Clinical trial NCT04742556
Conditions: Solid Tumors, KRAS Mutation
Sponsor: Boehringer Ingelheim
Start date: 2021-03-15; Completion date: 2022-10-20
Enrollment: 15 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This study is open to Japanese adults with different types of advanced cancer that are positive for NRAS/KRAS mutations. This is a study in people for whom previous treatment was not successful or no standard treatment exists.

The purpose of this study is to find the highest dose of BI 3011441 that Japanese people with advanced cancer can tolerate. BI 3011441 is a medicine that may turn off a signal by NRAS/KRAS that makes tumours grow.

Participants take BI 3011441 as capsules once a day. Participants can stay in the study as long as they benefit from treatment and can tolerate it. The doctors collect information on any health problems of the participants.

Detailed description:

Arms: arm 1: The patients were administered 4 milligram (mg) BI 3011441 soft capsule once daily during 4 weeks with water limited to a maximum of 100 milliliters (mL) per capsules, taken without food, at least 1 hour before a meal or 1 hour after a meal. Patients continued the treatment until undue drug toxicity, disease progression, or withdrawal of consent, whichever occurred first. arm 2: The patients were administered 6 milligram (mg) BI 3011441 soft capsule once daily during 4 weeks with water limited to a maximum of 100 milliliters (mL) per capsules, taken without food, at least 1 hour before a meal or 1 hour after a meal. Patients continued the treatment until undue drug toxicity, disease progression, or withdrawal of consent, whichever occurred first. arm 3: The patients were administered 8 milligram (mg) BI 3011441 soft capsule once daily during 4 weeks with water limited to a maximum of 100 milliliters (mL) per capsules, taken without food, at least 1 hour before a meal or 1 hour after a meal. Patients continued the treatment until undue drug toxicity, disease progression, or withdrawal of consent, whichever occurred first.
Interventions: intervention 1: BI 3011441
Intervention descriptions: intervention 1: BI 3011441

Protocol documents:
Prot_000.pdf: 




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Number of patients on 
each treatment
Approximately 12
Diagnosis
Patients with a confirmed diagnosis of NRAS/KRAS mutation 
positive advanced, unresectable, or metastatic refractory solid 
tumours .
Main in- and exclusion 
criteria
Main inclusion criteria
!
Must be at least 20 years of age at screening.
!
Signed and dated written informed consent in accordance with 
GCP and local legislation prior to admission to the trial.
!
Pathologically documented, locally-advanced or metastatic 
malignancy with previously-identified activating NRAS or 
KRAS mutation based on local test.  
!
Provision of archival tumor tissue, if available, to confirm 
retrospectively NRAS or KRAS mutation status and for 
biomarker assessment. 
!
Willingness to undergo pre- and on-treatment tumour biopsies 
. Patients 
can be enrolled without tumour biopsy upon agreement 
between the Investigator and the Sponsor if tumour biopsy is 
not feasible.
!
Must have either progressed despite appropriate prior standard 
therapies or for whom no standard therapy exists for their 
tumour type and disease stage.
!
Must have at least one target lesion that can be measured per 
RECIST version 1.1
!
Must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1.
!
Must show adequate organ function.
Main exclusion criteria
!
Previous anticancer chemotherapy within 3 weeks of the first 
administration of trial drug. 
!
Radiotherapy within 4 weeks prior to first administration of 
BI 3011441.
!
Major surgery within 4 weeks prior to start of treatment or 
scheduled during the projected course of the trial.
!
Previous treatment with a RAS, MAPK targeting agent.
!
Patients who have a history or current evidence/risk of retinal 
vein occlusion (RVO) or retinal pigment epithelial detachment 
or central serous retinopathy.
!
Patients who have visible retinal pathology that is considered a 
risk factor for RVO or central serous retinopathy as assessed 
by ophthalmic examination.
!
History or presence of cardiovascular abnormalities.


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!
Left ventricular ejection fraction (LVEF) <50 %.
!
Baseline QT interval corrected for heart rate using Fridericia’s 
formula (QTcF) >470 msec or congenital long QT syndrome
!
Leptomeningeal carcinomatosis.
!
Presence or history of uncontrolled or symptomatic brain 
metastases.
Test product(s)
BI 3011441
dose
4 mg, 6 mg, 8 mg per day (7 mg if necessary by the BLRM with the 
overdose control)
mode of 
administration
Per os / oral (p.o.)
Comparator product(s)
Not applicable
dose
Not applicable
mode of 
administration
Not applicable
Duration of treatment
Reiterated treatment cycles of 4 weeks as long as the patient has 
clinical benefit or until undue drug toxicity or withdrawal of consent, 
whichever occurs first
Statistical methods
Descriptive statistics will be used to describe safety and efficacy 
analyses.
Dose escalation will be guided by a Bayesian logistic regression 
model (BLRM) with overdose control that will be fitted to binary 
toxicity outcomes. 
The estimates of the model parameters will be updated as data are 
accumulating using the BLRM. 
At the end of the dose escalation, the toxicity probability at each dose 
level in each arm will be calculated to determine an estimate of the 
MTD.






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s)
Extended Follow-up for progressive disease visits for tumour assessment by imaging (CT scan or MRI) 
for patients who discontinue trial treatment without having progressive disease based on RECIST v1.1 
should be performed every 8 weeks (±4 days) until progressive disease or another withdrawal criterion 
is met. At these visits, SAEs and AESIs occurring during the trial that are considered to be related to 
trial treatment or procedures will be followed until resolution after EOR until the individual patient’s 
end of trial.
t)
Patients will remain hospitalised for at least three days after the first administration of BI 3011441. On 
day four or later, the investigator will then evaluate whether it is appropriate to discharge the patient 
based on the patient's condition. For this evaluation, the investigator will perform the assessment of 
adverseevents and if necessary haematology and clinical chemistry examination.
u)
X-ray for chest region will be conducted to determine presence of interstitial lung diseases on Day 1 of 
Cycle 2.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................16
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
1.4.1
Benefits.................................................................................................................21
1.4.2
Risks .....................................................................................................................21
1.4.3
COVID-19 related Benefit-Risk Assessment....................................................23
1.4.4
Discussion.............................................................................................................23
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................24
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........24
2.1.1
Main objectives....................................................................................................24
2.1.2
Primary endpoint(s)............................................................................................24
2.1.3
Secondary endpoint(s) ........................................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................26
3.1
OVERALL TRIAL DESIGN.............................................................................26
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................27
3.3
SELECTION OF TRIAL POPULATION .......................................................27
3.3.1
Main diagnosis for trial entry ............................................................................28
3.3.2
Inclusion criteria .................................................................................................28
3.3.3
Exclusion criteria ................................................................................................29
3.3.4
Withdrawal of patients from treatment or assessments..................................30
3.3.4.1
Discontinuation of trial treatment .........................................................................31
3.3.4.1.1
Enrolment stopping rules ......................................................................................32
3.3.4.1.2
Replacement of patients........................................................................................32
3.3.4.2
Withdrawal of consent to trial participation .........................................................33
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................33
4.
TREATMENTS...................................................................................................34
4.1
INVESTIGATIONAL TREATMENTS ...........................................................34
4.1.1
Identity of the Investigational Medicinal Products..........................................34


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4.1.2
Selection of doses in the trial..............................................................................34
4.1.3
Method of assigning patients to treatment groups...........................................35
4.1.4
Drug assignment and administration of doses for each patient......................35
4.1.4.1
Administration ......................................................................................................36
4.1.4.2
Dose reductions and dose delays ..........................................................................36
4.1.5
Blinding and procedures for unblinding...........................................................40
4.1.5.1
Blinding.................................................................................................................40
4.1.5.2
Unblinding and breaking the code ........................................................................40
4.1.6
Packaging, labelling, and re-supply...................................................................40
4.1.7
Storage conditions...............................................................................................40
4.1.8
Drug accountability.............................................................................................40
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................41
4.2.1
Other treatments and emergency procedures..................................................41
4.2.2
Restrictions ..........................................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment ......................................................41
4.2.2.2
Restrictions on diet and life style..........................................................................43
4.2.2.3
Contraception requirements..................................................................................44
4.3
TREATMENT COMPLIANCE........................................................................44
5.
ASSESSMENTS..................................................................................................45
5.1
ASSESSMENT OF EFFICACY........................................................................45
5.2
ASSESSMENT OF SAFETY.............................................................................45
5.2.1
Physical examination ..........................................................................................45
5.2.2
Vital signs.............................................................................................................46
5.2.3
Safety laboratory parameters ............................................................................46
5.2.4
Electrocardiogram ..............................................................................................47
5.2.5
Other safety parameters.....................................................................................48
5.2.6
Assessment of adverse events.............................................................................49
5.2.6.1
Definitions of AEs ................................................................................................49
5.2.6.1.1
Adverse event........................................................................................................49
5.2.6.1.2
Serious adverse event............................................................................................49
5.2.6.1.3
AEs considered “Always Serious”........................................................................50
5.2.6.1.4
Adverse events of special interest.........................................................................50
5.2.6.1.5
Intensity (severity) of AEs....................................................................................51
5.2.6.1.6
Causal relationship of AEs....................................................................................51
5.2.6.2
Adverse event collection and reporting ................................................................52
5.2.6.2.1
AE Collection........................................................................................................52
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................53
5.2.6.2.3
Pregnancy..............................................................................................................53
5.2.6.2.4
Exemptions to AE reporting .................................................................................54
5.2.6.3
Dose limiting toxicities.........................................................................................54
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................56
5.3.1
Assessment of pharmacokinetics .......................................................................56
5.3.2
Methods of sample collection .............................................................................56
5.3.2.1
Blood sampling for pharmacokinetic analysis......................................................56


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5.3.2.2
Urine sampling for pharmacokinetic analysis.......................................................57
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................58
5.4.1
Methods of sample collection .............................................................................59
5.5
BIOBANKING ....................................................................................................59
5.6
OTHER ASSESSMENTS...................................................................................59
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................60
6.
INVESTIGATIONAL PLAN.............................................................................61
6.1
VISIT SCHEDULE.............................................................................................61
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................61
6.2.1
Screening period(s) .............................................................................................61
6.2.2
Treatment period(s)............................................................................................62
6.2.3
Follow-up period and trial completion..............................................................62
6.2.3.1
End of treatment visit and EOR............................................................................62
6.2.3.2
Extended follow-up period....................................................................................62
6.2.3.3
Trial completion for an individual patient ............................................................63
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................64
7.1
STATISTICAL DESIGN – MODEL ................................................................64
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................67
7.3
PLANNED ANALYSES.....................................................................................67
7.3.1
General considerations .......................................................................................67
7.3.2
Primary endpoint analyses.................................................................................67
7.3.3
Secondary endpoint analyses .............................................................................68
7.3.5
Safety analyses.....................................................................................................68
7.3.6
Other Analyses ....................................................................................................69
7.3.7
Interim Analyses .................................................................................................69
7.4
HANDLING OF MISSING DATA ...................................................................69
7.5
RANDOMISATION ...........................................................................................69
7.6
DETERMINATION OF SAMPLE SIZE .........................................................69
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........70
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................70
8.2
DATA QUALITY ASSURANCE ......................................................................71
8.3
RECORDS...........................................................................................................71
8.3.1
Source documents ...............................................................................................71
8.3.2
Direct access to source data and documents.....................................................72
8.3.3
Storage period of records ...................................................................................72
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................73
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........73
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................73
8.6
TRIAL MILESTONES.......................................................................................73


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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................74
9.
REFERENCES....................................................................................................75
9.1
PUBLISHED REFERENCES............................................................................75
9.2
UNPUBLISHED REFERENCES......................................................................76
10.
APPENDICES.....................................................................................................77
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK)  SAMPLING ........77
10.2
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS .................................................................................79
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................88
11.1
GLOBAL AMENDMENT 1 ..............................................................................88
11.2
GLOBAL AMENDMENT 2 ..............................................................................89
12.
REFERENCES FOR CTP AUTHORS.............................................................91


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AO
Aldehyde oxidase
aPTT
Activated partial thromboplastin
AST
Aspartate transaminase
AUC
Area under the concentration-time curve of the analyte in plasma
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
BRAF
v-Raf murine sarcoma viral oncogene homolog B
CA
Competent Authority
CK
Creatine kinase
CK-MB
Creatine kinase myocardial band
CKD-EPI
Chronic Kidney Disease Epidemiology 
Cmax
Maximum measured concentration of the analyte in plasma
CRA
Clinical Research Associate
CRC
Colorectal cancer
CREE
Enzymatic serum creatinine assay
CREJ
Non IDMS standardized Jaffe
CREJIDMS
Isotype dilution mass spectrometry standardized Jaffe
CRF
Case Report Form 
CRO
Contract Research Organisation
CT
Computed Tomography
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol


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CYP
Cytochrome P450
DILI
Drug Induced Liver Injury
DLT
Dose limiting toxicity
ECG
Electrocardiography
ECOG
Eastern Cooperative Oncology Group
eDC
Electronic Data Capture
EGFR
Epidermal growth factor receptor
EOR
End of residual effect
EOT
End of Treatment
ERK
Extracellular signal-regulated kinases
EWOC
Escalation with overdose control
FFPE
Formalin-fixed paraffin-embedded
FU
Follow up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HCO3
Bicarbonate
IB
Investigator’s Brochure
IC50
Inhibitory concentration (50%)
IDMS
Isotype dilution mass spectrometry
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
KRAS
Kirsten rat sarcoma viral oncogene homologue
LVEF
Left ventricular ejection fraction
MAO
Monoamine oxidases
MAP
Mitogen-activated protein
MAPK
Mitogen-activated protein kinase


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MedDRA
Medical Dictionary for Drug Regulatory Activities
MEK
Mitogen-activated protein kinase kinase 
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NRAS
Neuroblastoma RAS viral (v-ras) oncogene homolog
NSCLC
Non-small cell lung cancer
OPU
Operative Unit
p.o.
per os (oral)
PD
Pharmacodynamics
PFS
Progression-free survival
PK
Pharmacokinetics
PT
Prothrombin time
QTcF
QT interval 
RAC
Accumulation Index
RAF
Rapidly Accelerated Fibrosarcoma
RAS
Rat sarcoma
RD
recommended dose
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual effect period
RPED
Retinal Pigment Epithelial Detachment 
SAE
Serious adverse event
SD
Standard deviation
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
SUSAR
Suspected unexpected serious adverse reaction
TSAP
Trial Statistical Analysis Plan


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ULN
Upper limit of normal
WHO
World Health Organisation
β -HCG
beta human chorionic gonadotropin 








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Data from clinical studies




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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
This trial is for patients with no therapy options of proven efficacy, or who are not
amenable to standard therapies. Anti-tumour activity was seen in BI 3011441 monotherapy in 
various RAS mutation positive tumour types from pre-clinical models. Moreover, the 
completed phase I study showed the clinical activity in RAS mutant solid tumours and 
therefore, it is anticipated that target patients for the study may still receive a benefit from the 
study treatment. 
1.4.2
Risks
The potential clinically important risks based on the BI 3011441 pre-clinical data and clinical 
data are displayed in Table 1.4.2: 1. 
The number of patients to be exposed to BI 3011441 monotherapy will take into account the 
characterisation of safety profile and anti-tumour activity of monotherapy. A Bayesian
Logistic Regression Model (BLRM) design will be used in order to escalate the dose into
8mg still minimizing the risk of undue toxicity.
A Safety Monitoring Committee (SMC) will assess trial data to ensure overall safety of the 
patients treated. Based on the accumulated data, the SMC will reach a joint recommendation 
on the next dose level of BI 3011441 to be investigated and the sample size for the next dose-
escalation cohort, and provide advice about the overall conduct of the trial.
Table 1.4.2:1 
Potentially clinically important risks, their rationale and mitigation 
strategy
Potential risks of
clinical relevance for
this trial
Summary of data, rationale
for the risk
Mitigation strategy
Investigational Medicinal Product BI 3011441
QT prolongation
Observed with 
 
.
Patients with history long QT 
syndrome, mean resting 
corrected QT interval (QTcF) 
>470 msec or patients with 
poorly controlled arrhythmia are 
excluded. Pre-planned 12-lead 
ECGs will be frequently 
performed.
Left ventricular ejection 
fraction (LVEF) decrease
Observed with 
 
.
Patients with LVEF <50 % are 
excluded. Pre-planned 
echocardiograms will be 
performed to measure LVEF. 




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1.4.3
COVID-19 related Benefit-Risk Assessment
To date, there is no evidence suggesting an association between COVID-19 and MEK1/2 
inhibition targeted by BI 3011441. Considering the currently limited data on risk factors that 
may increase the severity and mortality of COVID-19, there may be as yet unknown relevant 
risk factors in treating patients with BI 3011441. Information regarding relevant risk factors 
and recommendations from professional oncology organizations will be monitored as it 
evolves.
The protocol-defined trial procedures themselves do not impose any increased risk to study 
participants in developing COVID-19. The risk mitigation measures currently in place within 
the clinical trial protocols are a sufficient safeguard, as patients are frequently monitored with 
comprehensive safety evaluations. 
The investigators will take the totality of information related to each single patient and the 
local COVID-19 situation into consideration when performing  individual benefit-risk 
assessments on a case-by-case basis, in regards to any additional potential risks for patients 
receiving BI 3011441. Considering all relevant aspects relevant to the COVID-19 pandemic, 
the investigator will make individual benefit-risk assessments for each patient’s (continued) 
participation in the trial. BI as the sponsor, recommends to adhere to the trial protocol as 
much as possible and where required, will support the investigator in their decision finding.
1.4.4
Discussion
Based on pre-clinical and clinical results, BI 3011441 showed single agent anti-tumour 
activity in a xenograft mouse model as well as in subjects with RAS mutant solid tumours. 
The therapeutic benefit or specific adverse events in patients cannot always be anticipated
during the trial setup and therefore, patients should be advised and carefully monitored for 
the potential risk of side effects from this investigational drug.
The clinical trial sites qualified to participate in this trial will be experienced comprehensive 
cancer centres in treating patients with investigational drugs and with the necessary 
infrastructure. The Investigators and Sponsor will form a SMC. During the conduct of trial, 
the SMC will meet regularly and during dose escalation at minimum after all patients in each 
dose cohort have completed cycle 1. The Sponsor will continuously assess the risks and 
benefits of the trial based on accumulating clinical data from all clinical trials with 
BI 3011441. Any significant change in risk/benefit ratio will be communicated to 
Investigators and patients.
In summary, the present trial will implement a number of safety measures to mitigate
possible risks. Therefore, a potential benefit is offered to patients with advanced and/or
metastatic malignancies with no other approved treatment options with BI 3011441. The 
benefit-risk ratio of treating patients with BI 3011441 monotherapy is therefore considered to 
be acceptable.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of this trial is to confirm the safety and tolerability of previsouly 
identified MTD, BI 3011441 8mg (in Caucasian FIH study) as a single agent when 
administered orally to adult Japanese patients with NRAS/KRAS mutation positive advanced 
or metastatic refractory solid tumours. 
The MTD will be determined based on the frequency of patients experiencing DLTs during 
the MTD evaluation period. The MTD evaluation period is defined as first treatment cycle 
(28 days). At the end of the dose escalation, the BLRM will be rerun using all DLTs. This 
result as well as all available data will be used to define the recommended dose (RD).
The secondary objectives is to evaluate the safety and tolerability, and characterise PK of 
BI 3011441 as monotherapy in Japanese patients with NRAS/KRAS mutation positive 
advanced solid tumours
2.1.2
Primary endpoint(s)
- MTD defined as the highest dose with less than 25% risk of the true DLT rate being equal 
or above 33% during the MTD evaluation period. For the definition of DLTs, refer to 
Section 5.2.6.3
- Number of patients with DLTs in the MTD evaluation period. 
2.1.3
Secondary endpoint(s)
- Number of patients with DLTs during the entire on-treatment period 
- Number of patients with Grade ≥3 treatment-related adverse events  
- Number of patients with treatment related adverse events at each dose level  
- Pharmacokinetic parameters of BI 3011441: Cmax(,ss), and AUC0-tz(,ss)  


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
The trial is an open-label, non-randomised phase I trial of BI 3011441 as monotherapy to 
investigate the safety/tolerability, PD and PK profile at selected dose levels in Japanese 
patients with NRAS/KRAS mutation positive advanced or metastatic refractory solid tumours. 
Patients will be enrolled based on the available NRAS/KRAS mutation status previously 
identified by local test results performed prior to screening. The data obtained from the trial 
will determine the MTD estimate based on a Bayesian logistic regression model with 
overdose control (R13-4803). The BLRM estimates the MTD by updating estimates of the 
probability of observing a DLT in the MTD evaluation period for each dose level in the trial 
as patient information becomes available. At any time in the trial, it will not be permitted to 
escalate to a dose which does not fulfil the escalation with overdose control (EWOC) 
principle (refer to Section 7).
The provisional dose levels to be evaluated will be 4mg, 6mg and 8mg, which includes the 
previously established MTD of 8mg for Caucasian patients. For any dose-escalation cohort, 
at least 3 patients will be required (refer to Section 7). However, in the case that only 2 
patients are evaluable and neither has experienced a DLT within the MTD evaluation period, 
then dose-escalation can occur based on these 2 patients. For determination of MTD or RD, 6 
patients will be enrolled at least. A BLRM with overdose control will be performed once the 
enrolment of 3 patients at each dose level has been completed and these patients completed 
the first cycle of treatment of BI 3011441. Each cycle will consist of 28 days (4 weeks) and 
patients will continue the treatment until undue drug toxicity, disease progression, or 
withdrawal of consent, whichever occurs first. The longest treatment period will be 2 years if 
deemed safe and efficacious. Intra-patient dose escalation will be allowed if there is an 
indication from higher-dose cohorts that there is a positive-risk-benefit once the patient 
completed the 1st cycle of treatment including PK 
 sampling.  
Figure 3.1: 1 
Study design
The Safety Monitoring Committee (SMC, see Section 8.7) will recommend the size for the 
next dose escalation cohort. After all patients in a cohort have either experienced a DLT or 
have been observed for at least the MTD evaluation period without experiencing a DLT, the 
Bayesian model will be updated with the newly accumulated data. The overdose risk will 
then be calculated for each dose, and escalation will be permitted to all doses which fulfil the 
EWOC criterion and the additional 50 % escalation rule. Based on the model and on 


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additional information (PK, PD, patient profiles), the members of the SMC will reach a joint 
decision on the next dose level to be investigated.
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. The BLRM will be re-run to confirm 
that the dose level still fulfils the EWOC principle. Based on this information, the SMC will 
evaluate whether the next patients will be enrolled at the same dose level, or if they will be 
enrolled at a lower dose level.
The SMC may recommend stopping the dose escalation phase after the criterion for MTD 
(Section 7.1) is fulfilled. Further patients may be included to confirm this MTD estimate, i.e. 
to confirm that the EWOC criterion is still fulfilled. If no DLT is observed at a dose of which 
the efficacy is considered sufficient, the SMC may decide to include an additional number of 
patients at the same dose level and to declare this dose as the recommended.
The SMC can declare any dose fulfilling the EWOC criterion as the RD, independent of the 
MTD estimate.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The clinical data of BI 3011441 from the FIH study conducted in Caucasian patients allows 
to already define three dose levels to be investigated in this trial. 
Although provisional dose levels exist, dose escalation and cohort size will be still 
determined based on the recommendation of the SMC, guided by a BLRM with overdose 
control. An escalation with overdose control design will increase the chance of treating 
patients at efficacious doses while reducing the risk of overdosing. This design is based on 
practical experience and is an efficient method due to its ability to identify the dose with a 
desired toxicity rate and its allocation of a greater proportion of patients to doses at, or close 
to, that desired dose (R13-4802, R13-4804, R13-4805). The use of Bayesian models for 
Phase I studies has also been advocated by the EMA guideline on small populations (R07-
4856) and by the FDA (R13-4881). This trial is a single-arm trial with multiple dose cohorts 
and there is no control group.
3.3
SELECTION OF TRIAL POPULATION
Approximately 12 patients are planned to be included, but will be adjusted by DLT results. 
This trial will be conducted in Japan and provide the safety and PK
data in Japanese 
patients in multiple dose levels.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.


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3.3.1
Main diagnosis for trial entry
Patients with a confirmed diagnosis of NRAS or KRAS mutation positive advanced, 
unresectable and/or metastatic solid tumours, who have failed standard treatment(s), or for 
whom no therapy of proven efficacy exists, or who are not amenable to standard therapies.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1.
Must be at least 20 years of age at screening.
2.
Signed and dated written informed consent in accordance with GCP and local legislation 
prior to admission to the trial.
3.
Pathologically documented, locally-advanced or metastatic malignancy with previously 
identified activating NRAS or KRAS mutation based on local test. 
4.
Provision of archival tumor tissue, if available, to confirm retrospectively NRAS or
KRAS mutation status and for biomarker assessment. 
5.
Willingness to undergo pre- and on-treatment tumour biopsies 
 
. Patients can be enrolled without tumour biopsy upon 
agreement between the Investigator and the Sponsor if tumour biopsy is not feasible
(Apply only to study site which agreed to conduct biopsy).
6.
Must have either progressed despite appropriate prior standard therapies or for whom no 
standard therapy exists for their tumour type and disease stage 
7.
Must have at least one target lesion that can be measured per RECIST version 1.1
8.
Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 
1.
9.
Must show adequate organ function as follows:
a) Absolute neutrophil count (ANC) ≥1.5 x 109/L; hemoglobin ≥9.0 g/dL; platelets ≥100 
x 109/L without the use of hematopoietic growth factors.
b) Total bilirubin ≤1.5 times the ULN, or ≤4 x ULN for patients who are known to have 
Gilbert’s syndrome.
c) Creatinine ≤1.5 x ULN. If creatinine is >1.5 x ULN, patient is eligible if concurrent 
creatinine clearance ≥50 mL/min (measured or calculated by Chronic Kidney Disease 
Epidemiology [CKD-EPI] formula).
d) AST and ALT ≤3 x ULN if no demonstrable liver metastases, or otherwise ≤5 x ULN.
10. Creatine phosphokinase is <2.5 x ULN.
11. Must have recovered from any previous therapy related toxicity to Common 
Terminology Criteria for Adverse Events (CTCAE) grade ≤1 at C1V1 (except for 
alopecia; stable sensory neuropathy must be CTCAE grade ≤2).
12. Male patients able to father a child and/or female patients of childbearing potential must 
be able and willing to comply with contraceptive measures i.e. use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% 
per year when used consistently and correctly, prior to study entry and for the duration of 
study participation and for a minimum timeperiod after treatment has ended, at least 3 
months.
13. Women of childbearing potential who are not surgically sterilized must have a negative 
serum pregnancy test completed during the Screening period.


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14. Women who are nursing. Women who are nursing can be enrolled if they stop 
nursing. In this case, the patient cannot resume nursing until 30 days from 
discontinuation of study treatment.
*A woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming post-menopausal unless permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. Tubal ligation is NOT considered as a method of permanent 
sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. Addition to this, even no menses for 12 months, if possibility of 
amenorrhea caused by anti tumor treatement can not denied, pregnancy test should be 
conducted as same as WOCBP.
3.3.3
Exclusion criteria
1.
Previous anticancer chemotherapy within 3 weeks of the first administration of trial drug. 
Previous anticancer hormonal treatment or anticancer immunotherapy within 2 weeks of 
the first administration of trial drugs.
2.
Radiotherapy within 4 weeks prior to first administration of BI 3011441 except as 
follows 
! Palliative radiotherapy to regions other than the chest is allowed up to 2 weeks prior 
to start of treatment
! Single dose palliative radiotherapy for symptomatic metastasis within 2 weeks prior to 
start of treatment may be allowed but must be discussed with the sponsor.
3.
Major surgery within 4 weeks prior to start of treatment or scheduled during the 
projected course of the trial
4.
Previous treatment with a RAS, MAPK targeting agent
5.
Previous treatment with any investigational agent(s) or targeted treatment within 4 weeks
(28 days) prior to start of trial drug or concurrent participation in another clinical trial 
with an investigational device or drug. 
6.
Any history of or concomitant condition that, in the opinion of the investigator, would 
compromise the patient’s ability to comply with the study or interfere with the evaluation 
of the efficacy and safety of the study medications
7.
Patients who have a history or current evidence/risk of retinal vein occlusion (RVO) or 
retinal pigment epithelial detachment or central serous retinopathy; for example, 
predisposing factors of RVO or central serous retinopathy include uncontrolled glaucoma 
or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes.
8.
Patients who have visible retinal pathology that is considered a risk factor for RVO or 
central serous retinopathy as assessed by ophthalmic examination, such as:
! Evidence of new optic disc cupping
! Evidence of new visual field defects
! Intraocular pressure >21 mm Hg
History or presence of cardiovascular abnormalities such as uncontrolled hypertension, 
congestive heart failure NYHA classification of ≥2, unstable angina or poorly controlled 
arrhythmia which are considered as clinically relevant by the investigator; Myocardial 
infarction within 6 months prior to start of treatment. Uncontrolled hypertension is defined 


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as: Blood pressure measured in a rested and relaxed condition, where systolic BP >=140 
mmHg, or diastolic BP >= 90 mmHg, with or without medication. 
9.
Left ventricular ejection fraction (LVEF) <50 %.
10. Baseline QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 
msec or congenital long QT syndrome
11. Previous or concomitant malignancies at other sites, except effectively treated
! Non-melanoma skin cancers
! Carcinoma in situ of the cervix
! Ductal carcinoma in situ
! Other malignancy that has been in remission for more than 3 years and is considered 
to be cured.
12. Leptomeningeal carcinomatosis.
13. Presence or history of uncontrolled or symptomatic brain metastases, unless considered 
stable by the investigator and local therapy was completed. Use of corticosteroids is 
allowed if the dose was stable for at least 4 weeks. Inclusion of patients with newly 
identified brain metastasis/es at screening will be allowed if patients are asymptomatic. 
! Patients who have resected brain metastases, or have received radiation therapy that 
finished at least 4 weeks (whole brain radiation) or 2 weeks (stereotactic body 
radiotherapy) prior to treatment of the trial are considered eligible if they meet all of the 
following criteria: 
a) Residual neurological symptoms CTCAE grade ≤2
b) Are taking stable doses of dexamethasone, if applicable
c) Follow-up magnetic resonance imaging (MRI) shows no new lesions 
14. Known pre-existing interstitial lung disease 
15. Known active hepatitis B infection (defined as presence of Hep B sAg and/or Hep B 
DNA), active hepatitis C infection (defined as presence of Hep C RNA)
16. Active infectious disease which puts the patient at increased risk in the opinion of the 
investigator
17. Any history or presence of uncontrolled gastrointestinal disorders that could affect the 
intake and/or absorption of the study drug (e.g. nausea, uncontrolled vomiting, Crohn’s 
disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the 
investigator.
18. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g.chronic alcohol or drug abuse or any other condition 
that, in the investigator’s opinion, makes the patient an unreliable trial participant).
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see sections 3.3.4.1 and 
3.3.4.1.1 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.


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Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and Case report form (CRF). If applicable, 
consider the requirements for Adverse Event collection reporting (please see sections 
5.2.6.2.1 and 5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:
!
The patient wants to discontinue trial treatment, without the need to justify the 
decision.
!
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to adhere to the trial requirements in the future. 
!
The patient needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
!
The patient becomes pregnant.The patient can no longer receive trial treatment for 
medical reasons (such as surgery, adverse events or other diseases).
BI 3011441 should be permanently discontinued in case of :
!
Retinal vein occlusion (RVO)
!
Symptomatic heart failure
!
Interstitial lung disease/pneumonitis, regardless of grade
!
Recurrent Grade 4 AEs or persistent Grade 2 to 3 AEs that do not recover to Grade 1 
or less within 12 weeks
!
Drug-related Grade 4 AEs. 
An interruption of treatment or delayed start of treatment of more than 4 weeks or several 
interruptions exceeding a total of ≥28 days of BI 3011441 treatment due to SAEs/AEs will 
lead to permanent treatment discontinuation. However in well-justified cases if considered 
clinically indicated by the Investigator and aligned with the Sponsor (to be documented in 
writing), a patient can be re exposed to treatment.
In case of a temporary reason, trial treatment should be restarted if medically justified, please 
see section 4.1.4.
If new efficacy/safety information of BI 3011441 becomes available, Boehringer Ingelheim 
(BI) will review the benefit-risk-assessment and, if needed, pause or discontinue the trial 
treatment for all patients or take any other appropriate action to guarantee the safety of the 
trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flow Chart and section 6.2.3.


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3.3.4.1.1
Enrolment stopping rules
All safety information will be carefully analysed by the sponsor. Enrolment will be 
temporarily stopped if clinically relevant adverse events occur which meet both of the 
following criteria:
!
Clinically relevant adverse events that:
o
are associated with evidence suggesting a reasonable possibility that the 
investigational drug caused the adverse event; and
o
occur at frequency or with severity that suggest that the risk-benefit profile of 
the study drug(s) should be reassessed.
If the SMC determines that the above criteria are met the enrolment to the trial will be 
temporarily stopped to allow for in-depth analysis of the safety profile of BI 3011441. The 
benefit-risk profile of BI 3011441 will be re-assessed by the SMC. This assessment will be 
used to determine if the trial should be continued as planned, permanently discontinued or 
whether the trial should continue with modification to the protocol. The purpose of any 
modifications to the protocol will be to mitigate patient risk and ensure that the benefit-risk 
assessment for continued investigation of BI 3011441 remains positive. The SMC will also 
consider and provide guidance for the management of patients who are already receiving 
treatment. The outcome of the analysis and the recommendations will be shared with all 
involved regulatory health authorities prior to a planned re-start of enrolment. In case the 
benefit-risk assessment is no longer considered to be positive, the trial will be discontinued.
3.3.4.1.2
Replacement of patients
Patients who are not evaluable for the MTD determination will be replaced, and an additional 
patient will be entered at the same dose level, if not decided otherwise by the SMC (e.g. 
because the number of evaluable patients for the current dose level is considered high enough 
for a dose escalation decision). 
Patients who permanently discontinue treatment because of a DLT (please see section 
5.2.6.3) will not be replaced.
The following patients may be replaced:
!
Patients who have not received any drug after they have signed the informed consent. 
!
Patients who permanently discontinue treatment during the MTD evaluation period for 
reasons other than a DLT.
!
Patients who have missed more than 8 doses of BI 3011441 during the MTD evaluation 
period for reasons other than a DLT.
!
Patients who miss 2 or more partial or complete visits during the MTD evaluation period 
and (after discussion between the Sponsor and the Investigator) if the information needed 
to assess PK/PD and safety parameters (including evaluation for DLTs) is missing, unless 
they develop a DLT.
!
Patient who need palliative radiotherapy during MTD determination period (e.g. first 4
weeks).


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3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate 
conduct of the trial.
Further follow up of patients affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1:1 
Test product 1
The gelatin used for the manufacture of BI 3011441 soft capsules is manufactured from 
bovine bones free from skulls, spinal cord, and vertebrae from cattle over 30 months, which 
does not satisfy risk criteria in Japan for transmissible spongiform encephalopathy. However, 
appropriate acid process according to the Note for guidance on minimising the risk of 
transmitting animal spongiform encephalopathy agents via human and veterinary medicinal 
products (EMA/410/01 rev.3), (2011/C 73/01), from the European Union are used.
4.1.2
Selection of doses in the trial
A starting dose of 4 mg of BI 3011441 is expected to be a safe starting dose as this is 50% of 
the MTD, which was identified in Phase 1 study with Caucasian patients. For details please 
refer to the Investigator’s Brochure. Dose escalation steps will be guided by a BLRM. The 
provisional dose levels to be assigned to separate cohorts of patients are listed in Table 4.1.2: 
1. Intermediate or lower dose levels may be investigated, depending on the number of DLTs 
observed in the trial, as long as they fulfil the EWOC criterion and if agreed upon by the 
SMC. For dose level 3, proposed dose is 8 mg, but depend on BLRM, 7 mg might be 
selected. Based on result of dose level 3, further investigation of 7 mg or 8mg will be  
conducted depend on BLRM. 
Substance:
BI 3011441
Pharmaceutical formulation:
Capsules
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
0.5mg, 2 mg
Posology:
Once daily
Mode of administration:
Oral


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Table 4.1.2:1 
Provisional dose levels for escalation
Dose level
Proposed dose
Increment from previous dose
1
4 mg
Starting dose
2
6 mg
50 %
3-1
7 mg 
16.7 %
3-2
8 mg
  33.3 % (v.s  6 mg)
14.3 % (v.s. 7 mg)
At the end of each treatment cohort, BI will convene a meeting with the SMC members. At 
the dose escalation meeting, the clinical course (safety information including both DLTs and 
all CTCAE grade ≥2 toxicity data during the MTD evaluation period) for each patient in the 
current dose cohort will be described in detail (Including the adverse event information from 
patient who were excluded from DLT evaluation for reasons other than a DLT). Updated 
safety data on other ongoing patients, including data beyond the MTD evaluation period, will 
be discussed as well. Based on that, a decision on the next dose level(s) to be tested is made. 
Dose escalation will continue until identification of the MTD or RD, safety concerns arise, or 
the trial is terminated for other reasons.
4.1.3
Method of assigning patients to treatment groups
There will be no randomisation in this trial, as it is a single-arm open-label trial. 
Patients will be assigned into escalating dose groups by order of admission into the trial. An 
interactive response technology (IRT) system is used to register participation of patients in 
the trial. Upon acquisition of informed consent, study sites access the IRT to register patients 
for screening. After assessment of all inclusion and exclusion criteria, study sites access the 
IRT to register each eligible patient for treatment, and the IRT system will assign the patient 
to the cohort which is open for recruitment.
As soon as the planned number of patients in a cohort are registered for treatment, IRT will 
close the screening until the next cohort is opened for recruitment or until further treatment 
slots become available in the current cohort. Patients who are already in screening at the time 
of the closure of the screening and who then meet all eligibility criteria can be registered for 
treatment. If more patients are eligible than planned number of patients for a cohort, it is 
exceptionally allowed to register more patients than planned for ethical reasons
4.1.4
Drug assignment and administration of doses for each patient
Patients will be assigned to their doses based on the available toxicity information (including 
DLTs, AEs that are not DLTs, and AE information post MTD evaluation period), and anti-
tumour activity information, as well as the recommendations from the SMC members 
following the dose decision meeting, please see section 4.1.2. 


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4.1.4.1
Administration 
The different capsule strengths should not be combined in the same bottle at any time. 
BI 3011441 capusules must be stored in the containers provided and handled according to the 
labelled storage instructions and shelf life. Labels will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines.
Patients will be advised to return any unused BI 3011441 in the dispensed bottles, in addition 
to returning any empty bottles. All patients will be required to complete a patient diary to 
document BI 3011441 intake, which must be returned to the clinic for review at each clinic 
visit.
BI 3011441 doses should be taken orally at approximately the same time each morning with 
the exception of certain trial visit days. 
Whenever possible, all doses of BI 3011441 should be taken with water limited to a 
maximum of 100 mL per capsules and the total amount of water intake should be within the 
range of 300-500 mL. Capsules should be taken without food, at least 1 hour before a meal or 
1 hours after a meal. 
For all visits which plan to conduct PK sampling, patients will be asked to fast overnight 
(minimum of 10 hours) prior to the visit. Pre-dose laboratory samples will be collected prior 
to receiving the single morning dose.
Missed doses should not be made up if more than 6 hours have passed since scheduled dosing 
time. Missed doses must be recorded in the patient’s diary. 
Before initiating a new treatment cycle, all of the following criteria must be met:
!
Ophthalmologic exam (if scheduled at the respective cycle visit): No evidence of 
Retinal Pigment Epithelial Detachment (RPED) or Retinal Vein Occlusion (RVO)
!
Echocardiography (if scheduled at the respective cycle visit): 
o
No evidence of an absolute decrease in LVEF of 10 percentage points or 
greater from screening value, to a value that is below institutional lower limit 
of normal (LLN).
o
No evidence of an absolute decrease in LVEF of 15 percentage points or 
greater whether below or above institutional LLN, even if the patient is 
asymptomatic.
!
Absence of related clinically significant adverse events: At the planned start of a 
treatment cycle patients may continue therapy only after recovery to a level which 
would allow further therapy; i.e. CTCAE Grade 1 or pre-treatment value or 
considered not clinically significant (except for the following CTCAE Grade 2 AEs: 
neuropathy, alopecia and fatigue/asthenia). 
4.1.4.2
Dose reductions and dose delays
For the assessment of the severity of adverse events (AEs), CTCAE version 5 (R18-1357) 
will be used. Any SAEs/AEs of ≥Grade 2 deemed intolerable by the patient or the treating 
physician and not responding to appropriate medical management, and any related SAEs/AEs 
of ≥Grade 3 will result in the interruption of treatment with BI 3011441 until resolution to 
baseline or Grade 1. Please see section 3.3.4.1 for the permanent IMP discontinuation criteria. 


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If the treatment interruption is ≤2 weeks, the patient can be re-exposed to BI 3011441 at the 
same dose or one dose level lower than the dose administered before the interruption as long 
as the re-exposure is considered clinically indicated by the Investigator. However, dose 
reduction is not allowed for patient who uses 4 mg, and the study medication (BI 3011441) 
needs to be discontinued.
In case the treatment is delayed due to an AE, the patient should visit the site at least once a 
week for assessment of safety laboratory and AEs. More frequent visits may be appropriate 
as assessed by the Investigator. Any case of a delay in treatment cycle for more than 2 weeks 
should be communicated to the Sponsor. The Investigator in agreement with the Sponsor will 
decide about further treatment of individual patient, based on known risk/benefit of 
BI 3011441. 
A maximum of 1 dose reductions of BI 3011441 are allowed, if lower tested dose levels are 
available. Dose reductions will be only to doses previously explored in earlier cohorts.
In case of dose reductions, all future dose administrations will also be at the reduced dose 
level. If that is intolerable (as previously described), the treatment of that patient should be 
discontinued. Recommendations for dose reductions of BI 3011441 are given in Tables 
4.1.4.2: 1, 4.1.4.2: 2, and 4.1.4.2: 3. 


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Table 4.1.4.2: 1
Dose modification for BI 3011441 for haematologic and non-
haematologic toxicity toxicity related to treatment
Haematologic and 
non-haematologic 
toxicity
Dose modification 
Grade 1
! Continue BI 3011441 at full dose, monitor as clinically 
indicated.
Grade 2
! Provide appropriate medical management as clinically 
indicated. 
! Consider holding BI 3011441 until resolution to Grade 1 or 
baseline and resume BI 3011441 at the same dose. 
! Deemed intolerable by the patient or the treating physician in 
case of continuation of BI 3011441 and not responding to 
appropriate medical management, interrupt BI 3011441 until 
resolution to baseline or Grade 1 and then, resume 
BI 3011441 at the reduced dose by 1 dose level.
Grade 3a
! Interrupt BI 3011441 until toxicity is Grade 1 or baseline, 
and then reduce the dose of BI 3011441 by 1 dose level.
! The patient may be continued at the same dose if the toxicity 
is unequivocally considered to be unrelated to BI 3011441
by the Investigator in agreement with the Sponsor. 
! Continue monitoring as clinically indicated and provide 
appropriate medical management as needed. 
Grade 4a
! Discontinue BI 3011441.  
! Continue monitoring as clinically indicated and provide 
appropriate medical management as needed.
a If the patient has a Grade 3 or 4 laboratory abnormality that, in the judgement of the investigator, is not considered 
clinically significant, dose modification is not required. 


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Table 4.1.4.2: 2
Dose modification for retinopathy in BI 3011441
Adverse event
Dose modification
Grade 1
! Immediately refer to the patient for ophthalomologic exam 
(if an ophthalmologic exam cannot be performed within 
7 days, interrupt BI 3011441). 
! If an ophthalmologic exam is done within 7 days and no 
worsening, continue BI 3011441 and monitor as clinically 
indicated.
! If retinopathy worsens to Grade 2 or 3, see below for 
guidance.
Grade 2 or Grade 3
! Immediately refer to the patient for ophthalomologic exam.
! Interrupt BI 3011441 until resolution to baseline or Grade 1 
and then, resume BI 3011441 at the reduced dose by one 
dose level.
! Continue monitoring as clinically indicated and provide 
appropriate medical management as needed.
Grade 4
! Immediately refer to the patient for ophthalomologic exam.
! Permanently discontinue BI 3011441.  
! Continue monitoring as clinically indicated and provide 
appropriate medical management as needed.
Table 4.1.4.2: 3
Dose modification for LVEF decrease in BI 3011441
Adverse event
Dose modification
Grade 1
! Not applicable
Grade 2 a
! Interrupt BI 3011441 until resolution to the normal 
institutional range or to within 5 percentage points of the 
baseline value and then, resume BI 3011441 at the reduced 
dose by one dose level. 
! Continue monitoring as clinically indicated and provide 
appropriate medical management as needed.
Grade 3 and 4
! Permanently discontinue BI 3011441.  
! Continue monitoring as clinically indicated and provide 
appropriate medical management as needed.
a An absolute decrease in LVEF of 10 percentage points or greater from baseline value to a value that is below institutional 
LLN value, OR an absolute decrease in LVEF of 15 percentage points or greater and lower than 20 percentage points 
whether below or above institutional LLN value


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This phase I trial will be handled in an open fashion by the Sponsor throughout, i.e., also for 
the purpose of data cleaning and preparation of the analysis. The CRF will contain 
information on the treatment and the dose.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated Contract 
Research Organisation (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice (GMP). Re-supply to the sites will be managed 
via an IRT system, which will also monitor expiry dates of supplies available at the sites. For 
details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA) (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
!
Approval of the clinical trial protocol by the IRB / ethics committee.
!
Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site.
!
Approval/notification of the regulatory authority, e.g. competent authority.
!
Availability of the curriculum vitae of the Principal Investigator.
!
Availability of a signed and dated clinical trial protocol.
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 


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These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor, the investigator or designee must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in
the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Rescue medications to reverse the actions of BI 3011441 are not available. Adverse events 
should be treated symptomatically and must be recorded. Concomitant medications or 
therapy to provide adequate supportive care may be given as clinically necessary
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Concomitant therapy, with reasons for the treatment, must be recorded in the CRF during the 
screening and treatment periods, starting at the date of signature of informed consent and 
ending after the REP. After REP, only concomitant therapy indicated for treatment of a 
related AE has to be reported. If a new anti-cancer treatment is started, it will be documented 
in the CRF on a separate page of follow-up therapy, different from the concomitant therapies 
pages.
No anticancer therapy (including regular use of steroids exceeding 10 mg daily prednisone or 
equivalent) can be administered during treatment with BI 3011441. No other investigational 
drug must be used concomitantly with the study drug, and the patients are not allowed to 
participate concurrently in any other clinical study.
The use of concomitant medications that might lead to QT prolongation is prohibited and 
would require the discontinuation of the patient prior to starting the respective QT prolonging 
medication.
Pre-medications (e.g. antiemetics for nausea or vomiting) should not be given in cycle 1 to 
avoid masking the emergence of DLTs.
Prophylactic granulocyte colony stimulating factors are not allowed during the first 4 weeks 
of treatment






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4.2.2.3
Contraception requirements
Women of childbearing potential and men able to father a child must use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly. A list of contraception methods meeting these 
criteria is provided in the patient information.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on capsules counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the sponsor.
Treatment compliance (%) =
Number of capsules  actually taken  100
     Number of capsules which should have been taken as 
directed by the investigator
If the number of doses taken is not between 75-100%, staff will explain to the patient the 
importance of treatment compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Tumour response will be evaluated at the site according to RECIST version 1.1 (R09-0262). 
The assessment by the Investigator will be the basis for continuation or discontinuation of the 
trial in an individual patient (in addition to safety). 
The patients will be re-evaluated every 8 weeks until the earliest of progressive disease, death 
or last evaluable tumour assessment before start of subsequent anti-cancer therapy or until the 
end of the trial. The baseline scan(s) (CT scan and/or MRI according to Investigator’s 
decision) from screening must have been performed within 4 weeks prior to treatment with 
the trial drug(s) and the Investigator will record the target (5 target lesions in total and 
maximum 2 per organ) and non-target lesions at baseline in the patient’s medical records and 
in the CRF before the start of treatment. The same method of assessment and the same 
technique must be used to characterise each reported lesion at baseline and during treatment. 
In case of suspected (but not otherwise confirmed) bone metastasis at screening, tumour 
assessment at screening should include a bone scan. If bone lesions are already known or 
confirmed at screening, correlative imaging (X-ray or CT scan) should be performed. 
Correlative imaging should then be repeated at each tumour assessment.  Lesions in 
previously irradiated areas may not be considered measurable at baseline unless the lesions 
occurred after irradiation. Lesion used for biopsies should not be selected for target lesion 
evaluation. Tumour assessment will be performed at screening (as close as possible to the 
treatment start and no more than 28 days before the start of trial treatment), at week 8 and 
every 8 weeks thereafter, and at the EOT visit (if not performed within the last 4 weeks).
If the patient discontinues the trial medication for another reason than progression, the 
tumour assessment according to RECIST v1.1 will continue every 8 weeks until the last 
follow-up needed according to protocol (progression, death, lost to follow-up, end of the 
trial).
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow
chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 
Measurement of height and body weight will be performed at the time points specified in the 
Flow chart.
During the physical examination, the patient should be assessed for possible adverse events.
The results must be included in the source documents available at the site. 


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5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling and trial treatment administration.
This includes body temperature, systolic and diastolic blood pressure and pulse rate 
(electronically or by palpation count for 1 minute), and saturation of percutaneous oxygen. 
All except body temperature need to be taken in a seated position after 5 minutes of rest. 
Oxygen saturation will be measured, if needed. The results must be included in the source 
documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. For the sampling time 
points please see the Flow Chart. All analyses will be performed locally. Patients do not have 
to be fasted for the blood sampling for the safety laboratory tests.
Clinically relevant abnormal findings as judged by the Investigator will be reported as 
adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
Table 5.2.3:1 
Safety laboratory tests
Haematology
Haemoglobin, red blood cell count, haematocrit, mean corpuscular 
volume, white blood cell count, and differential blood count (preferably 
expressed in absolute values), and platelets.
Biochemistry
Glucose, sodium, potassium, chloride, calcium, creatinine, phosphate, 
venous bicarbonate (HCO3), AST, ALT, alkaline phosphatase, lactate 
dehydrogenase, lipase, bilirubin (direct and indirect bilirubin in case of 
elevated total bilirubin values), total protein, albumin, urea nitrogen, uric 
acid and creatinine kinase (CK; if CK is elevated, then myoglobin and 
creatine kinase myocardial band (CK-MB) [cardiac] should also be 
measured; if a patient has signs/symptoms of myocardial ischemia and 
CK elevation, then CK-MB ,Troponin I or Tshould also be reactively 
tested).
Note: Creatinine can be assessed by any of these methods: CREE 
(enzymatic serum creatinine assay), CREJIDMS (isotype dilution mass 
spectrometry (IDMS) standardized Jaffe), or CREJ (non IDMS 
standardized Jaffe).
Coagulation
Activated partial thromboplastin time (aPTT) or prothrombin time (PT)
(expressed either in seconds or as percentage) 
Urine
Urine (pH, glucose, erythrocytes, leukocytes, protein, and nitrite) will be 
analysed by dipstick (semi-quantitative measurements).


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Table 5.2.3:1 Safety laboratory tests (cont.)
Pregnancy test
A beta human chorionic gonadotropin (β-HCG) pregnancy test in serum 
will be performed for women of childbearing potential at screening. 
Thereafter, this test may be done in serum or urine on Day 1 of each 
cycle, at the EOT visit, and at the 30-day safety follow-up visit.
Virology 
(screening)
Hepatitis B (HBs-Ag, and if HBs-Ag is negative anti-HBs, anti-HBc 
antibodies and HBV DNA will be measured) and hepatitis C (PCR)
If laboratory safety investigations have been performed >72 hours prior to the first trial 
treatment, the results of the new safety laboratory investigations performed within 72 hours 
of first treatment must be available to reconfirm eligibility.
5.2.4
Electrocardiogram
Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 - V6) resting electrocardiograms (ECGs) will 
be digitally recorded in triplicate (3 single ECGs within a maximum period of 5 minutes) and 
performed for each patient at various time points during the trial according to the appropriate 
Flow Chart and Appendix 10.1. This will include triplicate readings at every PK sampling 
time point during Cycle 1 on Days 1, 15, and 16.
All ECGs will be obtained after the patient has been resting supine for at least 5 minutes prior 
to the indicated times. All ECGs should be recorded with the patient in the same physical 
position.
Electrocardiogram machines will be provided to facilitate central retrospective readings. 
Before trial start, the trial sites will be trained for the proper use of the equipment and transfer 
of the electronic data to the vendor. While all ECGs will be transmitted to the central vendor, 
they will be analysed only after PK analysis points to a tmax. 
ECGs may be repeated for quality reasons and the repeated recording used for analysis. If 
necessary, additional ECGs may be recorded for safety reasons. 
The ECG recordings must be analysed and checked for abnormality by the Investigator (or 
designated physician) who will also calculate the QTcF value for each time point as the mean 
of the 3 ECGs. Clinically relevant abnormal findings will be reported either as baseline 
condition (if identified at the screening visit) or otherwise as adverse events and will be 
followed up and/or treated as medically appropriate. CTCAE version 5.0 will be used for the 
grading of prolonged QTcF intervals. Dated and signed printouts of ECG with findings 
should be documented in patient’s medical record.
In case of related ECG changes and whenever the Investigator deems necessary, additional 
ECG monitoring will be performed in the respective and later courses of treatment. To allow 
for a heart rate correction of QT intervals the QT intervals will be matched to the preceding 
RR intervals using at least QTcF (Fridericia’s formula QTcF = QT/RR-1/3) and QTcB 
(Bazett’s formula QTcB = QT/RR-1/2).


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In case of QTcF prolongation to >500 ms (mean of 3 ECGs) AFTER receiving therapy, the 
Investigator will initiate further ECG monitoring and diagnostics (e.g., check electrolytes and 
check concomitant therapy that may be contributing to QTcF prolongation) and if required 
provide adequate treatment according to medical standards. The patient will be discharged 
from the investigational site only after resolution of ECG findings as assessed by the 
Investigator.
In case of occurrence of symptoms suggestive of arrhythmia related to QTcF prolongation, a 
cardiologic evaluation will be performed, and treatment will be provided according to 
medical standards at the discretion of the Investigator.
In order not to confuse an ECG recording, PK samples should be taken after performing the 
ECG.
Centralised ECG evaluation
Abnormalities detected during centralised ECG evaluation will not necessarily qualify as 
AEs. In case of clinically relevant abnormalities (e.g., heart blocks or large changes in 
interval duration) the ECG core laboratory may contact the Investigator and vice versa.
Centrally assessed ECGs will comply with the ICH E14 guidance document and supplements 
(R05-2311, R13-0801, R13-4095) as well as the FDA requirements for annotated digital 
ECGs (R09-4830).
5.2.5
Other safety parameters
ECOG
The ECOG performance status will be assessed at the times indicated in the Flow Chart.
Ophthalmological assessments
Patients are required to have a standard ophthalmologic exam performed by an 
ophthalmologist at baseline, at each defined timepoint (see Flow Chart) and as clinically 
indicated. The exam will include indirect fundoscopic examination, visual acuity, visual field 
examination, tonometry and slit lamp examination with special attention to retinal 
abnormalities that are predisposing factors for RVO or retinopathy. 
In addition, it is recommended that patients have baseline color fundus photographs to 
document baseline appearance. In patients with clinical suspicion of RVO or retinopathy, 
additional color fundus photographs are recommended, and fluorescein angiography and/or
optical coherence tomography are recommended. 
Echocardiography
Echocardiography will be performed to assess cardiac ejection fraction and other 
abnormalities if applicable as indicated in the Flow Chart. Additional echocardiography 
assessments may be performed if clinically indicated. 


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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable 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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
! Worsening of the underlying disease or of other pre-existing conditions, see section 
5.2.6.2.4 for further detail.
! Changes in vital signs, ECG, physical examination, laboratory test results, 
ophthalmological assessment and echocardiography if they are judged clinically 
relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
Patients may be hospitalized for administrative reasons during the trial, including 
hospitalisation for respite care. These as well as hospitalisations/surgical procedures which 


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were planned before the patient signed informed consent need not be reported as SAEs if they 
have been documented at or before signing of the informed consent and have been performed 
as planned (the condition requiring hospitalisation/surgical procedure has not 
changed/worsened after signing informed consent)
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture (eDC)
system. A copy of the latest list of “Always Serious AEs” will be provided upon request. 
These events should always be reported as SAEs as described in section 5.2.6.2.
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the time since the discontinuation of the trial medication and must be reported 
as described in section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:
Dose-limiting toxicities
DLTs are considered to be AESIs, and must be reported as such. The definition of DLTs is 
presented in Section 5.2.6.3.
Potential severe drug-induced liver injury (DILI) 
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined by the
 following alterations of hepatic laboratory parameters: For patients with normal 
aminotransaminase levels at baseline:
!
An elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN either measured in the same blood draw sample, or in samples 
drawn within 30 days of each other; or
!
Aminotransferase (ALT and/or AST) elevations ≥10 fold ULN.
!
For patients with abnormal aminotransaminase levels between >1 and <3 x ULN at 
baseline: 


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!
An elevation of AST and/or ALT ≥3 fold the baseline value combined with an 
elevation of bilirubin ≥2 fold ULN or ≥2 fold the baseline value (if bilirubin is 
elevated at baseline) in the same blood sample, or in samples drawn within 30 days of 
each other ; or
!
Aminotransferase elevations ≥5 fold the baseline value.
!
For patients with abnormal aminotransaminase levels between ≥3 and ≤5 x ULN at 
baseline:
!
An elevation of AST and/or ALT ≥2 fold the baseline value combined with an 
elevation of bilirubin ≥2 fold ULN or ≥2 fold the baseline value (if bilirubin is 
elevated at baseline) in the same blood sample, or in samples drawn within 30 days of 
each other; or
!
Aminotransferase elevations ≥3 fold the baseline value.
These lab findings constitute a potential hepatic injury alert and the patients showing these 
lab abnormalities need to be followed up according to the “DILI checklist” provided in the 
ISF. For further details, see figure 5.2.6.1.4: 1 below.
Figure 5.2.6.1.4: 1 Hepatic injury reporting 
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the CRF 
according to the CTCAE version 5.0 (R18-1357).
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 


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relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
!
The event is consistent with the known pharmacology of the drug.
!
The event is known to be caused by or attributed to the drug class.
!
A plausible time to onset of the event relative to the time of drug exposure.
!
Evidence that the event is reproducible when the drug is re-introduced.
!
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
!
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
!
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
!
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
!
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
!
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
!
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the EOR all AEs (non-serious and 
serious) and all AESIs.
•
After EOR until the individual patient’s end of trial:
cancers of new histology and exacerbations of existing cancer, all trial treatment related 
SAEs and all trial treatment related AESIs.


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•
After the individual patient’s end of the trial: 
the investigator does not need to actively monitor the patient for new AEs but should 
report any occurrence of cancer and trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form (see 
section 5.2.6.2.2), but not on the CRF.
The rules for Adverse Event Reporting exemptions still apply, please see section 5.2.6.2.4.
Vital Status Data Collection
Patients who discontinue trial medication prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed up as described in section 3.3.4.1, 
withdrawal from trial treatment. From then on until the individual patient’s end of the trial the 
investigator must report all deaths/fatal AEs regardless of relationship, and trial treatment 
related SAEs and trial treatment related AESIs the investigator becomes aware of. 
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point. <for Japan only> 
Pregnancy until 6 months after the last dose of study medication should be reported as a drug 
exposure during pregnancy.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner; in 
the event that consent cannot be obtained, information will be collected and reported in 
accordance with regulatory requirements. The ISF will contain the trial specific information 
and consent for the pregnant partner. 


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The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.6.2.4
Exemptions to AE reporting
Collection and reporting of progressive disease
The outcome “disease progression” is used to assess trial endpoints for the analysis of
efficacy and will be recorded on the appropriate page of the eCRF. 
Disease progression will not be considered as an 'always serious' AE for this study. Only if 
disease progression meets standard seriousness criteria (see Section 5.2.6.1.2, Serious 
adverse event), will it be recorded on the AE page in the eCRF as well as on the BI SAE 
form, and the SAE reporting process will be followed. The exemption to reporting disease 
progression as an AE or SAE applies when disease progression is observed on imaging in an
asymptomatic patient with no clinical signs of disease progression.
However if there is evidence suggesting a causal relationship between the investigational
drug and the progression of the underlying malignancy, the event must be recorded as an
SAE on the AE page in the eCRF and reported as an SAE on the SAE Form.
Clinical symptoms and/or signs of disease progression will be recorded on the AE page in the 
eCRF. If signs and symptoms of disease progression of the patient's underlying malignancy
meet standard seriousness criteria, they will additionally be reported as SAEs on the BI SAE 
form and SAE reporting procedures will be followed. If signs and symptoms are attributable 
to a diagnosis, reporting the diagnostic term is preferable (e.g. pulmonary embolism rather
than dyspnoea; intestinal obstruction rather than abdominal pain).
Lab values meeting the potential severe DILI definition in section 5.2.6.1.4 must always be
reported as AESI, even if the most likely cause is disease progression. No exemption to AE
reporting applies.
Exempted events are reviewed at appropriate intervals by the Sponsor and the SMC.
5.2.6.3
Dose limiting toxicities
DLTs will be recorded throughout the trial. Any DLT must be reported to the Sponsor by the 
Investigator or designee within 24 hours of first knowledge using the same procedure as SAE 
reporting. Only DLTs occurring in the first 4 weeks (the first cycle) of treatment are 
considered for dose-escalation decisions made by the SMC. DLTs observed during the MTD 


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evaluation period will be considered for MTD determination. In addition, DLT(s) observed 
during the ophthalmological assessment and echocardiographic assessment of Cycle 2 Day 1
will be considered for MTD determination. However, all AEs and SAEs meeting criteria of 
DLT observed in all treatment cycles will be considered for determining a RD.
Any of the following AEs will be classified as DLTs if assessed as possibly related to 
BI 3011441, i.e., unless unequivocally due to underlying malignancy or an extraneous cause 
and will be reviewed by the SMC.  
Haematologic 
!
CTCAE Grade 4 neutropenia (<500/mm3) lasting ˃7 days without documented infection.
!
CTCAE Grade ≥3 neutropenia (<1000/mm3) with documented infection.
!
CTCAE Grade ≥3 febrile neutropenia, where Grade 3 febrile neutropenia is defined as 
ANC <1000/mm3 and a single temperature of >38.3°C (101°F) or a sustained 
temperature of ≥38°C (100°F) for more than one hour; Grade 4 neutropenia is defined as 
life-threatening consequences or urgent intervention indicated; and Grade 5 neutropenia 
is defined as a fatal neutropenia
!
CTCAE Grade 3 thrombocytopenia (≥25,000/mm3 and <50,000/mm3) associated with 
bleeding
!
CTCAE Grade 4 (<25,000/m3) thrombocytopenia
!
Thrombocytopenia or anaemia requiring transfusion per local or international guidelines.
Non-haematologic 
!
Grade ≥3 non-haematologic (not laboratory) toxicities despite the use of adequate 
medical interventions and/or prophylaxis as dictated by local institutional clinical 
practices, the clinical trial protocol, and/or the judgment of the Investigator. The 
following exceptions apply:
o
In a patient with pre-existing fatigue at baseline, Grade 3 fatigue will only be 
considered as a DLT if it lasts for more than 7 days despite adequate medical 
interventions and baseline fatigue was no more than Grade 1.
o
Grade 3 nausea or Grade 3 vomiting will be defined as a DLT when it persists at 
Grade 3 longer than 48 hours despite adequate medical intervention
o
Grade ≥3 diarrhea will be defined as a DLT only when hospitalisation is required, 
and the event persists at Grade ≥3 for more than 48 hours despite adequate 
medical intervention.
o
Hypertension will be defined as a DLT only when a patient was enrolled with 
controlled hypertension as per the exclusion criteria, and systolic blood pressure 
has increased >=160 mm Hg or diastolic blood pressure increased >=100 mm Hg,
which cannot be controlled by hypertensive medication and which requires a dose 
reduction / discontinuation of study drug. 
!
Any Grade 3 or Grade 4 non-haematologic laboratory value if:
o
Medical intervention is required to treat the patient, except Grade 3 electrolyte 
abnormality that lasts <72 hours, is not clinically complicated and resolves 
spontaneously or responds to conventional medical intervention, or
o
The abnormality leads to hospitalisation, or
o
The abnormality persists for >1 week, and considered significant enough to be 
qualified as DLT in the opinion of the Investigator, and confirmed by the SMC.


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!
An absolute decrease in LVEF of 10 percentage points or greater from screening value to 
a value that is below institutional LLN value, OR an absolute decrease in LVEF of 15 
percentage points or greater whether below or above institutional LLN, even if the patient 
is asymptomatic, will be defined as a DLT if:
o
After holding the trial drug and obtaining a follow-up echocardiography within 4 
weeks, LVEF has not returned within the normal institutional range or to within 5 
percentage points of the screening value; OR
o
After holding the trial drug and obtaining a follow-up echocardiography within 4 
weeks, LVEF has returned within the normal institutional range or to within 5 
percentage points of the screening value, but on re-challenge there is second 
decline of an absolute decrease in LVEF of 10 percentage points or greater from 
screening value, whether above or below institutional LLN.
!
Symptomatic heart failure
!
Any retinopathy ≥ Grade 2
!
Retinal vein occlusion of any grade.
!
Interstitial lung disease/pneumonitis of any grade
!
Hepatic injuries assessed as related to trial drug and which meet the AESI criteria for 
hepatic injury in Section 5.2.6.1.4
!
Treatment pause of BI 3011441 for ≥14 days, or dose reduction in Cycle 1 due to 
treatment-related AEs
!
Any treatment-related ≥ Grade 2 toxicity that persists and results in a more than 2 weeks 
delay of administration of BI 3011441 on Cycle 2 Day 1
!
Any treatment-related AE that would require permanent discontinuation of BI 3011441.
Any other toxicity considered significant enough to be qualified as DLT in the opinion of the 
Investigators, and confirmed by the SMC, will be reported as a DLT.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Blood 
 samples will be collected for the purose of PK analysis. Further information 
about sampling is provided in section 5.3.2. Actual data and clock times of PK sampling will 
be recoreded in CRF.
The planned PK analyses will require blood 
 samplings at the time points indicated 
in the Flow Chart and Table 10.1: 1. Correct, complete and legible documentation of drug 
administrations and PK sampling times, as well as adequate handling and identification of PK 
samples, are mandatory to obtain data of adequate quality of the PK analysis.
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
General aspects for all analytes
At a minimum, the sample tube labels should list BI trial number, patient number, visit, and 
planned sampling time. Further information such as matrix and analyte may also be provided.




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5.4
ASSESSMENT OF BIOMARKER(S)


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5.4.1
Methods of sample collection
5.5
BIOBANKING
NA
5.6
OTHER ASSESSMENTS
NA


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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are in accordance with measurements in Phase I 
oncology trials and will be performed in order to monitor safety aspects and to determine 
efficacy and PK
 parameters in an appropriate way.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The visit schedule is in detail described in the Flow Chart for all patients enrolled into this 
trial. Unscheduled visits can be performed as necessary and assessments will be performed as 
required at the discretion of the Investigator.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
See the Flow Chart and Section 5 for details on the procedures performed at each visit.
6.2.1
Screening period(s)
Screening Period
All patients will need to sign the informed consent form (ICF). Only patients who have tested 
positive for activating NRAS/KRAS mutations by prior local analysis conducted in an 
international or country-specific certified laboratory (e.g. CAP/CLIA or ISO) are eligible for 
the trial. An archival tumour tissue sample will be submitted to the central laboratory to 
retrospectively confirm the NRAS/KRAS mutation status (see Section 5.4).
Demographic information (sex, year of birth, race) will be obtained, based on information in 
the patients’ medical records.
Examinations and assessments per Flow Chart will be conducted and patients’ medical 
history will be collected. Inclusion and exclusion criteria must be assessed (see Sections 3.3.2
and 3.3.3). Baseline images must be available as outlined in the Flow Chart.
Concomitant diagnoses and/or therapies present during trial participation (between first ICF 
and the first follow-up visit) will be recorded in the CRF. Medical history of the tumour 
disease will be obtained and reported in the CRF:
! The date of first histological diagnosis
! The primary tumour site
! The number and location of metastatic sites
! Previous treatment for the tumour disease, including any surgery, radiotherapy, and/or 
systemic therapy, including start and end dates and the outcome.
Examinations during the screening period also include electrocardiography, 
echocardiography, and an eye exam.
Re-screening will be allowed once for unexpected reason such as schedule conflict. Re-
screened patients will receive a new patient number. In case of re-screening any procedures 
that fall outside the required screening window as defined in Flow Chart must be repeated.
A repeat testing during the screening period for items not meeting the eligibility criteria is 
basically not allowed. 


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6.2.2
Treatment period(s)
Treatment visits are specified in the Flow Chart and must be conducted as scheduled and 
outlined there. Treatment cycles are 4 weeks (28 days) in duration.
All planned visit dates are calculated from the start of Day 1 (Visit 1) of Cycle 1. If a patient 
misses a scheduled visit, and reports to the Investigator between the missed visit and the next 
scheduled visit, the assessments for the missed visit must be done with the actual date and the 
reason must be given for the delayed visit. All subsequent visits must adhere to the scheduled 
programme of visits for all cycles of treatment. Hospitalisation for administrative reasons 
(e.g. for the first days of Cycle 1) will not be considered as SAE. PK blood sampling 
timepoints are outlined in Appendix 10.1 and biomarker sampling is detailed in Section 5.4.
Imaging visits must adhere to the schedule provided in the Flow Chart at all times, 
unless they are scheduled for suspected progressive disease.
6.2.3
Follow-up period and trial completion
6.2.3.1
End of treatment visit and EOR
The EOT visit will be performed as soon as possible (within 7 days) after permanent 
discontinuation of all trial medications for any reason or as soon as possible after the 
Investigator became aware that the trial medication had been terminated. The assessments of 
the EOT visit will then be performed instead at the next planned visit. If the patient finishes 
active treatment without having progressive disease, tumour assessment/imaging must be 
performed at the time of treatment discontinuation, unless it has been done within the past 
4 weeks. 
The EOR will be performed 30 (+7) days after permanent discontinuation of all trial 
medications and is primarily to collect follow-up safety information as required by regulatory 
authorities. For the majority of patients, progression will already be documented at this point.
6.2.3.2
Extended follow-up period
For patients who did not discontinue treatment due to progressive disease, additional follow-
up visits after the 30-day safety follow-up visit will be performed every 8 weeks to continue 
tumour imaging until progressive disease or another withdrawal criterion is met. 
The follow-up for progression period will end at the time that one of the following events is 
met:
!
Disease progression based on RECIST 1.1
!
Start of a new anti-cancer therapy
!
Lost to follow-up
!
Death
!
End of whole trial as specified in Section 8.6.
The following will be obtained and/or performed during the follow-up visits for progression.
!
For each reportable SAE/AESI, the Investigator should provide the information with 
regard to concomitant medication and the medication administered to treat the AE on the 


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appropriate CRF pages and the SAE form including trade name, indication and dates of 
administration
!
Perform physical examination
!
Record performance score/status (e.g., ECOG)
!
Perform tumour assessment and imaging
!
Treatment and date with any subsequent anti-cancer drug / therapy including the name 
and type of the anti-cancer drug and/or best supportive care (if applicable)
!
Outcome (date of and reason for death [if applicable], in case the patient had progressive 
disease the actual date of progressive disease shall be recorded).
6.2.3.3
Trial completion for an individual patient
A patient is considered to have completed the trial in case any of the following applies:
!
Completion of planned follow-up period
!
Lost to follow-up
!
Refusal to be followed-up
!
Death.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The trial will be performed as an open-label trial. The objective of the design is to determine 
the MTD defined as the highest dose with less than 25% risk of the true DLT rate being equal 
or above 0.33 (EWOC criterion). The phase I dose-finding will be guided by a Bayesian 2-
parameter logistic regression model with overdose control (R13-4806; R13-4803).
The model is given as follows:
logit (πd) = log(α) + β*log(d/d*), 
where logit (π) = log (π/(1-π)).
πd represents the probability of having a DLT in the MTD evaluation period at dose d, d* = 8 
mg is the reference dose, allowing for the interpretation of α as the odds of a DLT at dose d*, 
and θ = (log(α), log(β)) with α, β > 0 is the parameter vector of the model. The estimated 
probability of a DLT at each dose level from the model will be summarized using the 
following intervals:
Under toxicity: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over toxicity: [0.33, 1.00]
The BLRM-recommended dose for the next cohort is the level with the highest posterior 
probability of the DLT rate falling in the target interval [0.16, 0.33) among the doses 
fulfilling EWOC. Applying the EWOC criterion, it should be unlikely (<25% posterior 
probability) that the DLT rate at that dose will exceed 0.33. However, the maximum 
allowable dose increment for the subsequent cohort will be no more than 50 % for each dose 
level.
The MTD may be considered reached if one of the following criteria is fulfilled:
1.
The posterior probability of the true DLT rate in the target interval [0.16 –
0.33) of the MTD is above 0.5, OR
2. At least 12 patients have been treated in the dose escalation phase of the trial, 
of which at least 6 at the MTD.
The SMC may recommend stopping the dose escalation phase after the criterion for MTD is 
fulfilled. Further patients may be included to confirm this MTD estimate. If no DLT is 
observed at a dose of which the efficacy is considered sufficient, the SMC may decide to 
include an additional number of patients at this dose level and to declare this dose as the dose 
recommended for further testing
Since a Bayesian approach is applied, a prior distribution f(θ) for the unknown parameter 
vector θ needs to be specified.
This prior distribution will be specified as a mixture of three multivariate normal 
distributions, i.e.
а(θ) = a1f1(θ) + a2f2(θ) + a3f3(θ) 


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with
ai, i = 1, 2, 3 the prior mixture weights (a1+ a2+ a3 = 1)
and
fi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where
Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
Prior derivation:
For the current trial, relevant information in the form of human data was available. Therefore, 
the three mixture components were established as follows:
1. The MAP prior using the historical data for LPN3794, modified to include grade 2 
retinopathy as DLT, can be found in Table 7.1:1
Table 7.1:1 Historical data for LPN3794 (modified to include grade 2 retinopathy as DLT)
Trial
Dose (mg)
N of patients with DLTs 
during MTD evaluation 
period / N of patients
LPN3794 (including grade 2 
retinopathy as DLT)
2
0/1
(including grade 2 
retinopathy as DLT)
4
0/1
6
0/3
8
3/9
10
2/5
16
1/1
This yields μ1 = (-0.94, 0.61). The standard deviations were set such that large uncertainty 
about the parameter means is reflected, and the correlation was set to 0, thus yielding σ1,11 = 
0.91, σ1,22 = 0.91 and ρ1 = -0.08, respectively. The prior weight a1 for the first component was 
chosen as 0.8.
2. A high-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much more toxic than expected. For this prior component, it was 
assumed that the median DLT rate at 2 mg would equal 0.10, and the median DLT at 
the anticipated MTD of 8 mg would equal 0.70. These assumptions yield μ2 = (0,85 , 
0.79). The standard deviations and correlations were set identical to the weakly 
informative prior, i.e. σ2,11 = 2, σ2,22 = 1 and ρ2 = 0, respectively. The prior weight a2
for the second component was chosen as 0.1.


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3. A low-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much less toxic than expected. For this prior component, it was 
assumed that the median DLT rate at 2 mg would equal 0.005, and the median DLT at 
the anticipated MTD of 8 mg would equal 0.1. These assumptions yield μ3 = (-2.20, 
0.80), i.e. basically a flat curve. The standard deviations and correlations were set to 
σ3,11 = 2, σ3,22 = 1. The correlation was set to 0, i.e. ρ3 = 0. The prior weight a3 for the 
third component was chosen as 0.1.
A summary of the prior distribution is provided in Table 7.1:2. Additionally, the prior 
probabilities of DLTs at different doses, as well as the corresponding probability of under-, 
targeted and over toxicity, are shown in Table 7.1:3. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.1:1. As can be seen from both, 
the table and the figure, the prior medians of the DLT probabilities are in-line with the prior 
medians derived from the weakly informative prior, and the uncertainty around the medians 
is large, showing the low amount of information this prior provides. This is also supported by 
the prior sample size, i.e. the information contained in the prior. This is approximately equal 
to 2.8 patients at 4 mg.  A detailed evaluation of the model using hypothetical data scenarios 
and operating characteristics is provided in the statistical Appendix 10.2.
Table 7.1:2
Summary of prior distribution
Prior 
Component
Mixture Weight
Mean Vector
SD Vector
Correlation
1: MAP prior
0.800
(-0.94, 0.61)
(0.91,0.91)
-0.08
2: High Tox.
0.100
(0.85,0.79)
(2,1)
0
3: Low Tox.
0.100
(-2.20,0.80)
(2,1)
0
Table 7.1:3
Prior probabilities of DLTs at selected doses
Dose
Probability of true DLT rate in
Quantiles
[0-0.16)
[0.16-0.33)
[0.33-1)
Mean
SD
2.5%
50%
97.5%
4 mg
0.682
0.189
0.128
0.147
0.182
0.000
0.081
0.688
6 mg
0.492
0.274
0.233
0.224
0.205
0.003
0.164
0.804
7 mg
0.370
0.320
0.310
0.272
0.213
0.012
0.218
0.853
8 mg
0.248
0.330
0.422
0.329
0.220
0.024
0.285
0.897


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Figure 7.1:1
Prior medians and 95% credible intervals 
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory. No formal statistical test will be 
performed.
7.3
PLANNED ANALYSES
7.3.1
General considerations
For the determination of the MTD, only MTD evaluable patients will be considered. For the 
analysis of secondary and further endpoints, all patients in the treated set (i.e. patients treated 
with at least one dose of trial medication) will be included in the analysis. Any other analysis 
sets will be defined in the TSAP.
7.3.2
Primary endpoint analyses
In order to identify the MTD, the number of evaluable patients with DLTs during the MTD 
evaluation period at each dose level must be presented. Replaced patients will be excluded 
from the determination of MTD.
The main analysis of the MTD will use the BLRM model described above using DLT data 
from the MTD evaluation period.
For the analysis of tolerability and safety, please refer to Section 7.3.5.


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7.3.3
Secondary endpoint analyses
The number of patients with DLTs at each dose level during the on-treatment period will be 
analyzed descriptively in terms of a frequency table.
The number of patients with CTCAE Grade ≥3 treatment-related adverse events observed 
during the on-treatment period will be analyzed descriptively in terms of a frequency table.
The number of patients with treatment related adverse events at each dose level will be 
analyzed descriptively in terms of a frequency table.
7.3.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the residual effect period (REP), a period 
of 30 days after the last dose of trial medication, will be assigned to the on-treatment period 
for evaluation. 
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned. 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP (Section 1.2) Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA 
at database lock. 
Laboratory data will be analyzed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Other safety analyses (AESIs, centrally evaluated ECG, etc.) will be specified in detail in the 
TSAP.


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7.3.6
Other Analyses
The pharmacokinetic parameters listed in Section 2.1.3 will be calculated according to the 
internal BI standard operating procedure (SOP). PK analyses will be performed using 
validated software programs, normally, Phoenix WinNonlin (Pharsight®) with applications 
validated for the respective purpose. Graphs and tables will be generated using validated 
customised SAS® macros or appropriate graphic software.
7.3.7
Interim Analyses
The sponsor will continuously monitor the safety. The dose escalation design foresees that 
the sponsor and the SMC perform regular safety evaluations. These evaluations will be 
unblinded to dose.
7.4
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data. Missing baseline laboratory 
values will be imputed with the respective values from the screening visit. No other 
imputations will be performed on missing data unless otherwise specified in the TSAP. Every 
effort will be made to obtain complete information on all adverse events, with particular 
emphasis on DLTs. 
Handling of missing PK data will be performed according to the internal BI SOP.
 
7.5
RANDOMISATION
No randomisation will be performed. Patients will be assigned to escalating dose groups by 
order of admission into the trial.
7.6
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations to determine sample size were performed for these 
parts of the trial. Approximately 12 patients (including at least 6 patients at MTD) are 
expected for dose escalation based on the number of dose levels/cohorts that are tested. 
Fewer or more patients might be needed based on the recommendation of the SMC. However, 
the actual number of patients will depend on the number of dose cohorts tested. Detailed 
information of simulation study to evaluate operating characteristics of the BLRM will be 
provided in section 10.2.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC)
and the harmonised standards for Medical Devices (ISO 14155, current version).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the Japanese 
GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997) and 
other relevant regulations. Investigators and site staff must adhere to these principles. 
Deviation from the protocol, the principles of ICH GCP or applicable regulations as will be 
treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 


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The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or his delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 


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retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
Patient identification: gender, year of birth (in accordance with local laws and regulations)
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
Dates of patient’s visits, including dispensing of trial medication
Medical history (including trial indication and concomitant diseases, if applicable)
Medication history
Adverse events and outcome events (onset date (mandatory), and end date (if available))
Serious adverse events (onset date (mandatory), and end date (if available))
Concomitant therapy (start date, changes)
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
Prior to allocation of a patient to a treatment into a clinical trial, there must be documented 
evidence in the source data (e.g. medical records) that the trial participant meets all inclusion 
criteria and does not meet any exclusion criteria. The absence of records (either medical 
records, verbal documented feedback of the patient or testing conducted specific for a 
protocol) to support inclusion/exclusion criteria does not make the patient eligible for the 
clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
Exemptions from expedited reporting are described in section 5.2.6.2.4, if applicable.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection and future use of 
biological samples and clinical data, in particular
!
Sample and data usage has to be in accordance with the informed consent
!
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials
!
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
!
A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage
!
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
!
Samples and/or data may be transferred to third parties and other countries as 
specified in the  ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 


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the trial medication until 30 days after LPLT at their site. Early termination of the trial is 
defined as the premature termination of the trial due to any reason before the end of the trial
as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A SMC composed of participating investigators and members of the BI trial team will be 
established to review individual and aggregated safety and efficacy data to determine the 
safety profile and risk/benefit ratio and recommend next dose level/does escalation/de-
escalation/modification/next cohort size, and appropriateness of further enrolment. Details of 
the SMC responsibilities and procedures are described in the SMC charter. Regarding SMC 
please see also sections 2.1, 3.1, 3.2, 4.1 and 7.1 of the clinical trial protocol.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central logistic laboratory service and an IRT vendor will be used in this trial. Details will 
be provided in the IRT Manual and Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R05-2311
ICH E14: The clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonised 
tripartite guideline, recommended for adoption at step 4 of the ICH process 
on 12 May 2005 by the ICH Steering Committee). www.emea.eu.int, 1-14 
(2005).
R07-4856
European Medicines Agency (EMEA) Committee for Medicinal Products 
for Human Use (CHMP): Guideline on clinical trials in small populations 
(London, 27 July 2006, doc. ref. CHMP/EWP/83561/2005). London: 
EMEA (2006).
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et 
al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 45, 228-47 (2009).
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R13-0801
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs: 
questions and answers (R1) (ICH, October 2012). 
R13-4095
European Medicines Agency (EMA) Committee for Medicinal Products for 
Human Use (CHMP): ICH guideline E14 – questions and answers: step 5 
(May 2012, EMA/CHMP/ICH/310133/2008).
R13-4802
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol 71, 1107-14 
(2013).
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the 
Bayesian approach to phase I cancer trials. Stat Med 2008. 27:2420-39.
R13-4804
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. 
Translation of innovative designs into phase I trials. J Clin Oncol 25 (31), 
4982-6 (2007).
R13-4805
Tourneau C le, Gan HK, Razak ARA, Paoletti X. Efficiency of new dose 
escalation designs in dose finding phase I trials of molecularly targeted 
agents. Plos One 7 (12), e51039 (2012).
R13-4806
Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose 
escalation with overdose control. Stat Med 1998. 17:1103-20.
R13-4881
FDA’s critical path initiative; Silver Spring: U.S. Food and Drug 
Administration (2012).
R18-1357
U.S. Department of Health and Human Services. Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published November 27, 
2017).
R19-0761
Liu F, Yang X, Geng M, Huang M. Targeting ERK, an Achilles’ heel of the 
MAPK pathway, in cancer therapy. Acta Pharm Sin B 8 (4), 552-62 (2018).
R19-3904
Burotto M, Chiou VL, Lee JM, Kohn EC. The MAPK pathway across 
different malignancies: a new perspective. Cancer 120, 3446 - 3456 (2014)


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9.2
UNPUBLISHED REFERENCES
c30780360
Investigator’s Brochure: BI 3011441; current version


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10.
APPENDICES
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) SAMPLING
Table 10.1: 1 Time schedule for PK blood 
sampling and ECG
Cycle Visit
Day
Time Point 
[hh:min]
CRF Time
/PTM
Event
Drug 
administr.
PK Blood 
and ECG
1
1
1
Just before drug
administration
-0:05
X
0:00
0:00
X
0:30
0:30
X
0:45
0:45
X
1:00
1:00
X
1:30
1:30
X
2:00
2:00
X
2:30
2:30
X
3:00
3:00
X
4:00
4:00
X
6:00
6:00
X
8:00
8:00
X
10:00
10:00
X
12:00
12:00
X a
2
2
Just before drug 
administration
23:55
X
4
8
Just before drug 
administration
167:55
X
5
15
Just before drug 
administration
335:55
X
0:00
336:00
X
0:30
336:30
X
0:45
336:45
X
1:00
337:00
X
1:30
337:30
X
2:00
338:00
X
2:30
338:30
X
3:00
339:00
X
4:00
340:00
X
6:00
342:00
X
8:00
344:00
X
10:00
346:00
X
12:00
348:00
X a




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10.2
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE AND 
DATA SCENARIOS
A Bayesian logistic regression model with overdose control will be used to guide dose 
escalation in this trial. The BLRM is introduced in Section 7.1, which also specifies the prior 
for the model. After patients in each cohort have completed at least one cycle of treatment, 
the prior distribution will be updated through Gibbs sampling procedures with the 
accumulated DLT data from the MTD evaluation period. Posterior probabilities for the rate of 
DLTs will be summarised from BLRM. Selection of the next dose will be based on these 
probabilities as well as on other safety and laboratory data.
The purpose of this statistical appendix is to present performance metrics (operating 
characteristics) that illustrate the precision of the design in estimating the MTD under various 
dose-toxicity relationships through computer simulation. These results are summarized in
Table 10.2:3. In addition, recommendations of the next dose level  by the BLRM with 
overdose control principle are also provided under various hypothetical outcome scenarios in 
early cohorts to show how it facilitates on-trial dose-escalation decisions (see Table 10.2:1). 
For simplicity reasons, a cohort size of 3 patients who are all evaluable is assumed.
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.2:1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model. It is assumed that 
each cohort has exactly three patients who are all evaluable. For each scenario, the 
probability of overdose for the current dose, as well as the next potential dose and related 
probabilities of under-dosing, target dose, and over-dosing are shown.
For example, scenario 1 represents the case that no DLT is observed in the first three patients 
at the starting dose of 4 mg. In this case, the next optimal dose, i.e. the dose with the highest 
probability of being in the target interval, is 7 mg.  Since the escalation is restricted to a 
maximum of 50 % from the previous dose per protocol, the next dose to be tested in the trial 
would be 6 mg. 
Scenario 4 is the case that one DLT is observed in the first three patient at the starting dose of 
4mg and no DLT is observed in second three patient at 4mg; in this case the model 
recommend to escalate 6 mg . Scenario 5 is the case that one DLT is observed in the first 
three patient at the starting dose of 4 mg and one DLT is observed in second three patient at 4 
mg; in this case the model recommend to 4 mg. Scenario 6 represents the case that 3 patients 
have been treated at 4 mg and 3 patients at 6 mg, none of them with a DLT. In this case, the 
model recommends to escalate to 8 mg.
Scenarios 16 to 22 are the cases where doses of 4 mg and 6 mg have been completed with no 
DLT and the BLRM recommends 8mg to be tested next. More specifically, scenarios 18, 21 
and 22 are the cases that dose of 8 mg have been completed and BLRM recommend to reduce 
to 7mg. Scenario 19, 20 illustrate a case where escalation has proceeded up to the highest 
dose of 8 mg, where the MTD could be declared at 8 mg. 
Scenarios 23 to 26 are the cases that 1 DLT out of 6 patients in 4mg cohort and no DLT in 3 
patients in 6 mg cohort, BLRM recommends 7 mg to be tested next. In scenarios 23, the next 
optimal dose, i.e. the dose with the highest probability of being in the target interval, is 8 mg. 
In such cases, SMC will suggest whether to open up 8mg cohort or keep treating patients at 
7mg. In scenarios 25, the next optimal dose, i.e. the dose with the highest probability of being 
in the target interval, is 8 mg. In such cases, SMC will suggest whether to open up 8 mg 


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cohort or claiming 7 mg as MTD according to BLRM. Scenario 26 illustrates a case when we 
can claim 7 mg as MTD according to BLRM.
Scenarios 27, 28, 30 and 31 are the cases that no DLT out of 3 patients in 4mg cohort and one 
DLT in 6 patients in 6 mg cohort, BLRM recommends 7 mg to be tested next. In scenarios 27 
and 29, the next optimal dose, i.e. the dose with the highest probability of being in the target 
interval, is 8 mg.  In scenarios 28, the next optimal dose, i.e. the dose with the highest 
probability of being in the target interval, is 7 mg. Scenario 30 illustrates a case when we can 
claim 7 mg as MTD according to BLRM. Scenario 31 illustrates a case when we can claim 6 
mg as MTD according to BLRM.
Scenarios 32 to 36 are the cases that 1 DLT out of 6 patients in 4mg cohort, no DLT in 3 
patients in 6 mg cohort and no DLT in 3 patients in 7 mg cohort BLRM recommends 8 mg to
be tested next. 
Scenarios 37 to 41 are the cases that 1 DLT out of 6 patients in 4mg cohort, no DLT in 3 
patients in 6 mg cohort and one DLT in 6 patients in 7 mg cohort BLRM recommends 8 mg 
to be tested next.
Scenarios 42 to 46 are the cases that no DLT out of 3 patients in 4mg cohort, one DLT in 6 
patients in 6 mg cohort and no DLT in 3 patients in 7 mg cohort BLRM recommends 8 mg to 
be tested next. 
Table 10.2:1
Hypothetical data scenarios
Scenario
Dose 
(mg)
# 
Patients
# DLT
Current 
Dose : P 
(OD)
Next 
recomm
ended 
dose *
Next dose:
P (UD)
P (TD)
P (OD)
1
4 mg
3
0
0.026
6 mg
[7 mg]
0.636
[0.486]
0.270
[0.339]
0.095
[0.175]
2
4 mg
3
1
0.194
4 mg
0.442
0.365
0.194
3
4 mg
3
2
0.569
NA
4
4 mg
6
1
0.065
6 mg
0.309
0.459
0.233
5
4 mg
6
2
0.249
4 mg
0.273
0.478
0.249
6
4 mg
6 mg
3
3
0
0
0.027
8 mg
0.440
0.375
0.185
7
4 mg
6 mg
3
3
0
1
0.153
6 mg
0.427
0.420
0.153
8
4 mg
6 mg
3
6
0
1
0.049
7 mg
0.377
0.480
0.143
9
4 mg
6 mg
3
6
0
2
0.178
6 mg
0.304
0.518
0.178


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Table 10.2:1
Hypothetical data scenarios (cont.)
10
4 mg
6 mg
3
6
0
3
0.397
4 mg
0.484
0.400
0.116
11
4 mg
6 mg
3
6
0
4
0.658
4 mg
0.318
0.449
0.233
12
4 mg
6 mg
6
3
1
0
0.096
7 mg
0.335
0.474
0.192
13
4 mg
6 mg
6
3
1
1
0.243
6 mg
0.215
0.542
0.243
14
4 mg
6 mg
6
6
1
1
0.125
7 mg
0.212
0.553
0.235
15
4 mg
6 mg
6
6
1
2
0.288
4 mg
0.504
0.424
0.072
16
4 mg
6 mg
8 mg
3
3
3
0
0
0
0.058
8 mg
0.604
0.338
0.058
17
4 mg
6 mg
8 mg
3
3
3
0
0
1
0.234
8 mg
0.281
0.485
0.234
18
4 mg
6 mg
8 mg
3
3
3
0
0
2
0.500
7 mg
0.304
0.481
0.214
19
4 mg
6 mg
8 mg
3
3
6
0
0
0
0.023
8 mg
0.731
0.245
0.023
20
4 mg
6 mg
8 mg
3
3
6
0
0
1
0.106
8 mg
0.443
0.451
0.106
21
4 mg
6 mg
8 mg
3
3
6
0
0
2
0.274
7 mg
0.453
0.464
0.083
22
4 mg
6 mg
8 mg
3
3
6
0
0
3
0.501
7 mg
0.287
0.519
0.195


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Table 10.2:1
Hypothetical data scenarios (cont.)
23
4 mg
6 mg
7 mg
6
3
3
1
0
0
0.076
8 mg
[7 mg]
0.364
[0.483]
0.484
[0.442]
0.152
[0.076]
24
4 mg
6 mg
7 mg
6
3
3
1
0
1
0.209
7 mg 
0.234
0.557
0.209
25
4 mg
6 mg
7 mg
6
3
6
1
0
1
0.092
8 mg
[7 mg]
0.247
[0.368]
0.560
[0.540]
0.193
[0.092]
26
4 mg
6 mg
7 mg
6
3
6
1
0
2
0.225
7 mg
0.174
0.602
0.225
27
4 mg
6 mg
7 mg
3
6
3
0
1
0
0.052
8mg
[7 mg]
0.335
[0.534]
0.492
[0.413]
0.173
[0.052]
28
4 mg
6 mg
7 mg
3
6
3
0
1
1
0.177
7 mg
0.278
0.546
0.177
29
4 mg
6 mg
7 mg
3
6
6
0
1
1
0.224
8 mg
[7 mg]
0.222
[0.404]
0.554
[0.530]
0.224
[0.066]
30
4 mg
6 mg
7 mg
3
6
6
0
1
2
0.199
7 mg
0.200
0.602
0.199
31
4 mg
6 mg
7 mg
3
6
6
0
1
3
0.363
6 mg
0.263
0.589
0.148
32
4 mg
6 mg
7 mg
8 mg
6
3
3
3
1
0
0
0
0.065
8 mg
0.510
0.425
0.065
33
4 mg
6 mg
7 mg
8 mg
6
3
3
3
1
0
0
1
0.178
8 mg
0.258
0.563
0.178


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Table 10.2:1
Hypothetical data scenarios (cont.)
34
4 mg
6 mg
7 mg
8 mg
6
3
3
6
1
0
0
0
0.023
8 mg
0.637
0.340
0.023
35
4 mg
6 mg
7 mg
8 mg
6
3
3
6
1
0
0
1
0.077
8 mg
0.380
0.544
0.077
36
4 mg
6 mg
7 mg
8 mg
6
3
3
6
1
0
0
2
0.207
8 mg
0.188
0.605
0.207
37
4 mg
6 mg
7 mg
8 mg
6
3
6
3
1
0
1
0
0.100
8 mg
0.366
0.534
0.100
38
4 mg
6 mg
7 mg
8 mg
6
3
6
3
1
0
1
1
0.226
8 mg
0.177
0.597
0.226
39
4 mg
6 mg
7 mg
8 mg
6
3
6
6
1
0
1
0
0.041
8 mg
0.490
0.468
0.041
40
4 mg
6 mg
7 mg
  8 mg
6
3
6
6
1
0
1
1
0.109
8 mg
0.272
0.619
0.109
41
4 mg
6 mg
7 mg
8 mg
6
3
6
6
1
0
1
2
0.236
8 mg
0.139
0.625
0.236
42
4 mg
6 mg
7 mg
8 mg
3
6
3
3
0
1
0
0
0.074
8 mg
0.495
0.431
0.074


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Table 10.2:1
Hypothetical data scenarios (cont.)
43
4 mg
6 mg
7 mg
8 mg
3
6
3
3
0
1
0
1
0.200
8 mg
0.240
0.560
0.200
44
4 mg
6 mg
7 mg
8 mg
3
6
3
6
0
1
0
0
0.025
8 mg
0.615
0.360
0.025
45
4 mg
6 mg
7 mg
8 mg
3
6
3
6
0
1
0
1
0.082
8 mg
0.369
0.549
0.082
46
4 mg
6 mg
7 mg
8 mg
3
6
3
6
0
1
0
2
0.232
8 mg
0.162
0.606
0.232
* Model recommendation is higher than allowed by additional rules in the CTP. Dose in 
brackets represents next dose with taking into account the CTP-specific rules.


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Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MTD. Under an assumed true dose-toxicity 
curve, metrics such as the probability of recommending a dose with true DLT rate in the 
target interval can be approximated via simulation. Table 10.2:2 describes 6 assumed true 
dose-toxicity scenarios which were used to assess the operating characteristics of the model. 
These scenarios reflect a wide range of possible cases as follows:
!
Scenario 1: aligned with prior means
!
Scenario 2: high-toxicity scenario
!
Scenario 3: low-toxicity scenario
!
Scenario 4: non-logistic dose-toxicity scenario
!
Scenario 5: low-toxicity followed by high-toxicity
!
Scenario 6: too-toxicity scenario
Table 10.2:2
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
4 mg
6 mg 
7mg
8 mg
1: Prior
P(DLT)
0.147
0.224
0.272
0.329
2: High Tox
0.22
0.34
0.40
0.45
3: Low Tox
0.04
0.11
0.13
0.16
4: Non-
Logistic
0.1
0.2
0.25
0.3
5: Low-High
0.04
0.2
0.40
0.45
*6:Too Tox
0.42
0.68
0.75
0.81
Bold numbers indicate true DLT rates in the target interval [0.16, 0.33].
* For Scenario 6, 2mg dose with 32% true DLT probability was added to the simulation 
condition in order for the R package to run (which needs at least one provisional dose level 
with true DLT probability in the target range).
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
It was then assessed how often a dose was declared as MTD with true DLT rate in the under-, 
targeted or over-dose range.
Furthermore, the average, minimum and maximum number of patients per trial and the 
average number of DLTs per trial are reported. Results are shown in Table 10.2:3.


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Table 10.2:3
Simulated operating characteristics
Scenario
% of trials declaring a MTD with true DLT rate in
# Patients
# DLTs
under dose
target dose
overdose
Stopped
Mean 
(Min-
Max)
Mean
(Min-
Max)
1
19.4
66.3
0
14.3
15.3
(3-33)
3.4
(1-9)
2
0
25.2
32.2
42.6
11.6
(3-30)
3.4
(1-11)
3
26.2
72.6
0
1.2
16.8
(3-42)
1.9
(1-7)
4
11.7
76.7
0
11.6
13.6
(3-33)
2.7
(1-9)
5
14.4
48.7
35.1
1.8
15.9
(3-36)
3.7
(1-11)
6
0
20.8
12.8
66.4
8.6
(3-24)
3.7
(2-12)
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
66.3% of the simulated trials declared the dose 4 mg as MTD with true DLT rate under the 
targeted dose range.
Scenario 2 (high-toxicity scenario) shows, that when the true DLT rate is high, i.e. the 
majority dose levels with true DLT rate above the target interval, The probability of 
observing a DLT at 6 mg is 0.34 and therefore very close to the upper bound of the target 
range. This accounts for 17.7% out of 32.2% where we declared a dose as MTD in the 
overdose interval. 42.6% of the trials were stopped without declaring a MTD since all dose 
levels were too toxic. This is an expected situation for a high-toxicity scenario.
Scenario 3 shows that when the true DLT rate is low, 72.6% of the simulated trials declared 
the dose 4 mg as MTD with true DLT rate under the targeted dose range, and 26.2% of the 
simulated trials declared a MTD in the underdose interval.
Scenario 4 represents a case where the assumed true dose-toxicity curve does not follow a 
logistic shape. In this scenario, 76.7% of trials declared MTDs with true DLT rate in the 
target interval, and only a few trials declared MTDs with true DLT rate in the underdose 
interval. This illustrates that the model is not sensitive to model misspecification.
Scenario 5 shows that when the true DLT rate is low-high, 48.7% of the simulated trials 
declared a dose as MTD with true DLT rate in the targeted dose range.
Scenario 6 shows that when the true DLT rate is super high, 66.4% of simulated trials 
stopped, since none of the doses is considered tolerable anymore. This is an expected 
situation for a super high-toxicity scenario.


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The mean patient numbers range from 8.6 patients (Scenario 6) to 16.8 patients (Scenario 3) 
and the maximum number of patients was 42. Therefore, the patient numbers are as expected 
and increase when moving away from the high-toxicity scenario.
By reviewing the metrics presented in Table 10.2:3, it can be seen that the model is not 
sensitive to different scenarios of truth. In general, this model is conservative due to the 
overdose control criteria. In all scenarios, the probabilities of recommending a dose with true 
P(DLT) ≥ 33% as MTD are much smaller than probabilities of recommending a dose with 
true P(DLT) between 16% and 33% as MTD.
On-study recommendations based on the model are consistent with the clinical decision 
making process, and should be considered in conjunction with other available clinical 
information by the BI clinical trial team and trial investigators in deciding the dose levels to 
be tested in order to determine the MTD estimate.
R version 3.5.1 and JAGS were used for data scenarios and simulations.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
22 Jul 2020
EudraCT number
EU number
NA
BI Trial number
1469-0002
BI Investigational Medicinal 
Product(s)
BI 3011441
Title of protocol
A phase I open-label trial of BI 3011441 in 
Japanese patients with NRAS/KRAS mutation 
positive advanced, unresectable or metastatic 
refractory solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Flow chart
Description of change
LVEF measurement added on Day 15 of Cycle 1.
Footnote t) which is explaining hospitalisation 
period during Cycle 1 and u) which is about 
additional X-ray were added.
Rationale for change
Based on comment from authority to make sure 
patient safety.
Section to be changed
Section 3.3.2 and 3.3.4.1
Description of change
Inclusion criteria 13, 14, footnote and treatment 
discontinuation condition was added to explain 
more clearly about WOBCP definition and 
handling for related to pregnancy and nursing.
Rationale for change
Based on comment from authority to be clearer
about handling.
Section to be changed
Section 4.1.1
Description of change
Explanation about gelatin used for BI 3011441 was 
added.
Rationale for change
Based on comment from authority.
Section to be changed
Section 4.1.2 and 5.2.6.3
Description of change
DLT condition for MTD evaluation has updated to 
avoid underestimate of DLT.
Rationale for change
Based on comment from authority to make sure 
patient safety.


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Section to be changed
Section 5.2.2
Description of change
Measurement of saturation of percutaneous oxygen 
was added.
Rationale for change
To detect ILD earlier.
Section to be changed
Section 5.2.3
Description of change
Testing for HBV detection was corrected based on 
local guideline.
Rationale for change
Based on comment from authority to make sure 
patient safety.
Section to be changed
Section 5.4
Description of change
Additional explanation about disclosure of 
biomarker analyses result to patient and handling 
of data and sample after withdrawal were added.
Rationale for change
Based on comment from authority.
11.2
GLOBAL AMENDMENT 2
Date of amendment
19 Nov 2020
EudraCT number
EU number
NA
BI Trial number
1469-0002
BI Investigational Medicinal 
Product(s)
BI 3011441
Title of protocol
A phase I open-label trial of BI 3011441 in 
Japanese patients with NRAS/KRAS mutation 
positive advanced, unresectable or metastatic 
refractory solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Flowchart
Description of change
Footnote h) was updated to increase allowance for 
ophthalmological assessment.
Rationale for change
Based on comment from priniciple investigator.
Section to be changed
Section 1.2
Description of change
Drug interaction information was updated based on 
most recent information.
Description of safety information from previous 
study was updated based on recent IB.
Rationale for change
Same as above


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Section to be changed
Section 1.4.2
Description of change
Description was simplified and moved to Table 
1.4.2:1 based on internal consideration
Rationale for change
Same as above
Section to be changed
Section 1.4.3
Description of change
New section about COVID-19 related Benefit-Risk 
Assessment was added.
Rationale for change
Due to internal requirement
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria 8 was upodated to add more 
detail definition about hypertension.
Rationale for change
To make exclusion criteria clear
Section to be changed
Section 3.3.4.1.1
Description of change
Enrolment stopping rule was updated.
Rationale for change
Due to internal requirement
Section to be changed
Section 4.2.2.1
Description of change
Updated based on recent drug interaction 
information.
Rationale for change
Same as above
Section to be changed
Table 5.2.3:1
Description of change
Desnription about myoglobin and cratine kinase 
was updated.
Rationale for change
Based on request from Risk Management 
Physician.
Section to be changed
Section 5.2.6
Description of change
DILI definition was updated based on internal 
process update.
Rationale for change
Due to internal requirement
Section to be changed
Section 5.2.6.2.4
Description of change
Exemptions to AE reporting was updated based on 
internal process update.
Rationale for change
Due to internal requirement
Section to be changed
Section 5.2.6.3
Description of change
DLT definition about hypertension was updated 
based to make condition clearer.
Rationale for change
Same as above.


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12.
REFERENCES FOR CTP AUTHORS
NA


 
 
 
APPROVAL / SIGNATURE PAGE 
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Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TRIAL STATISTICAL ANALYSIS PLAN
c35537257-01
BI Trial No.:
1469-0002
Title:
A phase I open-label trial of BI 3011441 in Japanese patients with 
NRAS/KRAS mutation positive advanced, unresectable or 
metastatic refractory solid tumours
Based on revised Clinical Trial Protocol (c30222580-03; Version 
3.0; 19 November 2020)
Investigational
Product:
BI 3011441
Responsible trial 
statistician:
Telephone: 
, Fax: 
Date of statistical 
analysis plan:
23Dec2022 SIGNED
Version:
1.0
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reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...............................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY....................10
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT .....................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoint .....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................17
6.1
TREATMENT.....................................................................................................17
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................17
6.3
SUBJECT SETS ANALYSED...........................................................................18
6.5
POOLING OF CENTRES .................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................20
7.
PLANNED ANALYSIS......................................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........23
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................23
7.3
TREATMENT COMPLIANCE........................................................................23
7.4
PRIMARY ENDPOINT .....................................................................................24
7.4.1
Primary analysis of the primary endpoint........................................................24
7.5
SECONDARY ENDPOINTS.............................................................................24
7.5.1
Key secondary endpoint .....................................................................................24
7.5.2
Secondary endpoints...........................................................................................24
7.7
EXTENT OF EXPOSURE.................................................................................25
7.8
SAFETY ANALYSIS..........................................................................................25
7.8.1
Adverse Events ....................................................................................................25
7.8.1.1
Maximum tolerated dose and dose limiting toxicity.............................................25


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7.8.1.2
Adverse events ......................................................................................................26
7.8.2
Laboratory data ..................................................................................................27
7.8.3
Vital signs.............................................................................................................27
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................28
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............29
9. 
REFERENCES....................................................................................................30
11.
HISTORY TABLE..............................................................................................33


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LIST OF TABLES
Table 6.1: 1
Definition of analysis treatment periods for safety analysis.............................17
Table 6.7: 1
Nominal time points and windows for imaging ...............................................21
Table 11: 1
History table .....................................................................................................33


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AO
Aldehyde oxidase
aPTT
Activated partial thromboplastin
AST
Aspartate transaminase
AUC
Area under the concentration-time curve of the analyte in plasma
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
BRAF
v-Raf murine sarcoma viral oncogene homolog B
CA
Competent Authority
CK
Creatine kinase
CK-MB
Creatine kinase myocardial band
CKD-EPI
Chronic Kidney Disease Epidemiology 
Cmax
Maximum measured concentration of the analyte in plasma
CRA
Clinical Research Associate
CRC
Colorectal cancer
CREE
Enzymatic serum creatinine assay
CREJ
Non IDMS standardised Jaffe
CREJIDMS
Isotype dilution mass spectrometry standardised Jaffe
CRF
Case Report Form 
CRO
Contract Research Organisation
CT
Computed Tomography
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol


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CYP
Cytochrome P450
DCR
Disease Control Rate
DILI
Drug Induced Liver Injury
DLT
Dose limiting toxicity
ECG
Electrocardiography
ECOG
Eastern Cooperative Oncology Group
eDC
Electronic Data Capture
EGFR
Epidermal growth factor receptor
EOR
End of residual effect
EOT
End of Treatment
ERK
Extracellular signal-regulated kinases
EWOC
Escalation with overdose control
FFPE
Formalin-fixed paraffin-embedded
FMO
Flavin-containing monooxegenases
FU
Follow up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HCO3
Bicarbonate
IB
Investigator’s Brochure
IC50
Inhibitory concentration (50%)
IDMS
Isotype dilution mass spectrometry
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
KRAS
Kirsten rat sarcoma viral oncogene homologue
LVEF
Left ventricular ejection fraction
MAO
Monoamine oxidases
MAP
Mitogen-activated protein
MAPK
Mitogen-activated protein kinase


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MedDRA
Medical Dictionary for Drug Regulatory Activities
MEK
Mitogen-activated protein kinase kinase 
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NRAS
Neuroblastoma RAS viral (v-ras) oncogene homolog
NSCLC
Non-small cell lung cancer
OPU
Operative Unit
p.o.
per os (oral)
PFS
Progression-free survival
PK
Pharmacokinetics
PK/PD
Pharmacokinetics / Pharmacodynamics
PT
Prothrombin time
QTcF
QT interval 
RAC
Accumulation Index
RAF
Rapidly Accelerated Fibrosarcoma
RAS
Rat sarcoma
RD
recommended dose
REP
Residual effect period
RPED
Retinal Pigment Epithelial Detachment 
SAE
Serious adverse event
SD
Standard deviation
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
SUSAR
Suspected unexpected serious adverse reaction


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TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
WHO
World Health Organisation
β -HCG
beta human chorionic gonadotropin 


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the trial, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, and randomisation.
SAS® Version 9.4 will be used for all analyses.
Pharmacokinetics (PK) parameters will be calculated using Phoenix WinNonlinTM software
(version 8.1 or higher).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
This section is not applicable.
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary objective of this trial is to confirm the safety and tolerability of previously
identified MTD, BI 3011441 8mg (in Caucasian FIH study) as a single agent when 
administered orally to adult Japanese patients with NRAS/KRAS mutation positive advanced 
or metastatic refractory solid tumours. 
In this trial, the MTD is an unknown parameter to be determined as the highest dose with less 
than 25% risk of the true DLT rate being equal to or above 33%. It is estimated by the 
Bayesian Logistic Regression Model (BLRM), which is specified in CTP Section 7 based on 
the frequency of patients experiencing dose limiting toxicities (DLTs) during the MTD 
evaluation period. The MTD is determined by the SMC. For the definition of DLTs, refer to 
CTP Section 5.2.6.3.
The primary endpoints in this trial are specified in CTP Section 2.1.2; they are
-
MTD defined as the highest dose with less than 25% risk of the true DLT rate being 
equal
-
or above 33% during the MTD evaluation period.
- Number of patients with DLTs in the MTD evaluation period. 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
5.2.2
Secondary endpoints
The secondary endpoints are, as specified in CTP Section 2.1.3: 
- Number of patients with DLTs during the entire on-treatment period 
- Number of patients with Grade ≥3 treatment-related adverse events  
- Number of patients with treatment related adverse events at each dose level  
- Pharmacokinetic parameters of BI 3011441: Cmax (,ss), and AUC0-tz(,ss)  


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
The trial is an open-label phase I trial with dose escalation, confirmation and expansion of BI 
3011441 as monotherapy. For basic study information such as treatments to be administered, 
assignment of treatment groups, and selection of doses, see CTP Section 4.
For safety analyses, AEs will be classified to one of the following time periods: “Screening”, 
“On-treatment” or “Follow-up.” This will be applied for all adverse events. Detailed rule for 
assigning AEs to these time periods are listed below.
∀
If the date of informed consent ≤ AE onset date < date/time of first administration of 
trial treatment, then the AE is assigned to “Screening”;
∀
If date of first administration of trial treatment ≤ AE onset date ≤ date of last 
administration of trial treatment + 30 days of Residual Effect Period (REP), then the
AE is assigned to “On-treatment”;
∀
If AE onset date > date of last administration of trial treatment + 30 days, then the AE 
is assigned to “Follow-up”
Table 6.1: 1
Definition of analysis treatment periods for safety analysis
Analysing Treatment 
Period
Start Date
Stop Date 
Screening
Date of informed consent
Date/Time of the first 
administration of trial 
treatment
On-treatment
Date of the first administration 
of trial treatment
Date of the last 
administration of trial 
treatment + 30 days of REP
Follow-up
Date of the last administration 
of trial treatment + 31 days
Date of the last visit
MTD evaluation period*
Date of the first administration 
of trial treatment
Date of the first 
administration of trial 
treatment + 28 days (i.e., 
treatment cycle)
   *The MTD evaluation period is only applied to the patients in the dose escalation part of the trial.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the TMF in EDMS. 




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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Every effort should be made to collect complete data at each visit for each patient. If not 
specified otherwise, missing data will not be imputed and remain missing. Potential outliers 
will be reported and analysed as observed.
Missing or incomplete AE dates are imputed according to BI standard (see “Handling of 
missing and incomplete AE dates”) (2)
Missing data and outliers of PK data are handled according to the relevant BI standard (see 
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within
Clinical Pharmacokinetics/Pharmacodynamics” (5) and BI-KMED-TMCP-MAN-0014
“Noncompartmental Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” 
(6)). PK parameters that cannot be reasonably calculated based on the available drug
concentration-time data will not be imputed. 
In general, missing data not discussed in (2) and (6) will not be imputed unless required for 
the following analyses and definitions. Then the rules as described below apply.
Change of laboratory values from baseline
Laboratory values at baseline: For missing laboratory data at cycle 1 day 1 (before the 
first administration of any study medication) the data of preceding visits will be used 
if available. 
Definition of on-treatment period and actual treatment 
Date of permanent discontinuation of study medication: All reasonable efforts should 
be undertaken during the study to obtain the dates of permanent discontinuation of 
study medication. However, if the date of the very last administration is missing this 
will be imputed with:
∀
If only month and year are given, the last day of the month will be used for 
imputation
∀
If only the year is given, the 31st of December of this year will be used for 
imputation
If the imputed date leads to a date that is later than the date of the EOT visit, then the 
imputed date is the date of the EOT visit. If the imputed date leads to a date that is 
later than the death date, then the imputed date is the date of death.
Partial death dates 


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If a partial (year and month) death date is reported, the date will be imputed with the 
end of the month for the analysis of PFS. This is in line with the imputation of partial 
dates for the analysis of AEs. 
Partial or missing start date of subsequent anti-cancer therapy/subsequent radiotherapy 
If the day of the start date of subsequent systemic therapy/subsequent radiotherapy is 
missing, then the 1st of the month will be imputed unless this leads to a date before the 
stop date of study medication. In this case the stop date of study medication +1 day 
will be imputed.
If day and month, or day and month and year are missing, it will be distinguished 
whether the start date of subsequent systemic therapy/subsequent radiotherapy is 
required for censoring of PFS or for other descriptive statistics:
∀
For censoring of PFS: If only the year is reported, the 1st of January of this year 
will be imputed unless this leads to a date before the stop date of study medication. 
In this case the stop date of study medication +1 day will be imputed. In case of a 
completely missing start date of subsequent anti-cancer therapy/subsequent 
radiotherapy and the patient did not have any post-baseline tumour assessment or 
did not progress or die, the PFS of this patient will be censored at the day of first 
administration of study drug. Additionally, all imputed start dates of subsequent 
anti-cancer therapy/subsequent radiotherapy should be before death date, if 
available. 
∀
For descriptive statistics: Dates will not be imputed if more than only the day of 
the date is missing.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Unless otherwise specified baseline is defined as the time point closest to but prior to the first 
administration of any study medication. If no time is specified and the date is the same as the 
first administration date, then it will still be considered baseline if not specified otherwise. If 
there is no measurement earlier than the first administration of study medication, then no 
baseline will be derived.
For laboratory parameters for which not only the examination date but also the sampling time 
was recorded, examination time should be taken into consideration when defining baseline. 
That is a laboratory measurement on the same date as the first administration of study 
treatment is considered as baseline if and only if the examination time of this laboratory 
measurement is before the first administration of study treatment. If any of these times is 
missing and the date of laboratory assessment is the same as the date of first administration of 
study medication, then the laboratory assessment will be considered as according to protocol, 
i.e., as prior to first study medication.
Study days and visits will be labelled according to the flow charts in the CTP. Study day will 
be calculated relative to the date of the first administration of study drug. The day prior to first 


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administration of study drug will be ‘Day -1’ and the day of first administration of study drug 
will be ‘Day 1’; therefore ‘Day 0’ will not exist.
Imaging time windows:
Time windows and visits will be calculated to determine the planned day of tumour 
measurement and response status, based on the protocol-specified tumour imaging schedule.
For the presentation of tumour response data which will follow a calculated visit approach
based on the protocol specified tumour imaging schedule: Imaging will be performed at 
screening and every 8 weeks after the first administration of study treatment (i.e. Week 8, 16,
24 etc.). Image data will be slotted to Week 8, 16, 24 etc. based on their relative study day 
(from start of treatment) and using a ±4 week window (e.g., images taken in the first 6 weeks 
from start of treatment will be assigned to Week 8). If two or more images for a patient are 
assigned to one interval then the last assessment will be used to ensure PD is not missed.
In order to identify whether consecutive imaging time points are missing for a given patient, a 
nominal time point (i.e. Week 8, 16, 24 etc.) will be assigned to each and every image. This is 
achieved by creating windows for every radiological response assessment. These windows are 
defined in Table 6.7: 1. If a patient does not have an image in one of the windows described 
above, the patient will be considered to have missed an assessment for that time point.
Table 6.7: 1
Nominal time points and windows for imaging
Nominal time point (weeks 
from start of study 
medication)
Target day of the scan
(study day)
Window (study day)
8
57
1 to ≤ 85
16
113
86 to ≤ 141
24
169
142 to ≤ 197
32
225
198 to ≤ 253
40
281
254 to ≤ 309
48
337
310 to ≤ 365
56
393
366 to ≤ 421
Etc., 8 week interval
Etc.
Etc.
NOTE: The date of the first dose of study medication is Day 1




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The ADS “ADPC” (PK concentrations per time-point or per time-interval) contains column
variables ACEX and ACEXCO indicating inclusion/exclusion (ACEX) of a concentration and 
an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the analysis 
flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value will be 
excluded for all types of analyses based on concentrations. If ACEXCO is set to ‘DESC 
STATS’ the value will be excluded from descriptive evaluations per planned time point/time 
interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME DEVIATION’ 
the value can be used for further analyses based on actual times. If ACEXCO is set to ‘HALF 
LIFE’, the value will be excluded from half-life calculation (and, as a consequence, any 
calculation that relies on λz) only; the value is included for all other analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (6) and BI-KMEDTMCP-
MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (7).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only standard descriptive statistics and summary tables are planned for this section of the 
report based on the treated set and other subject sets as appropriate. Data will be summarized
by treatment group (i.e., dose cohort) and a “total” column will be included in the summary 
table.
Baseline demographics, oncological history, prior therapies, medical history, baseline eastern 
cooperative oncology group (ECOG) performance status, and baseline disease assessment are 
planned for this section.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report based on the treated set 
and other subject sets as appropriate. 
Concomitant diseases will be coded similarly as AEs based on the most current Medical
Dictionary for Regulatory Activities (MedDRA) version. A summary of concomitant diseases 
will be provided by treatment group, system organ class (SOC), and preferred term (PT).
Concomitant therapies (CTs) will be coded according to World Health Organisation Drug 
Dictionary (WHO DD version: latest version before Data base lock). CTs will be classified 
according to the Anatomical Therapeutic Chemical (ATC) classification system. The third 
ATC level will be used to categorise CTs by therapy type. In situations where a medical 
product may be used for more than one equally important indication, there are often several 
classification alternatives. As appropriate, patients receiving CTs with more than one possible 
ATC level 3 category will be counted more than once. Footnotes will clarify this possible 
double counting in tables.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.


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7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
For the determination of the MTD, only evaluable patients for MTD in the dose escalation 
part will be considered (i.e., the MTD set). In this section of the report the data that led to the 
determination of the MTD are documented and summarised. To be specific, an overall 
summary of the number of patients with DLTs during the MTD evaluation period (i.e., the 
first treatment cycle) will be provided for each dose cohort.
The dose escalation and determination of MTD is guided by the BLRM with overdose control 
specified in CTP Section 7 based on the DLT data in the MTD set. Specifically, estimation of 
the MTD will be based on the estimation of the posterior probability of the incidence of DLT 
in toxicity categories during the MTD evaluation period for all evaluable patients for MTD. 
Tables and bar charts displaying the posterior probabilities of the true DLT rates being in 
either the under-toxicity interval, the target-toxicity interval or the over-toxicity interval will 
be produced.   
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoints
The number of patients with DLTs during the on-treatment period at each dose level will be 
summarized in a frequency table.
The number of patients with CTCAE Grade ≥3 treatment-related adverse events observed 
during the on-treatment period at each dose level will be summarized in a frequency table
(provided tables should be refer to Section 7.8.1.2)  .
The number of patients with treatment related adverse events at each dose level will be 
summarized in a frequency table.
The secondary PK endpoints (refer to Section 5.2.2) will be analysed descriptively. The 
analysis of standard PK parameters is calculated according to the relevant BI internal 
procedures “Noncompartmental Pharmacokinetic / Pharmacodynamic Analyses of Clinical 
Studies” (6).


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7.7
EXTENT OF EXPOSURE
The total number of initiated cycles and treatment duration in days will be summarized 
descriptively for each dose cohort.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. Treated patients will be analyzed 
according to their initial treatment. 
Patients who were replaced within the MTD evaluation period will be excluded from the 
determination of the MTD in the dose escalation but will be considered for all other safety 
evaluations.
Safety data recorded during the Residual Effect Period (REP) of 30 days will be considered as 
on-treatment.
7.8.1
Adverse Events
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e., all adverse events occurring between start of treatment and end of the 
REP. All adverse events will be evaluated by initial treatment.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
7.8.1.1 Maximum tolerated dose and dose limiting toxicity
For the determination of MTD in this trial, the following will be evaluated: 
∀
Posterior distribution is based on the number of patients with DLTs with regard to the 
MTD set and DLTs occurring during the MTD evaluation period (i.e., the first 
treatment cycle in dose escalation). The toxicity rates for the respective toxicity 
intervals will be evaluated.
∀
A table displaying DLTs by primary system organ class and preferred term will be 
provided by initial treatment for the MTD evaluation period for the MTD Set as well 


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as for the treated set. The same table will additionally be displayed for all treatment 
cycles of the on-treatment period for the treated set.
∀
The purpose of these tables is to summarize and document the data that led to the 
selection of MTD. A summary of the number of patients with DLT within the MTD 
evaluation period and for all treatment cycles of the on-treatment period will be given 
by initial treatment for the treated set.
7.8.1.2 Adverse events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and NOT on the number of AEs. The 
analysis will be based on BI standards (3). AEs will be coded using the most recent version of 
MedDRA. The severity of AEs will be assessed according to the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0.
For analysis multiple AE occurrence data on the eCRF will be collapsed into an AE provided 
that all of the following applies:
∀
All AE attributes are identical (Low Level term [LLT], severity, action taken, therapy 
required, seriousness, reason for seriousness, relationship, outcome, AESI).
∀
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs occurring between first drug intake until 30 days of REP after last drug intake will be 
assigned to `on-treatment’. All AEs occurring before first drug intake will be assigned to 
‘screening’ and all AEs occurring after last drug intake + 30 days will be assigned to ‘follow-
up’ (for listings only). For details on the treatment definition, see Section 6.1.
The pre-specified Adverse events of special interest (AESIs) in this trial are DLTs and lab 
abnormalities in hepatic laboratory parameters. Refer to CTP Section 5.2.6.1.4 for details.
An overall summary of adverse events will be presented.
The frequency of patients with AEs will be summarized by treatment, primary system organ 
class (SOC) and/or preferred term (PT). The SOCs will be sorted by default alphabetically 
and PTs will be sorted by frequency within an SOC. Separated tables will be provided for 
patients with
∀
AEs
∀
Drug-related SAEs
∀
Drug-related AEs
∀
SAEs
∀
AESIs
∀
Grouped term AEs
∀
AEs leading to death
∀
AEs leading to discontinuation of trial medication


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∀
AEs leading to dose interruption 
∀
AEs leading to dose reduction 
∀
DLTs during the MTD evaluation period
∀
DLTs during the entire treatment period
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(4). 
The same on-treatment period as considered for the analysis of adverse events will be applied 
for laboratory values. Patients having at least one post-baseline laboratory value will be 
displayed in the descriptive analyses. Patients with missing CTCAE grade at baseline or no 
baseline value but with post-baseline values will be displayed in a new category “missing 
CTCAE grade at baseline” for those laboratory parameters where CTCAE grading is 
applicable. CTCAE grades for applicable laboratory parameters will be calculated according 
to CTCAE Version 5.0.
Descriptive statistics for laboratory values will be displayed using the converted values. Shift 
tables of change in laboratory measurements between baseline and worst value on treatment, 
between baseline and last value on treatment, and between worst and last value on treatment 
will also be presented.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will be 
done via comparison of laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be summarized. Treatment groups 
will be compared descriptively with regard to distribution parameters as well as with regard to 
frequency and percentage of patients with abnormal values or clinically relevant abnormal 
values.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
Vital signs, observed at screening, baseline, during the course of the trial and at the end-of-
trial evaluation will be assessed with regard to possible changes compared to findings before 
start of treatment.
7.8.4
ECG
Clinically relevant abnormal findings will be reported as adverse events. Scatterplot of the BI 
3011441 plasma concentration against the following individual QTcF values will be provided. 
Scatterplots of baseline and post QTcF against the following individual QTcF values will be 
provided.


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7.8.5
Others


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database after completion of enrolment.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
3.
BI-KMED-BDS-HTG-0041: “How to Guide: Analysis and Presentation of Adverse 
Event Data from Clinical Trials”, current version, IDEA for CON
4.
BI-KMED-BDS-HTG-0042: “How to Guide: Handling, Display and Analysis of 
Laboratory Data”, current version, IDEA for CON
5.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
6.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
7.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMED.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
23-DEC-22
None
Initial TSAP 


 
 
 
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