
reached
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Racc(Cmax)
Accumulation factor to asses increase in maximum concentration until 
steady state is reached
RECIST
Response Evaluation Criteria In Solid Tumours
RP2D
Recommended Phase II Dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease 
Sd
Standard Deviation
SDTM
Study Data Tabulation Model
SMC
Safety Monitoring Committee
SOC
System Organ Class
t1/2
Apparent terminal half-life
TEAE
Treatment Emergent Adverse Event
TLF
Tables, Listings, and Figures
UCI
Upper limit of confidence interval
ULOQ
Upper limit of quantification
tmax
Time to reach maximum observed concentration
VZ/f
Apparent volume of distribution during the terminal phase
WBC
White blood cells
WHO-DD
Word Health Organization – Drug Dictionary
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3
Modification History
Unique
Identifier for
Version
Date of
IAP Version
Author
Changes from the Previous Version
1.0
20 Apr 2018
 
 
 
 
Initial version
4
Purpose of the Integrated Analysis Plan
The purpose of this Integrated Analysis Plan (IAP, referred to as Statistical Analysis Plan in 
protocol version 2.0 of this study) is to document technical and detailed specifications for the 
final analysis of data collected for protocol MS1000015-0019. Results of the analyses described
in this IAP will partly be included in a Clinical Study Report (CSR) or a separate report (e.g. 
PopPK analysis). 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 a CSR but not identified in this prospective IAP will be clearly 
identified as such in the CSR. 
This IAP does not describe the analyses done for the Safety Monitoring Committee (SMC) 
meetings. Instead, details can be found in SMC IAP, version 1.0 dated Oct 2017.
The IAP is based upon Section 8 (Statistics) of the trial protocol and is prepared in compliance 
with ICH E9. 
5
Objectives and Endpoints
Objective
Endpoint
IAP 
Section
Primary
Objective
#
To determine the maximum 
tolerated dose (MTD) of M8891 
as a single agent in subjects with 
solid tumors.
#
Dose limiting toxicities (DLTs) during the 
first 21-day treatment cycle, based on a pre-
defined set of adverse events (AEs), to 
determine the MTD.
#
15.1
Secondary 
Objectives
#
To evaluate the safety profile 
and tolerability of M8891 as a 
single agent
#
To investigate the 
pharmacokinetic (PK) profile of 
M8891 as single agent
#
Incidence and severity of treatment-
emergent adverse events (TEAEs), and 
deaths, including cause of death, from 
screening up to the End of Treatment visit 
(EOT).
#
Changes in clinical laboratory measures, 
electrocardiogram (ECG) measures, vital 
signs, Eastern Cooperative Oncology Group 
Performance status (ECOG PS).
#
PK parameters of M8891 after QD and BID 
dosing, as applicable: Cmax, tmax, AUC0-t, 
AUC0-∞, AUC0-τ, t1/2, λz, CL/F, CLss/F, 
Vz/F, Racc(AUCτ) and Racc(Cmax)
#
14
#
15
#
16.1
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Objective
Endpoint
IAP 
Section
#
To assess the antitumor activity 
of M8891 as single agent 
according to RECIST v1.1
#
To determine the recommend 
Phase II dose (RP2D) as single 
agent.
#
Best overall response (BOR: complete 
response [CR], partial response [PR], stable 
disease [SD] or progressive disease [PD]) 
according to RECIST v 1.1. criteria as 
assessed by investigators
#
Clinical benefit defined as CR, PR, and SD 
for ≥ 12 weeks
#
PFS (progression-free survival) defined as 
the time from first study drug administration 
to either first observation of PD (as 
assessed by RECIST v 1.1) or occurrence 
of death due to any cause, whichever 
occurs first
The analyses of the endpoints will be described in the respective sections for efficacy, safety or 
other endpoints, regardless if the endpoint is a primary endpoint or not.
6
Overview of Planned Analyses
During the study, tables, listings and figures (TLFs) and dosing recommendations based on the 
Bayesian Logistic Model (BLM) will be provided to the SMC. These analyses are described in 
the separate SMC IAP.
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Unless there is a protocol amendment to include more than monotherapy dose escalation in this 
study, there won’t be a further interim analysis, and the main statistical analysis for the 
monotherapy dose escalation of the study is described within this IAP. This analysis will take 
place when dose escalation is completed (data cutoff see Section 9); after study completion (i.e. 
after last subject last visit, when all subjects terminated treatment) an update of the analysis will 
be provided. If combination dose escalation or expansion parts are added to the study after 
completion of the dose escalation part, this IAP will be amended.
A data review meeting (DRM) 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 Trial 
Protocol
In protocol Section 8.5.3.3, estimation of posterior probabilities for clinical benefit and disease 
control rate are mentioned. These analyses are only applicable for expansion cohorts, and may be 
performed accordingly at a later time point. For the end of monotherapy dose escalation, only 
confidence intervals will be presented for the clinical benefit rate.
8
Protocol Deviations and Analysis Sets
8.1
Definition of Protocol Deviations and Analysis Sets
Important protocol deviations (IPDs) 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. 
IPDs include:
# Subjects that are dosed on the study despite not satisfying the inclusion criteria;
# Subjects that develop withdrawal criteria whilst on the study but are not withdrawn;
# Subjects that receive the wrong treatment or an incorrect dose;
# Deviation from Good Clinical Practice (GCP)
# Missed safety assessments
IPDs are clinically important if they lead to the exclusion of a subject from an analysis set, or if 
they could impact the key objectives of the study (see Section 10.2).
A list of IPDs can be found in Appendix 18.1, including possible consequences for assignment to 
analysis sets; clinically important protocol deviations (cIPDs) are highlighted accordingly. The 
final assessment of whether these protocol deviations lead to exclusion from an analysis 
population will be made at the DRM.
8.2
Definition of Analysis Sets and Subgroups
For purposes of analysis, the following populations are defined in Table 1.
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Table 1
Analysis Sets
Population
Description
Screening 
All participants who sign informed consent
Dose Escalation 
All subjects treated in dose escalation cohorts who did not miss >4 cumulative 
days planned doses of M8891 in the first cycle of the dose escalation part for 
other than safety reasons
Safety
The Safety Analysis Set will include all subjects who receive at least one dose of 
trial treatment.
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 M8891 and have sufficient M8891 
plasma concentration data to enable the calculation of at least one PK 
parameter. Sufficient concentration data is defined as at least 3 valid, post-dose 
concentration points in the PK profile to obtain any PK parameter. 
PK Pharmacokinetic; WBC White blood cell.
9
General Specifications for Data Analyses
All tables and listings (and titles and footnotes for figures) will be produced using the Courier 
New font with a font size of 10 points. A font size of 9 points will be acceptable in cases where a 
font size of 10 points does not fit.
All TLFs will be produced using a paper size of US letter in landscape with 1 inch margins on all 
four sides. 
Significance level:
There is no formal significance level for this trial and all analyses are considered descriptive. If 
confidence intervals or credibility intervals are mentioned, the level will be 95% unless 
otherwise specified.
Cutoff
For the analysis after the end of dose escalation for monotherapy, the cutoff will be 22 days after 
the first treatment day of the last subject enrolled into the monotherapy dose escalation cohort.
Pooling of centers:
Because of the anticipated small number of subjects enrolled in each center data will be pooled 
across centers, and the factor center will not be considered in statistical models or for subgroup 
analyses. 
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Definition of baseline:
In general, the last non-missing measurement prior to first trial drug administration will be used 
as the baseline measurement, unless otherwise specified (e.g. Section 15.7).
Definition of duration:
Duration in days will be calculated by the difference of start and stop date + 1 day (e.g. survival 
time (days) = date of death – date of first treatment + 1).
In case smaller units are of interest, duration will be calculated as stop date and time – start date 
and time.
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 (e.g. Section 11.3, 15, 16.1), missing data will not be replaced. 
In all listings imputed information will be flagged accordingly.
Days in Trial and on Treatment:
The first study day is the day of informed consent. The first treatment day is the day of first 
administration of Investigational Medicinal Product (IMP). The day before the first 
treatment/study day will be labelled as study/treatment day -1; there will be no study/treatment 
day 0.
9.1
Listings
All original and derived parameters relevant to the study endpoints as well as demographic and 
disposition data will be listed, including repeated and unscheduled measurements.
All dates and times will be presented in the format ‘DDMMMYYYY’ and ‘HH:MM’,
respectively. Data will be listed with the same number of decimal places as in the original data. 
Subjects will be identified in listings by theirSubject ID.
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9.2
Tables
Presentation of continuous and categorical variables
The following summary statistics will be used to summarize the trial data (other than PK 
concentration and PK parameters) per dose group (as defined by both dosing level and 
frequency) unless otherwise specified:
# Continuous variables: number of non-missing observations, number of missing observations, 
arithmetic mean (Mean), standard deviation (Sd), median (Median), minimum (Min), and 
maximum (Max) (in case less than 5 individual values are present: only mean, min and max
will be given)
# Categorical variables: frequencies and percentages.
The following conventions are applied for reporting descriptive statistics of all continuous data 
(n refers to the number of decimal places reported for the original data):
Mean, Median
n decimal digits
Sd
n + 1 decimal digits
Min, Max
n decimal digits
Confidence Intervals (CIs)
n decimal digits
Credibility Intervals
n decimal digits
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.
In case the analysis refers only to certain cycles and/or visits, percentages will be based on the 
number of subjects still present in the trial at that cycle and/or visit, unless otherwise specified.
All tables will be sorted by scheduled time point in chronological order, unless otherwise 
specified. 
Unscheduled measurement will not be used for summary tables or statistical analysis, unless it 
was a repeated measurement, performed due to technical reason or unreliable values for a 
planned assessment.
Should a repeated measurement occur prior to IMP administration, the last obtained reliable 
value prior to dosing will be used as baseline, unless otherwise specified.
Should a repeated measurement occur after IMP administration, then the measurement closest to 
the scheduled time will be used in the descriptive statistics and for changes from baseline. In 
case this rule does not identify a unique measurement to use, the earliest one among those 
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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 
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 non-inclusion:
o
Subject did not meet all eligibility criteria (as specified in ClinBase, including the 
description of the violated criteria)
o
Subject withdrew informed consent
o
Other reasons (specified in ClinBase)
The disposition listings will be sorted by dose group and subject ID.
10.2
Protocol Deviations
10.2.1
Important Protocol Deviations
The following summary tables and listings of IPDs will be provided (separately for pre-/post 
inclusion deviations), based on the safety population:
# Frequency table of IPDs by classification and description
# Listing of IPDs (sorted by dose group and subject ID), indicating whether it was a cIPD
The frequency table will be by dose group and overall.
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
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11
Demographics and Other Baseline Characteristics
11.1
Demographics
Demographic characteristics will be listed (sorted by dose group and subject ID) and 
summarized by dose group and overall, based on the safety population, showing the following: 
# Demographic characteristics 
# Gender: male, female 
#
Race: White, Black or African American, Asian, Native Hawaiian or other Pacific 
Islander, American Indian or Alaska Native, Other 
# Ethnicity: Hispanic or Latino, Not Hispanic or Latino
# Age (years), calculated as (date of informed consent – date of birth + 1) / 365.25
# Age categories: <65, 65-74, 75-84, ≥85 years
# Weight (kg)
# Height (cm)
# Body Mass Index (BMI), calculated as (weight in kg) / (height in meters)2 (kg/m2) 
# Center
11.2
Medical History
The medical history will be coded with the most recent Medical Dictionary for Regulatory 
Activities (MedDRA®) version, Version 20.1 or later.
Medical history will be listed by subject, based on the safety population, and will include the 
following information:
# Description of medical condition
# System Organ Class (SOC)
# MedDRA Preferred Term (PT)
# Start/End Date (or ongoing, if applicable)
# Toxicity grade (if applicable)
# Relation to study condition
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11.3
Disease History and Prior Anti-Cancer Therapies
The safety population will be used for all disease history and prior anti-cancer therapy related 
outputs.
Disease history will be listed including the following information:
# Site of primary tumor
# Sub Sites
# Date of initial cancer diagnosis
# Date of documented locally advanced, inoperable or metastatic disease (if applicable)
# Histopathological classification
# T, N and M classification at initial diagnosis
# T, N and M classification at study entry
The disease history will be summarized by dose group and overall using the safety population for 
the following categorical variables:
# T, N and M stages at study entry
# Time since initial diagnosis (months)
# Time since documentation of locally advanced, inoperable or metastatic disease (months)
# Histopathological classification
Incomplete dates for disease history (initial diagnosis date, date of documented locally advanced, 
inoperable or metastatic disease) will be imputed as follows:
#
If the day is missing, it will be imputed to the 15th day of the month.
#
If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st.
#
If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st.
#
If the date is completely missing, no imputation will be performed.
Prior anti-cancer drug therapy will be listed including the following information:
# Regimen number
# Intent and type of therapy
# Reason for discontinuation
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# Best response 
# Date of documented progression disease (if applicable)
# For each drug given as part of the regimen:
o
Name of drug (coding as described in Section 12)
o
Start and end date
Prior anti-cancer radiotherapy will be listed including the information:
# Regimen number
# Location
# Start and end dates
# Total dose
# 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. 
12
Previous or Concomitant Medications/Procedures
The safety population will be used to list and summarize previous and concomitant medications.
Concomitant treatments are medications, other than trial medications, which are taken by 
subjects any time on-trial (on or after the first day of trial drug treatment for each subject) or 
within 28 days after last dose of trial drug. In case the date values will not allow to unequivocally 
allocate a medication to concomitant medication, the medication will be considered as 
concomitant medication.
Previous medications are medications, other than trial medications and pre-medications for trial 
drug, which started before first administration of trial drug. In case the date values will not allow 
to unequivocally allocate a medication to previous medication, the medication will be considered 
as previous medication.
All medication will be coded with the most current World Health Organization – Drug 
Dictionary (WHO-DD) version September 2017 or later.
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Both previous and concomitant medication will be listed including the following information:
# Name of medication
# Anatomical Therapeutic Chemical (ATC) 2nd level and Preferred Term (PT)
# Start and end date
# Dose and frequency
# Route of administration
# Reason for medication
All concomitant medication will be summarized by dose group and overall, ATC 2nd level and 
PT.
In case multiple ATC’s are assigned to a drug, all ATC 2nd level will be used for reporting.
All concomitant procedures, which were undertaken any time on trial, will be listed, showing 
the following information:
# Name of procedure
# Start and end date
# Reason for procedure
13
Treatment Compliance and Exposure
Exposure to the IMP will be listed using the safety population, showing the following 
information:
# Cycle and day in cycle
# Date and time of administration
# Actual dose
# Whether dose has been adjusted, and if yes, reason why
# Reason for no dose (if applicable)
Using the safety population, compliance and exposure will be summarized by dose group and 
overall, including duration of therapy (weeks), number of times dose missed (overall and by 
reason) and number of times dose was adjusted (overall and by reason).
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14
Efficacy Analyses
14.1
Analysis of Best Overall Response, Clinical Benefit and 
Progression-free Survival Time
All efficacy endpoints will be listed and summarized descriptively as described in Section 9.2. 
The following categorical variables will be included:
#
Best overall response (BOR: complete response [CR], partial response [PR], stable 
disease [SD] or progressive disease [PD] according to RECIST v 1.1; objective response 
rate [ORR=CR+PR].)
#
Clinical benefit (CR, PR and SD for ≥ 12 weeks: yes/no)
In addition, 95% exact Clopper Pearson Confidence intervals will be calculated for the overall 
clinical benefit rate and the ORR (regardless of dose level). 
Furthermore, the following variable will be analyzed:
#
Progression-free survival time (PFS) 
PFS time is defined as the time from start of treatment to the date of the first documentation of 
objective progression of disease (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) at data cutoff, or for patients with an event after two or more subsequent 
missing response assessments (i.e. 2 times the scheduled time interval between two subsequent 
response assessments, plus 1 week time window). Patients who do not have a baseline tumor 
assessment or who do not have any post-baseline tumor assessments will be censored at start of 
treatment unless death occurred on or before the time of the second planned tumor assessment in 
which case the death will be considered an event.
The date of the overall response assessment is the earliest date of imaging of target, non-target 
and new lesions of images taken at that response assessment.
Status
Censoring
Date of event / censoring
Progressed or died
Within two subsequent scheduled 
tumor assessments after last 
response assessment of CR, PR or 
SD or treatment start
Event
Minimum(Date of PD, Date of death)
Otherwise
Censored
Date of last tumor assessment with 
outcome CR, PR or SD or date of 
treatment start, whatever is later
Neither progressed nor died
Censored
Date of last tumor assessment with 
outcome CR, PR or SD or date of 
treatment start, whatever is later
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The censored values will be presented descriptively. Number of and reason (PD/Death after two 
or more subsequent missing response assessments, censored at treatment start, lost to follow-up / 
withdrew consent, due to data cutoff (administrative censoring)) for censored values will be 
displayed, including percentages.
In the listing censored values will be flagged and the reason for censoring will be displayed.
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-, 18-, 24-month 
survival rate estimates and estimates for every 6 months thereafter if applicable) including the 
corresponding two-sided 95% confidence intervals, presented overall, and for daily dose ≤/>
median daily dose.
The confidence intervals for the median will be calculated according to Brookmeyer and 
Crowley (1982) and confidence intervals for the survival function estimates at above defined 
time points will be derived using the log-log transformation according to Kalbfleisch and 
Prentice (1980). The estimate of the standard error will be computed using Greenwood's formula.
The safety population will be used for the analysis of efficacy.
14.2
Analysis of Response Evaluation Criteria in Solid Tumors 
(RECIST)
The results of the RECIST evaluation will be listed using the safety population and will contain 
the following information:
# Designation of lesion (target/non-target/new)
# Lesion number
# Site
# Assessment Method
# Imaging Date
# Type of lesion (primary, node or metastasis)
# Size (longest diameter for non-nodal, short axis for nodal)
# Sum of longest diameters of target lesions (mm, per assessment)
# PET result
The list will be sorted by dose group, subject, designation, number of lesion and date.
Overall disease assessment based on imaging (RECIST 1.1) will be listed, including the 
following information:
# Date of overall response assessment (as defined in Section 14.1)
# Time from start of treatment (months)
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# Response target lesions
# Response non-target lesions
# New lesions
# Overall response
The percent change from baseline in sum of longest diameters (mm) for target lesions will be 
summarized by dose group and overall, and by time point.
Spider plots per dose group and overall will be produced. For each subject a different 
combination of color and line type will be used; all subjects in the same dose group will be 
presented using the same color.
14.3
Eastern Cooperative Oncology Group Performance Status 
(ECOG PS)
The ECOG PS assessments will be listed using the safety population, including date of 
assessment and performance status.
The shift from baseline to best and worst on-treatment ECOG PS, respectively, will be 
summarized by dose group based on the safety population. The missing category will be 
included and the number of subjects in each cohort will be used as the denominator.
Also, the number of subjects with increase, decrease, as well as no change in ECOG PS 
compared to baseline during treatment, respectively, will be summarized.
15
Safety Analyses
15.1
Analyses of Dose Limiting Toxicities (Primary Endpoint)
The dose escalation set will be used for all analyses related to the primary endpoint. The 
frequency and percentage of subjects experiencing a dose limiting toxicity (DLT) will be 
summarized by dose group and overall. A listing will be provided as well (details on presented 
information, see Section 15.2).
In addition, the following will be presented:
#
Quantiles (2.5%, 25%, 50%, 75% and 97.5%) for the posterior probability of a subject 
experiencing a DLT at each of the dose levels used in the study according to the same 
Bayesian Logistic Model (BLM) as descripted in the SMC IAP, Section 14:
Bayesian two-parameter logistic model:
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 1 DLT.
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2) Steps 3) and 4) of the first approach will be followed.
3) The confidence interval for the DLT probability will be provided.
There will also be a plot showing both the observed percentage of DLTs and the 75% quantile 
for the predicted probability according to the BLM over dose. If the SMC decides to switch from 
QD to BID dosing, there will be a figure for QD and a figure for BID dosing.
Additionally, the posterior probability of toxicity will be plotted versus the dose, using East.
15.2
Adverse Events
All adverse events analyses will be based on the safety population.
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and unintended sign (including a 
laboratory finding), symptom or disease temporally associated with the use of an IMP, whether 
considered related to the IMP or not. All AEs will be coded using the most recent Medical 
Dictionary for Regulatory Activities MedDRA version, Version 20.1 or later.
A treatment emergent adverse event (TEAE) is defined as an AE that begins or worsens after at 
least one dose of the IMP has been administered. AEs that started before administration of IMP 
or more than 30 days after last dose of IMP will not be considered TEAEs.
Every AE listing will include the following information:
# System organ class (SOC) and preferred term (PT)
# Start and end date/time
# Days under treatment
# Duration
# Seriousness criteria
# Relationship with M8891
# Common Terminology Criteria for Adverse Events (CTCAE) toxicity grade
# Other causality factors
# Action taken with M8891
# Other actions taken
# Outcome
# Whether AE is dose-limiting toxicity
There will be a listing of all AEs, sorted by SOC and PT. 
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The following summaries will be presented by dose group and overall using the safety 
population:
# Number of subjects with the following kinds of TEAEs:
o
Any TEAE
o
Related TEAEs
o
TEAEs leading to withdrawal of trial drug
o
TEAEs leading to death (overall and by reason for death)
o
Serious TEAEs
o
Related serious TEAEs
o
TEAEs with CTCAE grade ≥ 3
o
Related TEAEs with CTCAE grade ≥ 3
o
TEAEs leading to dose reduction
o
TEAEs leading to temporary interruptions of trial drug 
# TEAEs by SOC and PT
# Serious TEAEs by SOC and PT
# TEAEs leading to withdrawal of trial drug, dose reduction, temporary interruptions of trial 
drug, and death
# Non-serious TEAEs occurring with incidence in PT greater than 5% in at least one dose 
group, by SOC and PT
AEs will be summarized by worst severity per subject, using the MedDRA PT as event category 
and MedDRA primary SOC as Body System category. 
In general, each subject will be counted only once within each PT or SOC. If a subject 
experiences more than one AE within a PT or SOC, only the AE with the strongest relationship 
or the worst severity, as appropriate, will be included in the summaries of relationship and 
severity. 
AEs with missing classifications regarding relationship to study treatment and start date greater 
or equal to start of study treatment will be considered as related to study treatment.
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 trial treatment then the onset date will be 
replaced by the minimum of start of trial 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 complete the stop date. 
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# In all other cases, the incomplete stop date will not be imputed. If the stop date of an AE is 
after date of cutoff, outcome of AE is ongoing at cutoff. 
# Further information after cutoff (like fatal outcome) might be taken from Safety data base 
and reported separately.
15.3
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
Listings will be presented for the following types of AEs:
# TEAEs leading to death, including flags for death within 30 days of last dose of IMP
# TEAES with CTCAE grade ≥3
# Serious TEAEs
# TEAEs leading to withdrawal, dose interruption or dose reduction of trial drug
15.3.1
Deaths
Deaths will be listed using the Safety Analysis Set, displaying by dose group the following:
# Deaths by primary reason of death
# Flags for death within 30 days of last dose of IMP.
15.4
Clinical Laboratory Evaluation
The safety population will be used for all clinical laboratory evaluations.
All laboratory results (biochemistry, hematology, coagulation, urinalysis, pregnancy test), will be 
listed by subject and time point. The following information will be included in the listing:
# Sex of subject
# Date/time of sample
# Treatment day
# Result
# Reference range (for continuous variables)
# Flag for values above (“H”) or below (“L”) the reference range (for continuous variables)
# Change from baseline (for continuous variables)
# NCI-CTCAE grade
# Flag for value with worst-on trial grade (“Y”)
All continuous laboratory results will be summarized by dose and time point, including absolute 
values and change from baseline.
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Laboratory results will also be classified by Grade according to NCI-CTCAE. The worst post-
baseline on-trial Grades will be summarized, as well as the worst post-baseline Grades within the 
first cycle. Shifts in toxicity grading from first treatment to highest Grade will be displayed: 
number of subjects with shift to any higher grade, to higher grade 3 or 4, to higher grade 4.
Results for variables that are not part of NCI-CTCAE will be presented as below, within, or 
above normal limits. Only subjects with post-baseline laboratory values will be included in these 
analyses.
D-dimer results will be listed with biochemistry. 
15.5
Vital Signs
The safety population will be used for all vital sign evaluation. Vital signs will be listed, 
including the following information:
# Date/Time of assessment
# Systolic blood pressure (mmHg)
# Diastolic blood pressure (mmHg)
# Position in which blood pressure was taken
# Heart rate (bpm)
# Temperature
# Respiratory rate (breaths/minute)
# Change from baseline for continuous variables
# Weight
All continuous variables will be summarized descriptively by dose group and time point, 
including absolute values and change from baseline. 
15.6
Lower Extremity Doppler Ultrasonography
The results of the lower extremity Doppler Ultrasonography will be listed by dose group and 
time point using the safety population and include the following information:
# Date/Time of assessment
# Whether deep vein thrombosis (DVT) was detected
# Location of DVT
# Size of DVT (cm)
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15.7
ECG
All analysis of electrocardiogram (ECG) data will be based on the safety population. 
Triplicate values will be handled as follows: listings will contain the individual triplicates and the 
aggregated results. Summaries will only use the aggregated values. The aggregation of triplicate 
ECGs will be performed using the arithmetic mean for all parameters at each time point. The 
aggregated values of the last triplicate ECG measurement prior to first trial drug administration 
will be used as the baseline measurement.
Results will be listed, including the following information:
# Time point
# Time of measurement
# Position
# Heart rate (beats/min)
# PQ/PR duration (ms)
# RR duration (ms)
# QRS duration (ms)
# QT corrected using Fridericia’s formula: QTcF = QT/√''
(
(ms)
# Rhythm evaluation
# Whether ECG is abnormal
# Clinical significance if ECG is abnormal
Potentially clinically significant abnormal values of ECG will be flagged according to the 
following criteria: 
Parameter
Potentially Clinically Significant Abnormalities (PCSA) Criteria
Heart rate
≤ 50 bpm and decrease from baseline ≥ 20 bpm
≥ 120 bpm and increase from baseline ≥ 20 bpm
PQ/PR 
≥ 220 ms and increase from baseline ≥ 20 ms
QRS
≥ 120 ms
QTcF absolute
Prolonged: >450 ms (Male), >470 ms (Female)
Potentially significant abnormality: ≥ 500 ms
QTcF change from baseline
Prolonged: Increase from baseline > 60 ms
Only the aggregated measurement will be flagged as described. The flagging of the aggregated 
measurement will be performed by applying the above rules directly on the averaged ECG 
parameters.
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For display of overall assessment of the result of the ECG as normal, abnormal not clinically 
significant, and abnormal clinically significant, the worst result of the triplicates will be 
considered for the analysis of the aggregated measurements.
The ECG parameters will be summarized by descriptive statistics per time point including 
absolute values and change from baseline. Number and percentages for subjects meeting the 
PCSA Criteria will also be provided. For the investigator’s overall ECG assessment, a shift table 
from baseline to the worst on-treatment result will be created.
Data will be further analyzed using concentration effect modeling for baseline corrected QTcF 
values.Change from baseline (QTcF) will be modelled using a linear mixed model, with baseline 
QTcF value and drug concentration as continuous covariates, and subject as a random factor,
using data from the first cycle, and additionally using all data until cut-off. One model will be 
run using an unstructured covariance matrix, another one using the compound-symmetry 
structure. The estimate for the concentration coefficient will be reported, including standard 
error, degrees of freedom and 95% confidence interval for the coefficient. The concentration 
effect model will be fit using the PK analysis set. The SAS code for this analysis can be found in 
the TFL shells.
15.8
Physical Examination
Physical examination (including neurologic examinations) will be listed using the safety 
population and include the following information:
# Date
# Neurological examination:
o
Mental Status (Normal/Abnormal)
o
Cranial Nerves (Normal/Abnormal)
o
Motor System (Normal/Abnormal)
o
Muscle Strength (Normal/Abnormal)
o
Gait, stance and coordination (Normal/Abnormal)
o
Sensation (Normal/Abnormal)
o
Reflexes (Normal/Abnormal)
o
Autonomic Nervous System (Normal/Abnormal)
# Mini-Mental State Examination (MMSE):
o
Result (Normal/Abnormal)
o
Score
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# International Cooperative Ataxia Rating Scale (ICARS):
o
Postural and Gait Disturbance
o
Limb Ataxia
o
Dysarthria
o
Oculomotor disorders
o
Total score
The results will be summarized by dose group and using the safety population, displaying counts 
and percentages for abnormal results and summary statistics for scores (considered as 
continuous, see Section 9.2 for details).
16
Analyses of Other Endpoints
16.1
Pharmacokinetics
16.1.1
Analysis of PK Concentrations
All individual pharmacokinetic (PK) plasma concentrations of M8891 will be listed by time 
point using the safety population. Subjects that are not included in the PK analysis set will be 
flagged, and the list will be sorted so that they are at the bottom of the list.
The listing for the plasma concentration of M8891 will include the following:
# Scheduled and actual date/time
# Concentration
# Time relative to scheduled time (HH:MM:SS)
The PK plasma concentrations will also be summarized descriptively using the PK Analysis Set 
by dose and time point using the PK analysis set. Values below the lower limit of quantification 
(LLOQ) will be taken as zero for descriptive statistics of concentrations.
Individual plasma concentration-time profiles (linear and semi-logarithmic scale) will be plotted 
using the safety population. Subjects that are not part of the PK analysis set will be flagged in the 
plot. 
Mean plasma concentrations per dose group and day will be plotted using scheduled time points 
on the linear (± Sd) and semi-logarithmic scale. If mean minus Sd is negative, Sd will be 
truncated at 0. In case PK blood samples were not performed within the time window specified 
in the protocol, these calculations and plots will be repeated excluding the respective plasma 
concentrations. The PK analysis set will be used for these figures.
The following tables and figures will be provided: 
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Tables
# Individual Plasma Concentrations of M8891 and Descriptive Statistics by Scheduled Time 
for Each Dose Group after Single Dosing (Cycle 1 Day 1)
# Individual Plasma Concentrations of M8891 and Descriptive Statistics by Scheduled Time 
for Each Dose Group after Multiple Dosing (Cycle 1 Day 15)
# Individual Trough Plasma Concentrations of M8891 and Descriptive Statistics by 
Scheduled Time and Dose Group
Figures
# Individual M8891 Plasma Concentration-Time Profiles by Dose Group and Day, Linear 
Scale
# Individual M8891 Plasma Concentration-Time Profiles by Dose Group and Day, Semi-
Logarithmic Scale
# Mean (±Sd) M8891 Plasma Concentration-Time Profiles by Dose Group and Day, Linear 
Scale
# Mean M8891 Plasma Concentration-Time Profiles by Dose Group and Day, Semi-
Logarithmic Scale
# Individual M8891 Plasma Concentration-Time Profiles for Single and Multiple Dose 
Overlaid, Linear Scale. (Overlaid means that the x-axis is hours post dosing on the same 
day.)
# Individual M8891 Plasma Concentration-Time Profiles for Single and Multiple Dose 
Overlaid, Semi-Logarithmic Scale
# Mean (±Sd) M8891 Plasma Concentration-Time Profiles by Dose Group, for Single and
Multiple Dose Overlaid, Linear Scale
# Mean M8891 Plasma Concentration-Time Profiles by Dose Group, for Single and Multiple 
Dose Overlaid, Semi-Logarithmic Scale
Results of the PK urine sampling will be listed using the safety population, including the 
following information:
# Time of last urination before start of dosing (HH:MM)
# Collection start and end date/time
# Volume collected
# Any comment recorded in the CRF
# Concentration of M8891
# Total amount of M8891 (calculated as volume x concentration)
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Subjects that are not included in the PK analysis set will be flagged, and the list will be sorted so 
that they are at the bottom of the list. The urine PK values (volume, concentration and amount) 
will also be summarized by dose group and study day for the scheduled measurements using the 
PK analysis set. 
Volume and amount will be added for multiple voidings and concentration will be calculated 
used an average weighted by volume.
16.1.2
Estimation of Individual PK Parameters
Pharmacokinetic parameters will be calculated by the PK/
 
Merck, Darmstadt, Germany, using standard non-compartmental methods and the actual
administered dose. PK parameters will be calculated using the actual elapsed time since dosing, 
given with a precision of 14 significant digits or the SAS format Best12. In cases where the 
actual sampling time is missing, calculations will be performed using the scheduled time and 
flagged in listings. For AUC0-24, if the actual sampling time at 24 hours is not equal to the 
scheduled observation time, AUC0-24 will be calculated based on estimated concentration at the 
scheduled time and not the concentration at the actual observation time. 
The following plasma PK parameters of M8891 will be calculated, when reliable on Day 1 and 
Day 15:
Cmax
Maximum observed concentration 
Cmax/Dose
The Dose normalized maximum observed concentration. Normalized using the 
actual dose, and the formula Cmax /Dose.
tmax
The time to reach the maximum observed concentration collected during a 
dosing interval (unless otherwise defined, take the 1st occurrence in case of 
multiple/identical Cmax values)
AUC0-t
The area under the concentration-time curve (AUC) from time zero (= dosing 
time) to the last sampling time (tlast) at which the concentration is at or above 
the lower limit of quantification. Calculated using the mixed log linear 
trapezoidal rule (linear up, log down).
AUC0-t/Dose
The Dose normalized AUC from time zero to the last sampling time (tlast) at 
which the concentration is at or above the lower limit of quantification. 
Normalized using the actual dose, and the formula AUC0-t /Dose.
AUC0-∀
The AUC from time zero (dosing time) extrapolated to infinity, based on the 
predicted value for the concentration at tlast , as estimated using the linear 
regression from λz determination. AUC0-∞=AUC0-t+Clast pred/ λz
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AUC0-∞/Dose
The Dose normalized AUC from time zero extrapolated to infinity. 
Normalised using actual dose, using the formula AUC0-∞ /Dose.
AUC!
The area under the concentration-time curve (AUC) over the dosing interval 
from T1=0 h to T2=τ h. Calculated using the mixed log linear trapezoidal rule 
(linear up, log down). For single dose, AUCτ is calculated as a partial area 
with the defined time range. In multiple dose profiles AUC! is calculated at 
steady state from one pre-dose time point to the dosing interval time. In cases 
where the actual observation time is not equal to the scheduled observation 
time AUC! will be calculated based on the estimated concentration at τ hours, 
and not the concentration at the actual observation time.
AUC!/Dose
The Dose normalized AUC over the interval from T1=0 h to T2=τ h. 
Normalized using actual dose, using the formula AUCτ /Dose.
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of AUC0-
∀. AUCextra% = (extrapolated area/AUC0-∞)*100 = (1－[AUC0-t/AUC0-∀])*100.
λz
Terminal first order (elimination) rate constant. Determined from the terminal 
slope of the log-transformed concentration curve using linear regression on 
terminal data points of the curve
t1/2
Apparent terminal half-life. t1/2  = ln (2)/λz
CL/f
The apparent total body clearance of drug following extravascular 
administration, taking into account the fraction of dose absorbed. 
CL/f = Dose p.o. /AUC0-∞. 
CLSS/f
The apparent total body clearance of drug at steady state following 
extravascular administration, taking into account the fraction of dose absorbed. 
CLSS/f = Dose p.o. / AUC!
CLR
The renal clearance of drug. CLR = Ae0-∞/AUC0-∞or Ae0-t /AUC0-t
VZ/f
The apparent volume of distribution during the terminal phase following 
extravascular administration, based on the fraction of dose absorbed. Vz/f = 
Dose/(AUC0-∞*λz) following single dose. Vz/f = Dose/(AUC!*λz) following 
multiple dose.
Racc(AUC)
The accumulation factor to assess the increase in exposure until steady state is 
reached. Racc(AUC)= (AUC! after multiple dose (at steady state)) / (AUC 0-∞after 
single dose)
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Racc(Cmax)
The accumulation factor to assess the increase in maximum concentration until 
steady state is reached. Racc(Cmax) = (Cmax after multiple dose (at steady 
state))/(Cmax after single dose) = Cmax D15/Cmax D1
The following urine PK parameters of M8891 will be calculated, when reliable, for the QD and 
BID dosing, on Day 1 and Day 15:
Ae!
The cumulative amount excreted during a complete dose interval at steady state. 
Amount_Recovered = Σ(Concentration * Volume) from T1 to T2, where T1 and 
T2 denote the start and end time of the dose interval at steady state respectively.
Ae!%
The cumulative percentage of dose excreted during a complete dose interval at 
steady state. Percent_Recovered = 100*Amount_Recovered/Dose.
Ae0-t
The cumulative amount excreted from time zero (= dosing time) to the end of the 
current collection interval after dosing. Amount_Recovered = Σ(Concentration * 
Volume)
Ae0-t%
The cumulative percentage of dose excreted from time zero (= dosing time) to 
the end of the current collection interval after dosing. Percent_Recovered = 
100*Amount_Recovered/Dose
Ae0-∀
The cumulative amount excreted from time zero (dosing time) to infinity. 
Ae0-∞=Ae0-t+((Ae0-(t-1)-Ae0-t)/(tlast-1-tlast))/λz where %z is the excretion rate or Ae0-∞
= (Ae0-t / AUC0-t) * AUC0-∀
Ae0-∀&
The cumulative percentage of the dose that is excreted from time zero (= dosing 
time) to infinity. Percent_Recovered = 100*Amount_Recovered/Dose
The following PK parameters will be calculated for diagnostic purposes and listed, but will not 
be summarized:
# The time interval (h) of the log-linear regression (λz low, λz upp) to determine λz. 
# Number of data points (Nλ) included in the log-linear regression analysis to determine λz.
# Goodness of fit statistic (Rsq) for calculation of λz.  
The regression analysis should contain data from at least 3 different time points in the terminal 
phase consistent with the assessment of a straight line on the log-transformed scale. Phoenix 
WinNonlin best fit methodology will be used as standard. The last quantifiable concentration 
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should always be included in the regression analysis, while the concentration at tmax and any 
concentrations <LLOQ which occur after the last quantifiable data point should not be used. 
AUCextra% should be less than 20%. If AUCextra% is greater than 20%, all parameters derived 
using λz (i.e. λz, t1/2, AUC0-∀AUCextra%, Vz, CL) will be included in the parameter outputs and 
descriptive statistics but will be flagged and discussed appropriately. Any flags should be 
included in the study specific SDTM.
The coefficient of correlation (R²) should be ≥0.8 and the observation period over which the 
regression line is estimated should be at least twofold the resulting t1/2 itself. If these criteria are 
not met, then the rate constants and all derived parameters (e.g.CL, and Vz etc.) will be included 
in the parameter outputs and descriptive statistics but will be flagged and discussed 
appropriately. Any flags should be included in the study specific SDTM. 
Partial areas AUCτ should be calculated using the scheduled dosing interval, as defined in the 
CTP. The actual dosing interval calculated from CRF time data should not be used. The 
following rules apply when calculating the partial area AUCτ within the observed time interval 
from T1 to T2:
# If the start time of the interval (T1) occurs before the first observation, the observation at T1
will be estimated using the linear interpolant between the first datapoint and C0. For single 
dose data C0= 0 when the drug was administered via an extravascular route or via infusion, 
and C0 is the estimated dosing time intercept when the drug was administered as an IV 
bolus. For steady state models, C0 is the minimum concentration value occurring within 
the time interval T1 to T2.
# If either T1 or T2 falls within the time range in which samples were taken, but does not 
coincide with an observed data point, then a linear or logarithmic interpolation is 
performed to estimate the corresponding concentration value. Whether a linear or 
logarithmic interpolation is used will depend on the method of AUC calculation e.g. linear 
up log down. 
# If the end time of the interval (T2) occurs after the last measurable concentration and the 
terminal regression (λz) is estimable, then λz is used to estimate the concentration at time 
T2. The log trapezoidal rule will be used to calculate the area from the last observation time 
to the end time of the partial area (T2). If λz cannot be estimated the partial area will not be 
calculated.
Concentrations below the lower limit of quantification (<LLOQ), which are before the last 
quantifiable data point, will be taken as zero for calculating the AUC. Unless otherwise specified 
in the CTP, pre-dose 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. The same applies to the very first pre-dose sample of a multiple dose study. 
Dose dependent parameters (e.g. CL, Vz) will not be calculated for metabolites.
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing.
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16.1.3
Analysis of PK Parameters
All PK parameters will be listed using the safety population. Subjects that are not included in the 
PK analysis set will be flagged, and the list will be sorted so that they are at the bottom of the 
list.
The PK parameters will also be summarized descriptively per day by dose group using the PK 
analysis set.
The following tables and figures will be provided:
Tables
Individual Pharmacokinetic Parameters of M8891 in Plasma and Descriptive Statistics by 
Treatment after Single Dosing (Cycle 1 Day 1)
Individual Pharmacokinetic Parameters of M8891 in Plasma and Descriptive Statistics by 
Treatment after Multiple Dosing (Cycle 1 Day 15)
Individual Accumulation Ratios of AUC, Ae and Cmax in Plasma and Descriptive Statistics by 
Treatment
Individual Dose Normalized Pharmacokinetic Parameters of M8891 in Plasma and Descriptive 
Statistics after Single Dosing (Cycle 1 Day 1)
Individual Dose Normalized Pharmacokinetic Parameters of M8891 in Plasma and Descriptive 
Statistics after Multiple Dosing (Cycle 1 Day 15)
Figures
Scatter Plots: M8891 Dose-normalized PK Parameter (eg, AUC0-t, AUC0-∞ and Cmax) versus 
Treatment, Single Dose (with linear regression)
Box Plots: M8891 Dose-normalized PK Parameter (eg, AUC0-t, AUC0-∞-, and Cmax) versus 
Treatment, Single Dose
Scatter Plots: M8891 Dose-normalized PK Parameter (eg, AUC, and Cmax) versus Treatment, 
Multiple Dose (with linear regression)
Box Plots: M8891 Dose-normalized PK Parameter (eg, AUC, and Cmax) versus dose
16.1.4
Analysis of Dose Proportionality
For the assessment of dose proportionality, the PK endpoints, AUC0-t, AUC0-∞, AUC0-τ and Cmax
of M8891 will be compared between dose levels for Day 1 and Day 15 separately.
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The PK parameters will be dose normalized
The dose normalized parameters and the overall mean (y-axis) will be plotted over the dose (x-
axis) on the linear scale and logarithmic (both axes) scale using the PK analysis set. The overall 
mean will be calculated on the scale that is used for the plot. 
Modeling on the log transformed scale will be applied to the dose normalized parameters 
including dose as covariate. Dose proportionality will also be checked using the power model, if 
appropriate. The relationship between the PK parameter y and the actual total dose is defined as 
follows:
y = α doseβ
On the log transformed scale this becomes a linear relationship to which a linear regression 
approach can be applied:
log(y) = log (α) + β*log (dose)
The estimate of β and 95% confidence intervals will be computed to quantify dose 
proportionality. If dose proportionality is given, β in theory is equal to 1 and the estimate of the 
model should not deviate strongly from 1. This linear regression will be calculated using the PK 
analysis set.
The SAS code for this analysis can be found in the TLF shells.
16.1.5
Population Pharmacokinetic Analysis
The PK and covariate data from this study may be analyzed jointly with data from other studies 
by nonlinear mixed effect approach, in order to describe the PK concentration time profile; to
identify covariates explaining (part of) the between subject PK variability; and to estimate the
residual PK variability. No standalone PopPK analysis on this trial is planned. For a combined 
PopPK analysis with other studies, more details will be given in a separate Data Analysis Plan
for Population Pharmacokinetic Analysis. The results will be reported separately.
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17
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Brookmeyer R, Crowley J. Confidence Interval for the Median Survival Time. Biometrics 
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Kalbfleisch JD, Prentice, RL. The Statistical Analysis of Failure Time Data, New York: John 
Wiley & Sons 1980
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I 
cancer trials. Stat Med 2008;27(13):2420-39.
Sweeting M, Mander A, Sabin T. Bayesian Continual Reassessment Method Designs for Phase I 
Dose-Finding Trials. Journal of Statistical Software. 2013;54:1-26.
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