A Randomized, Open-Label, Two Part Study to Explore the Performance of Entrectinib Prototype Mini-Tablet Formulations and the Effect of Drug Substance Particle Size On Entrectinib Bioavailability in Healthy Volunteers
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Genentech, Inc.

 
Official Title: A Randomized, Open-Label, Two Part Study to Explore the 
Performance of Entrectinib Prototype Mini-Tablet Formulations and 
the Effect of Drug Substance Particle Size on Entrectinib 
Bioavailability in Healthy Volunteers 
NCT Number: 
NCT03961100 
Document Date: 
Protocol Version 1: 04-April-2019 
Protocol Non-substantial Amendment Version 1.0: 11-July-2019 
 

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Entrectinib—Genentech, Inc. 
Protocol GP41341, Version 1 – 02 April 2019 
PROTOCOL 
TITLE: 
A RANDOMIZED, OPEN-LABEL, TWO PART 
STUDY TO EXPLORE THE PERFORMANCE OF 
ENTRECTINIB PROTOTYPE MINI-TABLET 
FORMULATIONS AND THE EFFECT OF DRUG 
SUBSTANCE PARTICLE SIZE ON ENTRECTINIB 
BIOAVAILABILITY IN HEALTHY VOLUNTEERS 
PROTOCOL NUMBER: GP41341 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2019-000783-15 
IND NUMBER: 
IND 120500 
TEST PRODUCT: 
Entrectinib (RXDX-101) (RO7102122) 
MEDICAL MONITOR: 
 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1.0 02 APR 2019 
 
 
 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 7 
PROTOCOL ACCEPTANCE FORM .................................................................... 8 
PROTOCOL SYNOPSIS ...................................................................................... 9 
1.
BACKGROUND .......................................................................................... 16
1.1 
Background on Entrectinib ..................................................... 16 
1.1.1 
Toxicology and Safety Pharmacology ................................... 16 
1.1.2 
Clinical Summary ................................................................... 17 
1.1.2.1 
Safety .................................................................................... 17 
1.1.2.2 
Pharmacokinetics .................................................................. 17 
1.2 
Study Rationale and Benefit-Risk Assessment ...................... 19 
1.2.1 
Study Rationale ..................................................................... 19 
1.2.2 
Risk-Benefit Assessment ....................................................... 19 
2.
OBJECTIVES AND ENDPOINTS ............................................................... 20
2.1 
Pharmacokinetic Objectives (Primary Study 
Objective) .............................................................................. 20 
2.2 
Safety Objective (Secondary Study Objective) ...................... 20 
2.3 
Additional Objective ............................................................... 20 
3.
STUDY DESIGN ......................................................................................... 20
3.1 
Description of the Study......................................................... 20 
3.2 
End of Study and Length of Study ......................................... 23 
3.3 
Rationale for Study Design .................................................... 24 
3.3.1 
Rationale for Subject Population ........................................... 24 
3.3.2 
Rationale for Entrectinib Dose and Schedule ........................ 24 
3.3.3 
Rationale for Pharmacokinetic Sampling 
Schedule ................................................................................ 24 
4.
MATERIALS AND METHODS .................................................................... 25
4.1 
Subjects ................................................................................. 25 
4.1.1 
Inclusion Criteria .................................................................... 25 
4.1.2 
Exclusion Criteria ................................................................... 26 
4.2 
Method of Treatment Assignment and Blinding ..................... 28 

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4.2.1 
Part 1 ..................................................................................... 28 
4.2.2 
Part 2 ..................................................................................... 28 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 29 
4.3.1 
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 29 
4.3.2 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................ 30 
4.3.2.1 
Entrectinib .............................................................................. 30 
4.3.3 
Investigational Medicinal Product Accountability ................... 30 
4.4 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 31 
4.4.1 
Permitted Therapy ................................................................. 31 
4.4.2 
Prohibited Therapy ................................................................ 32 
4.4.3 
Prohibited Food ..................................................................... 32 
4.4.4 
Additional Restrictions ........................................................... 32 
4.5 
Study Assessments ............................................................... 33 
4.5.1 
Informed Consent Forms and Screening Log ........................ 33 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................. 34 
4.5.3 
Physical Examinations ........................................................... 34 
4.5.4 
Vital Signs .............................................................................. 35 
4.5.5 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 35 
4.5.6 
Electrocardiograms ................................................................ 36 
4.5.7 
Palatability Questionnaire ...................................................... 37 
4.6 
Treatment, Subject, Study, and Site 
Discontinuation ...................................................................... 37 
4.6.1 
Stopping Criteria .................................................................... 37 
4.6.2 
Subject Discontinuation from the Study ................................. 38 
4.6.3 
Study Discontinuation ............................................................ 39 
4.6.4 
Site Discontinuation ............................................................... 40 
5.
ASSESSMENT OF SAFETY ....................................................................... 40
5.1 
Safety Plan ............................................................................ 40 
5.2 
Safety Parameters and Definitions ........................................ 40 

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5.2.1 
Adverse Events ..................................................................... 41 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 41 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 42 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 42 
5.3.1 
Adverse Event Reporting Period ........................................... 43 
5.3.2 
Eliciting Adverse Event Information ....................................... 43 
5.3.3 
Assessment of Severity of Adverse Events ........................... 43 
5.3.4 
Assessment of Causality of Adverse Events ......................... 44 
5.3.5 
Procedures for Recording Adverse Events ............................ 45 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 45 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 45 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 46 
5.3.5.4 
Abnormal Laboratory Values ................................................. 46 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 47 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 47 
5.3.5.7 
Deaths ................................................................................... 48 
5.3.5.8 
Preexisting Medical Conditions .............................................. 48 
5.3.5.9 
Hospitalization or Prolonged Hospitalization .......................... 48 
5.3.5.10 
Cases of Accidental Overdose or Medication 
Error....................................................................................... 49 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 50 
5.4.1 
Emergency Medical Contacts ................................................ 51 
5.4.2 
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest ........................... 51 
5.4.2.1 
Events that Occur Prior to Study Drug Initiation .................... 51 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 51 
5.4.3 
Reporting Requirements for Pregnancies .............................. 52 
5.4.3.1 
Pregnancies in Female Subjects ........................................... 52 
5.4.3.2 
Pregnancies in Female Partners of Male 
Subjects ................................................................................. 52 

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5.4.3.3 
Abortions ............................................................................... 52 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 53 
5.5 
Follow-Up of Subjects after Adverse Events .......................... 53 
5.5.1 
Investigator Follow-Up ........................................................... 53 
5.5.2 
Sponsor Follow-Up ................................................................ 53 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 53 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees .......................................................... 54 
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 55
6.1 
Determination of Sample Size ............................................... 56 
6.2 
Summaries of Conduct of Study ............................................ 56 
6.3 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 56 
6.4 
Safety Analyses ..................................................................... 56 
6.5 
Pharmacokinetic Analyses ..................................................... 57 
6.6 
Other Analyses ...................................................................... 57 
6.7 
Interim Analyses .................................................................... 57 
7.
DATA COLLECTION AND MANAGEMENT ............................................... 58
7.1 
Data Quality Assurance ......................................................... 58 
7.2 
Electronic Case Report Forms ............................................... 58 
7.3 
Source Data Documentation .................................................. 58 
7.4 
Use of Computerized Systems .............................................. 59 
7.5 
Retention of Records ............................................................. 59 
8.
ETHICAL CONSIDERATIONS .................................................................... 60
8.1 
Compliance with Laws and Regulations ................................ 60 
8.2 
Informed Consent .................................................................. 60 
8.3 
Institutional Review Board or Ethics Committee .................... 61 
8.4 
Confidentiality ........................................................................ 61 
8.5 
Financial Disclosure .............................................................. 62 
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION ..................................................................................... 62 

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9.1 
Study Documentation ............................................................ 62 
9.2 
Protocol Deviations ................................................................ 62 
9.3 
Site Inspections ..................................................................... 63 
9.4 
Administrative Structure......................................................... 63 
9.5 
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 63 
9.6 
Protocol Amendments ........................................................... 64 
10. REFERENCES ........................................................................................... 65
LIST OF TABLES 
Table 1 
Part 1 Treatment Sequences ...................................................... 28 
Table 2 
Part 2 Treatment Sequences ...................................................... 29 
Table 3 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 44 
Table 4 
Causal Attribution Guidance ....................................................... 45 
Figure 1 
LIST OF FIGURES 
Median entrectinib plasma concentration versus time profile 
following a single 600 mg dose to healthy volunteers under 
fed or fasted conditions ............................................................... 18 
Figure 2 
Overview of Part 1 Design .......................................................... 22 
Figure 3 
Overview of Part 2 Design .......................................................... 23 
LIST OF APPENDICES 
 Schedule of Activities ................................................................. 66 
 Schedule of Pharmacokinetic Samples ...................................... 69 
Appendix 1 
Appendix 2 
Appendix 3 
 Palatability Questionnaire .......................................................... 70 

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PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, OPEN-LABEL, TWO PART STUDY TO 
EXPLORE THE PERFORMANCE OF ENTRECTINIB PROTOTYPE 
MINI-TABLET FORMULATIONS AND THE EFFECT OF DRUG 
SUBSTANCE PARTICLE SIZE ON ENTRECTINIB 
BIOAVAILABILITY IN HEALTHY VOLUNTEERS 
PROTOCOL NUMBER: 
GP41341 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2019-000783-15 
IND NUMBER: 
IND 120500 
TEST PRODUCT: 
Entrectinib (RXDX-101) (RO7102122) 
MEDICAL MONITOR 
 
PHASE: 
I 
INDICATION: 
Oncology 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
This study will evaluate the bioavailability, palatability, safety and tolerability of entrectinib in 
healthy volunteers. Specific objectives and corresponding endpoints for the study are outlined 
below. 

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Objectives 
Endpoints 
Primary 
Part 1: To explore the relative 
bioavailability of entrectinib from 
two multi-particulate 
formulations and the reference 
F06 capsule formulation under 
fed conditions 
Part 2: To explore the relative 
bioavailability of two entrectinib 
F06 capsule formulations under 
fasted conditions 
The geometric mean ratio 
and associated 90% 
confidence intervals of 
entrectinib and M5 AUC0-inf 
and Cmax parameters 
Secondary 
 
To explore the safety and 
tolerability of a single oral dose 
of entrectinib in healthy 
volunteers 
Incidence and severity of 
adverse events, incidence of 
abnormalities in laboratory 
safety tests, physical 
examinations, 12-lead ECGs 
and vital sign measurements 
Additional 
To explore the palatability (taste 
and acceptability) of coated and 
uncoated multi-particulate 
formulations 
Completion of palatability 
questionnaire 
 
Study Design 
Description of Study 
This is a randomized, open-label, single-center, two-part study in healthy volunteers to explore 
the performance of entrectinib multi-particulate formulations (Part 1) and the effect of drug 
substance particle size on entrectinib bioavailability (Part 2). 
Part 1 
Part 1 is a randomized, open-label, three-treatment, three-period, three-sequence, three-way 
crossover design.  In each treatment period, subjects will receive a single 600 mg oral dose of 
entrectinib under fed conditions.  Entrectinib will be administered as one of three possible 
formulations: 
 
Multi-particulate formulation 1: Entrectinib film-coated mini-tablets, 600 mg (240 × 2.5 mg) 
(Ro 710 2122/F15) (test formulation 1; T1) 
 
Multi-particulate formulation 2: Entrectinib film-coated mini-tablets, 600 mg (240 × 2.5 mg) 
(Ro 710 2122/F16) (test formulation 2; T2) 
 
F06 capsule formulation:  Entrectinib (RXDX-101) F06 hard capsules, 3 × 200 mg (Ro 710 
2122/F04) (reference formulation; R) 
Study treatments will be administered orally within 30 mins of consumption of a standardized 
light “pediatric” breakfast.  The test formulation, provided in a bottle, will be mixed with 
approximately one tablespoon (~15 mL) of yogurt, which will be swallowed without chewing with 
approximately 240 mL of water.  In each period, palatability (taste and acceptability) of the test 
formulations will be assessed by completion of a questionnaire shortly after drug administration. 
The reference formulation will be dosed as 3 x 200 mg capsules, swallowed whole with 
approximately 240 mL of water. 
A total of 15 subjects will be enrolled.  Subjects will be randomly assigned to one of three 
treatment sequences (i.e., T1T2R, T2RT1, RT1T2) according to a pre-specified randomization 
scheme based on the order of study enrollment. 
Blood samples for measurement of plasma concentrations of entrectinib and its active 
metabolite M5 will be collected before and at intervals up to 96 hours after study drug dosing in 
each period.   

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Safety and tolerability will be monitored by clinical and laboratory assessments at intervals 
throughout the study.   
Part 2 
Part 2 is a randomized, open-label, two-treatment, two-period, two-sequence, two-way 
crossover design.  In each treatment period, subjects will receive a single 200 mg oral dose of 
entrectinib under fasted conditions.  Entrectinib will be administered as one of two possible 
formulations:  
 
Entrectinib F06 hydroxypropyl methylcellulose (HPMC) capsules (coarse active 
pharmaceutical ingredient [API]), 200 mg (test formulation; T) 
 
Entrectinib (RXDX-101) F06 hard capsules (fine API), 200 mg (Ro 710 2122/F04) 
(reference formulation; R) 
The formulations will be dosed as 1 × 200 mg capsules, swallowed whole with approximately 
240 mL of water after an overnight fast (minimum 8 hours). 
A total of 16 subjects will be enrolled.  Subjects will be randomly assigned to one of two 
treatment sequences (i.e., TR or RT) according to a pre-specified randomization scheme based 
on the order of study enrollment. 
Blood samples for measurement of plasma concentrations of entrectinib and its active 
metabolite M5 will be collected before and at intervals up to 96 hours after study drug dosing in 
each period.  
Safety and tolerability will be monitored by clinical and laboratory assessments at intervals 
throughout the study. 
Number of Subjects 
It is planned that total of 15 subjects will be enrolled in Part 1 and 16 subjects will be enrolled in 
Part 2 of the study to achieve 12 evaluable subjects in each part.  Subjects who withdraw from 
the study may be replaced at the discretion of the Sponsor and investigator to ensure that in 
each part 12 subjects complete the study and have evaluable pharmacokinetic data from all 
treatment periods. 
Target Population 
Inclusion Criteria 
Subjects must meet the following criteria for study entry: 
 
Able and willing to comply with the study restrictions and to give written informed consent 
before any study procedure.  
 
Healthy male or female subjects of non-childbearing potential aged 18 to 60 years, 
inclusive, at time of signing Informed Consent Form (ICF) 
 
A body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive, and weighing ı50 kg, at 
screening. 
 
Healthy in the opinion of the investigator.  Healthy is defined by the absence of evidence of 
any active disease or clinically significant medical condition based on a detailed medical 
history, physical examination, vital signs and 12-lead ECG assessment, and laboratory 
safety test results. 
 
Agreement to comply with measures to prevent pregnancy and restrictions on egg and 
sperm donation. 
Female subjects of non-childbearing potential do not need to use any methods of 
contraception.  Non-childbearing potential is defined as either post menopausal (at least 
12 months without a period [i.e., amenorrhea]; in a woman at least 45 years of age and 
documented by a serum follicle stimulating hormone (FSH) level consistent with 
postmenopausal status [e.g., 40 IU/L]), or surgically sterile (e.g., bilateral oophorectomy, 
bilateral salpingectomy, hysterectomy; note: tubal ligation is not considered an 
appropriate method of surgical sterilization) for at least 90 days.   
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
a condom plus an approved method of effective contraception, and agreement to refrain 
from donating sperm, as defined below: 

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With a female partner of childbearing potential, men must remain abstinent or use a 
condom plus an approved method of effective contraception (partner’s use of combined 
[estrogen and progestogen containing] hormonal contraception associated with 
inhibition of ovulation [oral, intravaginal, transdermal]; partner’s use of progestogen only 
hormonal contraception [oral, injectable/implantable, intrauterine hormone]; partner’s 
use of implantable intrauterine device; partner’s use of female cap or diaphragm (double 
barrier); surgical sterilization [e.g., vasectomy or partner’s bilateral tubal occlusion]) 
during the treatment period and for 104 days after the final dose of entrectinib to avoid 
exposing the embryo.  Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of preventing drug exposure.  If required per local guidelines or 
regulations, information about the reliability of abstinence will be described in the local 
ICF. 
 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from study entry: 
 
Women of childbearing potential, women or are pregnant or breastfeeding, or intending to 
become pregnant during the study or within 14 days after the final dose of entrectinib or 
have a pregnant partner.  
 
All women must have a negative serum pregnancy test at screening and a negative 
urine test at every admission. 
 
A clinical significant medical history of gastrointestinal surgery (e.g., gastric bypass) or other 
gastrointestinal disorder (e.g., malabsorption syndrome) that might affect absorption of 
medicines from the gastrointestinal tract. 
 
Presence of a clinically significant disease, illness, medical condition or disorder, or any 
other medical history determined by the investigator to be clinically significant and relevant.  
Ongoing chronic disorders which are not considered clinically significant are permissible 
providing they are stable. 
 
A clinically significant abnormality in laboratory test results.  In case of borderline or 
questionable results, tests may be repeated to confirm eligibility.  Red blood cell count must 
not be lower than the lower limit of normal (RBC<LLN). 
 
A clinically significant abnormal physical examination finding. 
 
QTcF interval >450 msec or the presence of any other abnormal ECG finding, which, in the 
investigator’s opinion, is clinically significant. 
 
Confirmed by repeat (e.g., 2 consecutive measurements) systolic blood pressure greater 
than 140 or less than 90 mmHg, or diastolic blood pressure greater than 90 or less than 50 
mmHg, or resting pulse rate greater than 90 or less than 40 beats per minute. 
 
Clinically significant change in health status, as judged by the investigator, or any major 
illness within the four weeks before screening, or clinically significant acute infection or 
febrile illness within the 14 days before screening. 
 
Any other ongoing condition or disease, or laboratory test result, that the investigator 
considers would render the participant unsuitable for the study, place the subject at undue 
risk, interfere with the ability of the subject to complete the study, or confound interpretation 
of study data. 
 
Use of moderate or potent inhibitors or inducers of CYP P450 3A4 enzyme or P gp 
transporter within the 28 days before screening, or use of other prohibited medications 
within the 7 days before screening. 
 
Participation in any other clinical study involving an investigational medicinal product (IMP) 
or device within 3 months prior to planned dosing day (Day 1). 
 
A positive test result for hepatitis B, hepatitis C (HCV), or human immunodeficiency virus 
(HIV). 

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 
Recent history of alcoholism, drug abuse, or addiction within the last year prior to screening, 
or a positive test for alcohol or drugs of abuse at screening or admission for each period. 
 
Regular alcohol consumption in males >21 units per week and females >14 units per week 
(1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, 
depending on type). 
 
Current smokers and those who have smoked within the last 12 months.  A confirmed (by 
repeat) breath carbon monoxide reading of greater than 10 ppm at screening or admission 
for each period. 
 
Current users of e-cigarettes and nicotine replacement products and those who have used 
these products within the last 12 months 
 
Known history of clinically significant hypersensitivity, or severe allergic reaction, to 
entrectinib or related compounds. 
 
Presence or history of clinically significant allergy requiring treatment, as judged by the 
investigator.  Hay fever is allowed unless it is active. 
 
Donation or loss of over 400 mL of blood within the three months before screening. 
 
Subjects who are study site employees, or immediate family members of a study site or 
Sponsor employee. 
 
Subjects who have previously been enrolled in this study. Subjects who have taken part in 
Part 1 are not permitted to take part in Part 2. 
 
Subjects who do not have suitable veins for multiple venepunctures/cannulation as 
assessed by the investigator or delegate at screening. 
 
Failure to satisfy the investigator of fitness to participate for any other reason. 
End of Study 
The end of this study is defined as the date when the last subject, last visit occurs or safety 
follow-up is received from the last subject, whichever occurs later.  The end of the study is 
expected to occur up to 10 weeks after the last subject is enrolled. 
Length of Study 
The total duration of the study for each enrolled subject (screening through to end of study) will 
be up to 10 weeks for subjects in Part 1 and up to 8 weeks for subjects in Part 2. 
Investigational Medicinal Products 
The IMP for this study is entrectinib; all treatments will be administered orally. 
Test Product (Investigational Drug)  
Part 1  
Multi-particulate formulation 1: Entrectinib film-coated mini-tablets, 600 mg (240 × 2.5 mg) (Ro 
710 2122/F15)  
Multi-particulate formulation 2: Entrectinib film-coated mini-tablets, 600 mg (240 × 2.5 mg) (Ro 
710 2122/F16)  
Part 2 
Entrectinib F06 hydroxypropyl methylcellulose (HPMC) capsules (coarse active pharmaceutical 
ingredient [API]), 200 mg  
Comparator 
The reference treatment in Part 1 and Part 2 is entrectinib (RXDX-101) F06 hard capsules (fine 
API), 200 mg (Ro 710-2122/F04) 
Statistical Methods 
Primary Analysis 
The plasma pharmacokinetics of entrectinib and M5 will be summarized by estimating the 
following PK parameters (as appropriate for data collected): 
 
tmax: the time to maximum plasma concentration  
 
Cmax: the maximum observed plasma concentration 

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 
AUC0-t: the area under the concentration-time curve from Hour 0 to the last measurable 
concentration, calculated using the linear trapezoidal rule for increasing concentrations and 
the logarithmic rule for decreasing concentrations 
 
AUC0-inf: area under the concentration-time curve extrapolated to infinity 
 
AUC%extrap: the percentage of AUC0-inf accounted for by extrapolation of the apparent 
elimination slope from Ct to infinity  
 
Z: apparent terminal elimination rate constant  
 
t1/2: apparent terminal elimination half-life (whenever possible) 
 
Vz/F: apparent volume of distribution base on area for oral dose 
 
CL/F: apparent clearance following oral dosing 
 
MPR: metabolite to parent ratio of AUC0-inf, where appropriate 
 
Frel: relative bioavailability for AUC0-inf, where appropriate 
The primary parameters for analysis will be Cmax and AUC0-inf of entrectinib and M5.  A linear 
mixed model will be applied to analyze the log-transformed primary pharmacokinetic 
parameters.  The model assumes fixed effects for treatment, period, and sequence, and a 
random effect for subject nested within sequence.  Estimates of geometric mean ratios on the 
original scale, together with the corresponding 90% CIs, will be derived for the comparisons 
between test and reference treatments. 
Determination of Sample Size   
It is planned that total of 15 subjects will be enrolled in Part 1 and 16 subjects will be enrolled in 
Part 2 of the study to achieve 12 evaluable subjects in each part.  Subjects who withdraw from 
the study may be replaced at the discretion of the Sponsor and investigator to ensure that in 
each part 12 subjects complete the study and have evaluable pharmacokinetic data from all 
treatment periods. 
The sample size has been chosen to ensure that the ratios of the geometric means for the 
pharmacokinetic parameters of entrectinib can be estimated with sufficient precision.  In a 
previous study (Study RXDX-101-15) the within-subject coefficients of variation for AUC0-inf and 
Cmax following administration of a single dose of entrectinib were estimated to be 20% and 16%, 
respectively.  Based on a coefficient of variation of 20%, with 12 evaluable subjects it is 
estimated that the lower and upper bounds of the 90% CIs of the ratio will be within 1.25x of the 
corresponding point estimates for each of the two entrectinib pharmacokinetic parameters 
(AUC0-inf and Cmax). 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ALK 
anaplastic lymphoma kinase 
API 
active pharmaceutical ingredient 
BMI 
body mass index 
CNS 
central nervous system 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
HCV 
hepatitis C 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
ISF 
Investigator Site File 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NCI 
National Cancer Institute 
NTRK 
neurotrophic tyrosine receptor kinase 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic 
QTc 
QT interval corrected for heart rate 
QTcF 
corrected QT interval by Fridericia’s formula 
SUSAR 
suspected unexpected serious adverse reaction 
TRK 
tyrosine receptor kinase 
ULN 
upper limit of normal 

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1. 
BACKGROUND 
1.1 
BACKGROUND ON ENTRECTINIB 
Entrectinib (RXDX-101) is a potent inhibitor of the tyrosine receptor kinases (TRK)A 
(encoded by the gene neurotrophic tyrosine receptor kinase [NTRK]1), TRKB (encoded 
by the gene NTRK2), TRKC (encoded by the gene NTRK3), ROS1 (encoded by the 
gene ROS1), and anaplastic lymphoma kinase (ALK; encoded by the gene ALK), with 
median inhibitory concentrations for kinase inhibition in the low nanomolar range (1.7, 
0.1, 0.1, 0.2, and 1.6 nM, respectively).  Gene rearrangements in each of these genes 
have been observed in a variety of tumor types, including non-small cell lung cancer, 
colorectal carcinoma, salivary gland cancers, papillary thyroid cancer, melanoma, and 
sarcomas; overexpression of NTRK2 and ALK and point mutations of ALK have also 
been observed in neuroblastoma.  Thus, a pan-TRK, ROS1, and ALK inhibitor such as 
entrectinib may have broad potential therapeutic utility.  Approval is being sought for use 
of entrectinib in adults and children for oncology indications.  
1.1.1 
Toxicology and Safety Pharmacology 
In in vivo toxicology studies, adverse findings were observed in the skin, liver, central 
nervous system (CNS), and hemolymphopoietic system of both rats and dogs, while 
gastrointestinal toxicity was also observed in dogs.  These effects were dose- and 
exposure-dependent, and exhibited reversibility.  Central and peripheral neurologic 
events were common, consistent with penetration of entrectinib into the CNS and the 
role of TRK receptors in neuronal development and maintenance; signs included 
incoordination, decreased activity, staggering, abnormal gait, tremors, hypoactivity, and 
depression.  In Good Laboratory Practices repeat-dose studies, no observed adverse 
effect levels were 7.5 mg/kg/day in rats and 15 mg/kg/day in dogs. 
Entrectinib inhibited human ether-à go-go-related gene tail current in vitro with a half-
maximal inhibitory concentration of 0.6 μM as free drug (approximating to 120 μM after 
correction for plasma protein binding in humans).  In in vivo preclinical studies, moderate 
but reversible prolongation of the QT interval corrected for heart rate (QTc) was noted on 
electrocardiograms (ECGs) at high doses in dogs. 
Entrectinib was not mutagenic or clastogenic in in vitro or in vivo genotoxicity studies.  
There was no evidence of adverse effects on reproductive organs in repeat-dose 
toxicology studies.  In an embryo-fetal developmental study, oral administration of 
entrectinib to pregnant rats during organogenesis caused developmental abnormalities 
at dose levels that also caused maternal toxicity. 
Entrectinib is not phototoxic based on results from an in vivo rat study.  However, 
microscopic findings in rats of neutrophil infiltrates of corneal stroma and single cell 
necrosis of the corneal epithelium at high doses were considered entrectinib-related. 

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1.1.2 
Clinical Summary 
The pharmacokinetics (PK) of entrectinib and its active metabolite (M5) and safety have 
been evaluated in healthy subjects following single doses of entrectinib in multiple 
clinical pharmacology studies. 
1.1.2.1 
Safety 
Safety data are available from 323 healthy subjects from 10 dedicated single dose 
clinical pharmacology studies.  Single doses of between 100 mg and 800 mg entrectinib 
were generally well tolerated when administered to healthy subjects.  No serious 
adverse events (SAEs) were reported.  The most commonly reported adverse events 
were gastrointestinal disorders or nervous system disorders including oral paresthesia, 
oral hypoesthesia, dysgeusia, constipation, diarrhea, and headache.   
As of 8 March 2018, 394 patients have received entrectinib in the four ongoing clinical 
studies of entrectinib: 57 in study ALKA-372-001 (ALKA), 78 in study RXDX-101-01 
(STARTRK-1), 239 in study RXDX-101-02 (STARTRK-2), and 20 in study RXDX-101-03 
(STARTRK-NG).  Entrectinib has been well tolerated.  Across the 4 main entrectinib 
clinical studies in patients, the most common (ı10% incidence) treatment-related 
adverse events were dysgeusia (39 %), fatigue (31%), dizziness (23%), constipation 
(22%), diarrhea (19%), nausea (19%), paresthesia (17%), weight increased (17%), 
blood creatinine increased (14%), myalgia (14%), vomiting (12%), peripheral edema 
(12%), anemia (11%), and arthralgia (10%).  All adverse events were reversible with 
dose modifications, and importantly, there was no evidence of cumulative toxicity, 
clinically significant hepatic toxicity, or QTc prolongation.  
Across the four main clinical studies, 141 (36%) patients experienced a serious adverse 
event, regardless of causality.  Thirty-one (8%) patients experienced a treatment-related 
serious adverse event.  One fatal treatment-related serious adverse event has been 
reported (sudden death not otherwise specified).  Most treatment-related serious 
adverse events resolved with dose interruption or permanent discontinuation of study 
drug. 
1.1.2.2 
Pharmacokinetics 
Entrectinib is readily absorbed following oral administration with reasonable oral 
bioavailability (31% to 76% in preclinical species) and with peak concentrations typically 
occurring approximately 4 hours after dosing with immediate release capsules 
(Figure 1).  Entrectinib exposure is dose proportional, with no significant dose- or 
time-dependency.  The terminal half-life of entrectinib is approximately 20 to 30 hours. 
Food has no clinically relevant effect on entrectinib oral bioavailability from capsule 
formulations (Figure 1). 

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1.2 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.2.1 
Study Rationale  
An entrectinib capsule formulation is proposed for clinical use by adults and children who 
are able to swallow capsules.  However, an age-appropriate formulation for younger 
children and adult patients with difficulty swallowing is also required.  Two 
multi-particulate formulations (entrectinib film-coated mini-tablets [Ro 710-2122/F15 and 
Ro 710-2122/F16]) have been developed for administration with soft food, one with a 
functional coating for taste masking and one with a simple aesthetic coating.  The 
principal aim of the first part of this study is to explore the in vivo pharmacokinetic 
performance of the two multi-particulate formulations in comparison with the F06 capsule 
formulation (entrectinib [RXDX-101] F06 hard capsule [Ro 710-2122/F04]) under typical 
clinical dosing conditions.  These data will be used in order to support introduction of the 
multi-particulate formulation into an ongoing pediatric study (Study CO40778 
[RXDX-101-03]). 
Physiologically-based pharmacokinetic modelling indicates that particle size of the drug 
substance is not an important factor influencing entrectinib bioavailability, but there are 
limited observed data from clinical dosing to validate this conclusion.  The principal aim 
of the second part of this study is therefore to explore the effect of drug substance 
particle size on entrectinib bioavailability by comparing entrectinib exposures from two 
F06 capsule formulations containing coarsely- and finely-milled drug substance with 
different particle size distributions. 
1.2.2 
Risk-Benefit Assessment 
There will be no therapeutic benefit for the volunteers participating in the study.  
The risks of participation are primarily those associated with adverse reactions to the 
study drug, although there may also be some discomfort from collection of blood 
samples and other study procedures.  The tolerability profile of entrectinib from 
administration of single doses up to 800 mg to healthy subjects has been characterized 
from previous clinical studies.  There have been few adverse events following entrectinib 
dosing in previous clinical studies in healthy volunteers and no specific safety concerns 
have been identified about the use of 600 mg entrectinib in healthy volunteers in this 
study.  Of the potential risks identified in the IB, none require specific monitoring or risk 
mitigation procedures.  Potential drug-drug interactions with other medications are 
addressed by restrictions on concomitant medication use.  Potential risks to a 
developing fetus from entrectinib exposure in utero are addressed by exclusion of 
pregnant females from the study and the requirement for all participants to use effective 
contraception throughout the study. 
Overall, no significant safety concerns have been identified about the use of 600 mg 
entrectinib in healthy volunteers.  All volunteers will be resident in the clinic and remain 
under medical supervision following study drug administration and will undergo a 

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standard battery of safety assessments.  Hence, the risks to participants in this study are 
considered acceptable. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the bioavailability, palatability, safety and tolerability of 
entrectinib in healthy volunteers.  Specific objectives and corresponding endpoints for 
the study are outlined below. 
2.1 
PHARMACOKINETIC OBJECTIVES (PRIMARY STUDY 
OBJECTIVE) 
The primary objectives for this study are to explore the relative bioavailability of 
entrectinib from two multi-particulate formulations and the reference F06 capsule 
formulation under fed conditions (Part 1) and to explore the relative bioavailability of two 
entrectinib F06 capsule formulations under fasted conditions (Part 2) on the basis of the 
following endpoints:  
 
The geometric mean ratio and associated 90% confidence intervals (CI) of 
entrectinib and M5 area under the concentration–time curve from Time 0 to infinity 
(AUC0-inf) and maximum concentration observed (Cmax) parameters 
 
2.2 
SAFETY OBJECTIVE (SECONDARY STUDY OBJECTIVE) 
The safety (secondary) objective for this study is to explore the safety and tolerability of 
a single oral dose of entrectinib in healthy volunteers on the basis of the following 
endpoints: 
 
Incidence and severity of adverse events,  
 
Incidence of abnormalities in laboratory safety tests, physical examinations, 12-lead 
ECGs and vital sign measurements 
  
2.3 
ADDITIONAL OBJECTIVE 
An additional objective for this study is to explore the palatability (taste and acceptability) 
of coated and uncoated multi-particulate formulations on the basis of the following 
endpoint: 
 
Completion of palatability questionnaire  
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a randomized, open-label, single-center, two part study in healthy volunteers to 
explore the performance of entrectinib multi-particulate formulations (Part 1) and the 
effect of drug substance particle size on entrectinib bioavailability (Part 2). 

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Part 1 
Part 1 is a randomized, open-label, three-treatment, three-period, three-sequence, 
three-way crossover design.  In each treatment period, subjects will receive a single 
600 mg oral dose of entrectinib under fed conditions.  Entrectinib will be administered as 
one of three possible formulations: 
 
Multi-particulate formulation 1: Entrectinib film-coated mini-tablets, 600 mg (240 × 
2.5 mg) (Ro 710-2122/F15) (test formulation 1; T1) 
 
Multi-particulate formulation 2: Entrectinib film-coated mini-tablets, 600 mg (240 × 
2.5 mg) (Ro 710-2122/F16) (test formulation 2; T2) 
 
F06 capsule formulation:  Entrectinib (RXDX-101) F06 hard capsules, 3 × 200 mg 
(Ro 710-2122/F04) (reference formulation; R) 
Study treatments will be administered orally within 30 mins of consumption of a 
standardized light “pediatric” breakfast.  The composition of the “pediatric” breakfast is 
as follows: 
 
1 hard-boiled egg 
 
2 slices of wholemeal bread 
 
Fruit (e.g., strawberry) jam 
The test formulation, provided in a bottle, will be mixed with approximately one 
tablespoon (~15 mL) of yogurt, which will be swallowed without chewing with 
approximately 240 mL of water.  In each period, palatability (taste and acceptability) of 
the test formulations will be assessed by completion of a questionnaire shortly after drug 
administration. 
The reference formulation will be dosed as 3 x 200 mg capsules, swallowed whole with 
approximately 240 mL of water. 
A total of 15 subjects will be enrolled.  Subjects will be randomly assigned to one of 
three treatment sequences (i.e., T1T2R, T2RT1, RT1T2, [Table 1]) according to a 
pre-specified randomization scheme based on the order of study enrollment. 
Blood samples for measurement of plasma concentrations of entrectinib and its active 
metabolite M5 will be collected before and at intervals up to 96 hours after study drug 
dosing in each period.   
Safety and tolerability will be monitored by clinical and laboratory assessments at 
intervals throughout the study.   
The total duration of the study for each enrolled subject (screening through to end of 
study) will be up to 10 weeks, divided as follows: 

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Clinical Study Report: entrectinib - F. Hoffmann-La Roche Ltd
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Subject Population 
Healthy volunteers, instead of a patient population, have been chosen for this study as 
the US Food and Drug Administration (FDA, 2002) and European Medicines Agency 
(EMA, 2010) guidelines recommend that healthy subjects be included in trials assessing 
bioavailability and bioequivalence. 
Based on the above considerations and target population, healthy female subjects of 
non-childbearing potential and healthy male subjects, aged ≥18 and ≤60 years are 
considered suitable for this study.   
 
3.3.2 
Rationale for Entrectinib Dose and Schedule 
Part 1  
The recommended dose of entrectinib for cancer patients is 600 mg once daily and 
600 mg is therefore the dose chosen for Part 1.  Single doses of entrectinib up to 
800 mg have been administered to healthy volunteers in previous clinical pharmacology 
studies without notable safety or tolerability findings.   
Entrectinib will be given with food in order to match dosing instructions for patients in 
pivotal and supportive clinical trials, which recommend administering entrectinib within 
30 minutes following a meal.  Following advice from the US FDA on pharmacokinetic 
bridging between F1 and F06 formulations, the meal composition (i.e., size and fat 
content) has been selected in order to be representative of a typical breakfast for a 
pediatric population. 
Part 2 
The recommended dose of entrectinib for cancer patients is 600 mg once daily 
administered as 3 × 200-mg capsules, and so a single dose of the highest available 
capsule strength (200 mg) will be used in Part 2.  Single doses of entrectinib up to 
800 mg have been administered to healthy volunteers in previous clinical pharmacology 
studies without notable safety or tolerability findings. 
3.3.3 
Rationale for Pharmacokinetic Sampling Schedule  
The pharmacokinetic sampling schedule has been selected on the basis of data from 
previous studies in which single doses of entrectinib have been administered to healthy 
volunteers and patients.  The frequent sampling schedule that follows the single dose of 
entrectinib is designed to capture data at a sufficient number of time points to provide a 
detailed profile of the absorption, distribution, and elimination of this drug, including time 
to maximum observed concentration (tmax) and terminal half-life (t1/2). 

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4. 
MATERIALS AND METHODS  
4.1 
SUBJECTS 
Approximately 31 (15 in Part 1 and 16 in Part 2) healthy male and female volunteers will 
be enrolled at one investigative site located in the UK. 
Up to 4 replacement subjects per study part are permitted in this study to ensure 
sufficient evaluable subjects; a maximum of 19 subjects in Part 1 and 20 subjects in 
Part 2 may be dosed in each study part. 
Quotient Sciences (the Clinical Research Unit) must have a full medical history from 
each subject’s general practitioner within the last 12 months, prior to enrollment in the 
study.  
Before subjects are admitted to the clinic, The Over Volunteering Prevention System 
(TOPS) will be checked to ensure that each subject has not participated in a study at 
another site within at least 3 months of the dosing date. 
4.1.1 
Inclusion Criteria 
Subjects must meet the following criteria for study entry: 
1. 
Able and willing to comply with the study restrictions and to give written informed 
consent before any study procedure.  
2. 
Healthy male or female subjects of non-childbearing potential aged 18 to 60 years, 
inclusive, at time of signing Informed Consent Form (ICF) 
3. 
A body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive, and weighing 
≥50 kg, at screening. 
4. 
Healthy in the opinion of the investigator.  Healthy is defined by the absence of 
evidence of any active disease or clinically significant medical condition based on a 
detailed medical history, physical examination, vital signs and 12-lead ECG 
assessment, and laboratory safety test results. 
5. 
Agreement to comply with measures to prevent pregnancy and restrictions on egg 
and sperm donation. 
 
Female subjects of non-childbearing potential do not need to use any methods of 
contraception.  Non-childbearing potential is defined as either post-menopausal (at 
least 12 months without a period [i.e., amenorrhea]; in a woman at least 45 years of 
age and documented by a serum follicle stimulating hormone (FSH) level consistent 
with postmenopausal status [e.g., 40 IU/L]), or surgically sterile (e.g., bilateral 
oophorectomy, bilateral salpingectomy, hysterectomy; note: tubal ligation is not 
considered an appropriate method of surgical sterilization) for at least 90 days.   
  
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom plus an approved method of effective contraception, and agreement 
to refrain from donating sperm, as defined below: 

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With a female partner of childbearing potential, men must remain abstinent or 
use a condom plus an approved method of effective contraception (partner’s 
use of combined [estrogen and progestogen-containing] hormonal 
contraception associated with inhibition of ovulation [oral, intravaginal, 
transdermal]; partner’s use of progestogen-only hormonal contraception [oral, 
injectable/implantable, intrauterine hormone]; partner’s use of implantable 
intrauterine device; partner’s use of female cap or diaphragm (double barrier); 
surgical sterilization [e.g., vasectomy or partner’s bilateral tubal occlusion]) 
during the treatment period and for 104 days after the final dose of entrectinib 
to avoid exposing the embryo.  Men must refrain from donating sperm during 
this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local ICF. 
Inclusion criterion 4 from the list above will be reassessed at admission/pre-dose in 
Period 1.   
 
4.1.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from study entry: 
1. Women of childbearing potential, women who are pregnant or breastfeeding, or 
intending to become pregnant during the study or within 14 days after the final 
dose of entrectinib or have a pregnant partner.  
All women must have a negative serum pregnancy test at screening and 
a negative urine test at every admission. 
2. A clinical significant medical history of gastrointestinal surgery (e.g., gastric 
bypass) or other gastrointestinal disorder (e.g., malabsorption syndrome) that 
might affect absorption of medicines from the gastrointestinal tract. 
3. Presence of a clinically significant disease, illness, medical condition or disorder, 
or any other medical history determined by the investigator to be clinically 
significant and relevant.  Ongoing chronic disorders which are not considered 
clinically significant are permissible providing they are stable. 
4. A clinically significant abnormality in laboratory test results.  In case of borderline 
or questionable results, tests may be repeated to confirm eligibility.  Red blood 
cell count be lower than the lower limit of normal (RBC<LLN). 
5. A clinically significant abnormal physical examination finding. 
6. QTcF interval >450 msec or the presence of any other abnormal ECG finding, 
which, in the investigator’s opinion, is clinically significant. 
7. Confirmed by repeat (e.g., 2 consecutive measurements) systolic blood pressure 
greater than 140 or less than 90 mmHg, or diastolic blood pressure greater than 

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90 or less than 50 mmHg, or resting pulse rate greater than 90 or less than 40 
beats per minute. 
8. Clinically significant change in health status, as judged by the investigator, or any 
major illness within the four weeks before screening, or clinically significant acute 
infection or febrile illness within the 14 days before screening. 
9. Any other ongoing condition or disease, or laboratory test result, that the 
investigator considers would render the participant unsuitable for the study, place 
the subject at undue risk, interfere with the ability of the subject to complete the 
study, or confound interpretation of study data. 
10. Use of moderate or potent inhibitors or inducers of CYP P450 3A4 enzyme or 
P-gp transporter within the 28 days before screening, or use of other prohibited 
medications within the 7 days before screening. 
11. Participation in any other clinical study involving an investigational medicinal 
product (IMP) or device within 3 months prior to planned dosing day (Day 1). 
12. A positive test result for hepatitis B, hepatitis C (HCV), or human 
immunodeficiency virus (HIV). 
13. Recent history of alcoholism, drug abuse, or addiction within the last year prior to 
screening, or a positive test for alcohol or drugs of abuse at screening or 
admission for each period. 
14. Regular alcohol consumption in males >21 units per week and females >14 units 
per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 
125 mL glass of wine, depending on type). 
15. Current smokers and those who have smoked within the last 12 months.  A 
confirmed (by repeat) breath carbon monoxide reading of greater than 10 ppm at 
screening or admission for each period. 
16. Current users of e-cigarettes and nicotine replacement products and those who 
have used these products within the last 12 months 
17. Known history of clinically significant hypersensitivity, or severe allergic reaction, 
to entrectinib or related compounds. 
18. Presence or history of clinically significant allergy requiring treatment, as judged 
by the investigator.  Hay fever is allowed unless it is active. 
19. Donation or loss of over 400 mL of blood within the three months before 
screening. 
20. Subjects who are study site employees, or immediate family members of a study 
site or Sponsor employee. 
21. Subjects who have previously been enrolled in this study. Subjects who have 
taken part in Part 1 are not permitted to take part in Part 2. 
22. Subjects who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator or delegate at screening. 
23. Failure to satisfy the investigator of fitness to participate for any other reason. 

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Exclusion criteria 1, 4, 6, 7, 9, 10, 15, 23 from the list above will be re-assessed at 
admission in Period 1.  
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This study is open-label; no blinding is required.  
4.2.1 
Part 1 
Using a computer-generated randomization schedule, subject numbers will be allocated 
to one of three treatment sequences (Table 1) in Part 1.  The allocation will be balanced 
with 5 subjects assigned to each of the treatment sequences.   
Table 1 
Part 1 Treatment Sequences 
Treatment 
Sequence 
Period 1 
Period 2 
Period 3 
T1T2R 
Test formulation 1 
Test formulation 2 
Reference formulation 
T2RT1 
Test formulation 2 
Reference formulation 
Test formulation 1 
RT1T2 
Reference formulation 
Test formulation 1 
Test formulation 2 
T1; Test formulation 1 = Multi-particulate formulation 1:  Entrectinib film-coated mini-tablets, 
600 mg (240 × 2.5 mg) (Ro 710-2122/F15)  
T2; Test formulation 2 = Multi-particulate formulation 2:  Entrectinib film-coated mini-tablets, 
600 mg (240 × 2.5 mg) (Ro 710-2122/F16)  
R; reference formulation = F06 capsule formulation:  Entrectinib (RXDX-101) F06 hard 
capsules, 600 mg (3 × 200 mg) (Ro 710-2122/F04) 
 
Eligible subjects will be assigned a unique identification number on the morning of 
dosing in Period 1 according to the code 
 to 
 for Part 1, using the lowest number 
available.  Replacement subjects will be allocated subject numbers 
 to 
, where 
the last 2 digits are the same as those of the original subject (e.g., if Subject 
 
withdraws the replacement will have Subject Number 
).  Replacement subjects will 
be assigned to the same treatment sequence as the subject they replaced.   
A treatment allocation list will be produced prior to dosing using the randomization 
schedule and will be retained in the Investigator Site File (ISF).  
The original randomization schedule and proof of quality control procedures will be held 
by the Data Sciences department at Quotient Sciences until the study is archived, at 
which time the randomization materials will be retained in the ISF. 
4.2.2 
Part 2 
Using a computer-generated randomization schedule, subject numbers will be allocated 
to a treatment sequence (Table 2) in a 1:1 ratio in Part 2.  The allocation will be 
balanced with 8 subjects assigned to each treatment sequence.  

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Table 2 
Part 2 Treatment Sequences 
Treatment Sequence 
Period 1 
Period 2 
TR 
Test formulation 
Reference formulation 
RT 
Reference formulation 
Test formulation 
T = Test formulation; Entrectinib F06 HPMC Capsules (coarse API), 200 mg 
R = Reference formulation; Entrectinib (RXDX-101) F06 hard capsules, 200 mg (fine API) 
(Ro 710-2122/F04) 
 
A treatment allocation list will be produced prior to dosing using the randomization 
schedule and will be retained in the ISF.  
The original randomization schedule and proof of quality control procedures will be held 
by the Data Sciences department at Quotient Sciences until the study is archived, at 
which time the randomization materials will be retained in the ISF. 
Eligible subjects will be assigned a unique identification number on the morning of 
dosing in Period 1 according to the code 
 to 
, using the lowest number available.  
Replacement subjects will be allocated subject numbers 
 to 
, where the last 
2 digits are the same as those of the original subject (e.g., if Subject 
 withdraws the 
replacement will have Subject Number 
).   
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The IMP for this study is entrectinib.  
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
The reference treatment in Part 1 and Part 2, Entrectinib (RXDX-101) F06 hard 
capsules, 200 mg (fine API) (Ro 710-2122/F04) will be provided by the Sponsor as 
capsules for oral administration.  
In Part 1, two multi-particulate formulations will be investigated.  The formulations will be 
manufactured, packaged, and provided by the Sponsor as 2.5 mg film-coated 
mini-tablets for oral administration.  The formulation will be supplied as a 600-mg dose in 
a bottle. 
In Part 2, the test formulation, Entrectinib F06 HPMC Capsules 200 mg (coarse API) for 
oral administration will be manufactured by Quotient Sciences.  
For information on the formulation and handling of entrectinib, see the Investigational 
Medicinal Product Dossier (IMPD).  

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4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Refer to the dosing instructions for detailed instructions on drug preparation, storage, 
and administration. 
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.3.5. 
Guidelines for treatment interruption or discontinuation for subjects who experience 
adverse events are provided in Section 4.6. 
4.3.2.1 
Entrectinib 
In Part 1, each subject will be randomized to receive a single oral dose of 600 mg 
entrectinib in each of three treatment periods; the following formulations will be 
administered: 
 
Multi-particulate formulation 1: Entrectinib film-coated mini-tablets, 600 mg (240 × 
2.5 mg) (Ro 710-2122/F15) (test formulation 1; T1) 
 
Multi-particulate formulation 2: Entrectinib film-coated mini-tablets, 600 mg (240 × 
2.5 mg) (Ro 710-2122/F16) (test formulation 2; T2) 
 
F06 capsule formulation: Entrectinib (RXDX-101) F06 hard capsules, 600 mg (3 × 
200 mg) (Ro 710-2122/F04) (reference formulation; R) 
The test formulation will be mixed with approximately one tablespoon (~15 mL) of 
yoghurt which will be swallowed without chewing with approximately 240 mL of water. 
The reference formulation will be dosed as 3 × 200 mg capsules, swallowed whole with 
approximately 240 mL of water.  Additional water may be given with the IMP if required. 
In Part 2, each subject will be randomized to receive a single oral dose of 200 mg 
entrectinib under fasted conditions in each of two treatment periods; the following 
formulations will be administered: 
 
Entrectinib F06 HPMC capsules (coarse API), 200 mg (test formulation; T) 
 
Entrectinib (RXDX-101) F06 hard capsules, 200 mg (Ro 710-2122/F04) (fine API) 
(reference formulation; R) 
The formulations will be dosed as 1 × 200 mg capsules, swallowed whole with 
approximately 240 mL of water after an overnight fast (minimum 8 hours). 
4.3.3 
Investigational Medicinal Product Accountability 
Quotient Sciences will manufacture the Entrectinib F06 HPMC capsules (coarse API).  
The Entrectinib (RXDX-101) F06 hard capsules (fine API) (Ro 710-2122/F04) and the 

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multi-particulate formulations (Entrectinib film-coated mini-tablets), will be provided by 
the Sponsor.  
The study site will acknowledge receipt of IMPs supplied by the Sponsor by returning the 
appropriate documentation form to confirm the shipment condition and content.  Any 
damaged shipments will be replaced. 
Investigational medicinal products (IMPs) will either be disposed of at the study site 
according to the study site's institutional standard operating procedure or be returned to 
the Sponsor with the appropriate documentation.  The site's method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, topical medications, herbal or homeopathic remedies, 
nutritional supplements) used by a subject in addition to protocol-mandated treatment 
from screening until the Follow-up phone call (12 to 14 days after the last dose of study 
drug).  All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy  
Paracetamol up to 4 g per day, medications to treat adverse events, vitamins and 
minerals, hormonal contraceptives and hormone replacement therapy are allowed 
throughout the study.  Other medications for chronic, non-clinically significant, conditions 
(e.g., thyroid hormone replacement medication) may be permitted providing the subject 
has been on a stable dose and dosing regimen for at least 3 months preceding 
screening. 
If any medication is required, the name, strength, frequency of dosing and reason for its 
use will be documented in the subject's source data. 

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4.4.2 
Prohibited Therapy 
Subjects should not take any prescription or over-the-counter medication from 14 days 
prior to dosing until after the Follow-up phone call (12 to 14 days after the last dose of 
study drug) unless the investigator has given prior consent.  The following categories of 
medication are specifically prohibited: 
 
Moderate or potent inhibitors or inducers of CYP3A enzymes or P-gp transporter. 
 
Gastric pH-modifying agents such as proton pump inhibitors, H2 receptor 
antagonists, and antacids. 
 
Psychoactive drugs or other drugs used for mental disorders.  Examples include 
antidepressants, anti-psychotics, sedatives, and stimulants. 
 
4.4.3 
Prohibited Food 
Subjects should refrain from eating food containing poppy seeds for 48 hours prior to 
screening and for 48 hours prior to admission until 96 hours post-dose in each period. 
Subjects should not consume grapefruit, Seville oranges or food and beverages 
containing caffeine/xanthines during the study (from 24 hours prior to admission in 
Period 1 until 96 hours post-dose in each period).   
Subjects will be required to refrain from smoking from 12 months prior to screening until 
96 hours after the final dose of IMP, and abstain from consumption of alcohol during the 
24 hours prior to screening and from admission to the clinic in Period 1 until 96 hours 
post-dose in each period.  
4.4.4 
Additional Restrictions 
No food or fluids other than water will be allowed for 8 hours prior to each study visit until 
after study laboratory samples are obtained (see Appendix 1).  
In Part 1, subjects will be provided with a light snack on the evening of Day -1 and will 
fast from all food and drink (except water) until the following morning, when they will be 
provided with a pediatric breakfast.  The breakfast should be consumed over a 
maximum period of 25 minutes, with dosing occurring 30 minutes after the start of 
breakfast.  Subjects should be encouraged to eat their meal evenly over the 25-minute 
period.  It is acknowledged that some subjects will take less time to eat, but dosing 
should still occur 30 minutes after the start of breakfast. 
In Part 2, subjects will be provided with a light snack on the evening of Day -1 and no 
food will be allowed until 4 hours after dosing and water will be permitted freely until 
1 hour prior to and after 1 hour following dosing of entrectinib.   
Lunch will be provided at approximately 4 h post-dose, an evening meal at 
approximately 10 h post-dose and an evening snack at approximately 14 h post-dose.  

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On subsequent days, meals will be provided at appropriate times.  Meals will be similar 
among cohorts. 
Subjects will be allowed water up to 1 hour before the scheduled dosing time and will be 
provided with 240 mL of water at 1 hour post dose.  Water will be allowed ad libitum after 
1 h post-dose.  Decaffeinated fluids will be allowed ad libitum from lunch time on the day 
of dosing. 
Subjects should refrain from strenuous exercise from 48 hours prior to admission to the 
clinic and during the period of confinement and will otherwise maintain their normal level 
of physical activity throughout the entire study (i.e., will not begin a new exercise 
program or participate in any unusually strenuous physical exertion). 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each subject.   
There are times where the protocol requires more than one procedure to be completed 
at the same time point.  In these instances, the following will apply to post-dose time 
points: 
Pharmaockinetic samples should take priority over other procedures scheduled at the 
same time point. 
ECGs 
 
Vital signs 
 
PK blood 
sampling 
 
Other 
assessments 
Electrocardiograms should be taken prior to vital signs when both measurements are 
scheduled at the same time point.  Other assessments, e.g., physical examinations etc., 
will be performed within the required time windows.  
All safety assessments will be timed and performed relative to the start of dosing. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled subjects and for subjects who are not subsequently enrolled 
will be maintained at the study site. 
Subjects will be provided with a written explanation of the study at least the day before 
the screening visit.  A physician or nurse will explain to each subject the nature of the 
study, its purpose, expected duration and the benefits and risks involved in study 
participation.  Subjects will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that carry out 
clinical studies in the local area.  Subjects will then be given the opportunity to ask 

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questions and will be informed of their right to withdraw from the study without prejudice.  
After this explanation and before entering the study, the subject will voluntarily sign an 
ICF.  Until written consent has been obtained from the subject, no study specific 
procedure or investigation will be performed.  If an amendment is made to the participant 
information sheet, participants will be re consented to the most current version of the 
ICF(s) where appropriate. 
All screening evaluations must be completed and reviewed to confirm that subjects meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
If the start of the study is delayed for any reason so that the interval between screening 
and first dose exceeds 28 days, all or part of the screening procedures may be repeated 
at the discretion of the investigator.   
This study permits the re-screening of a subject who has discontinued the study as a 
pre-treatment failure (i.e., subject has not been randomized/has not been treated); the 
reason for failure must be temporary and expected to resolve.  If re-screened, the 
subject must be re-consented. 
4.5.2 
Medical History, Concomitant Medication, and Demographic 
Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline (screening). 
In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the subject since 
screening will be recorded.   
Demographic data will include age, sex, and self-reported race/ethnicity. Height and 
weight will be recorded at screening. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening, should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Any abnormality 
identified at baseline (Period 1 admission) should be recorded on the General Medical 
History and Baseline Conditions eCRF.  
Limited, symptom-directed physical examinations should be performed on Day -1, and 
as clinically indicated throughout the study.  Changes from baseline abnormalities 
should be recorded in subject notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.  

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4.5.4 
Vital Signs  
Vital signs will include measurements of pulse rate, and systolic and diastolic blood 
pressure while the subject is in a supine position for 5 minutes, and oral temperature.  
The acceptable deviations from the nominal vital signs measurement time points are:  
 
The pre-dose vital signs measurements will be taken İ 2 hours before dosing.  
 
Post-dose vital signs measurements will be taken ± 15 minutes from the nominal 
post-dose time points. 
 
Discharge vital signs measurements will be taken ± 1 hour from the nominal time 
point. 
 
For return visits vital signs measurements will be taken ± 4 hours from the nominal 
return visit time point. 
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. The Day 1, pre-dose assessment in each 
period will be used as baseline. 
4.5.5 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to The Doctors Laboratory for 
analysis:  
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 
 
Chemistry panel (serum):  sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, 
alkaline phosphatase, ALT, AST, urate, and LDH 
 
Coagulation:  INR, aPTT, and PT 
 
Virology: HIV, hepatitis B surface antigen (HBsAg), Anti-HCV at screening 
 
Follicle Stimulating Hormone (FSH; post-menopausal female subjects only) 
 
Pregnancy test 
All women will have a serum pregnancy test at screening and a urine 
pregnancy test on Day -1 of each period. 
 
Urinalysis (pH, specific gravity, glucose, protein, ketones, blood) and urine drug 
screen samples will be analyzed by dipstick at the clinic.  The urine drug screen will 
test for the following: amphetamines, barbiturates, benzodiazepines, cocaine, 
marijuana/cannabis, methadone, methamphetamine/ecstasy, morphine/opiates, 
phencyclidine, and tricyclic anti-depressants.  Microscopic urinalysis examination, if 
required (sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria) 

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Scheduled blood samples for safety laboratory tests will be taken following an 8-hour 
fast.  The acceptable deviation from the nominal post-dose time point (96 hours) is 
±2 hours.  
Alcohol breath tests and carbon monoxide breath tests will be performed at the clinic.  A 
positive alcohol breath test will exclude that subject from dosing during that admission.  
A carbon monoxide result of greater than 10 ppm will exclude the subject from the study. 
Samples for the following laboratory tests will be sent to 
 
for analysis: 
 
Plasma samples for pharmacokinetic analysis 
For sampling procedures, storage conditions, and shipment instructions, see the Clinical 
Sample Processing Manual. 
The total blood volume for each subject will not exceed 550 mL in a 4-week period.  The 
first 0.5 mL of blood withdrawn via cannula will be discarded. 
Residual pharmacokinetic samples will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed. 
When a subject withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the subject specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.6 
Electrocardiograms 
Single ECG recordings will be obtained at specified time points, as outlined in the 
schedule of activities (see Appendix 1).  The acceptable deviations from the nominal 
ECG measurement time points are: 
 
The pre-dose ECG measurements will be taken İ 2 hours before dosing 
 
Post-dose ECG measurements will be taken ± 15 minutes from the nominal post-
dose time point 
 
Discharge ECG measurements will be taken ± 1 hour from the nominal time point.  
 
For return visits ECG measurements will be taken ± 4 hours from the nominal return 
visit time point.  
ECGs acquired on different days should be as closely time-matched as feasible.  ECG 
recordings may be obtained at unscheduled time points as indicated.  The Day 1, 
pre-dose assessment in each period will be used as baseline.  

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All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the subject has been resting in a supine position for at least 5 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal, whenever feasible.  Circumstances that may induce changes in heart 
rate, including environmental distractions (e.g., television, radio, conversation), should 
be avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the subject's permanent 
study file at the site.  The following should be recorded in the appropriate eCRF:  heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QTcF based 
on the machine readings of the individual ECG tracings.  Any morphologic waveform 
changes or other ECG abnormalities must be documented on the eCRF.  If considered 
appropriate by the Sponsor, ECGs may be analyzed retrospectively at a central 
laboratory. 
If at a particular post dose time point the mean QTcF is  500 ms and/or 60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  If a pharmacokinetic sample is 
not scheduled for that time point, an unscheduled pharmacokinetic sample should be 
obtained.  A decision on study drug discontinuation should be made, as described in 
Section 4.6.1.  The investigator should also evaluate the subject for potential concurrent 
risk factors (e.g., electrolyte abnormalities, co-medications known to prolong the QT 
interval, severe bradycardia). 
4.5.7 
Palatability Questionnaire  
Subjects will be asked to complete the palatability questionnaire presented in 
Appendix 3 at the times indicated in the schedule of activities (Appendix 1).  
4.6 
TREATMENT, SUBJECT, STUDY, AND SITE 
DISCONTINUATION 
4.6.1 
Stopping Criteria  
The study will be halted, and the risk to other subjects evaluated if any of the following 
criteria are met: 
 
A serious adverse reaction (i.e., a serious adverse event considered at least 
possibly related to the IMP administration) in one subject. 
 
Severe non-serious adverse reactions (i.e., severe non-serious adverse events 
considered at least possibly related to the IMP administration) in two subjects in the 

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same cohort of the study, independent of within or not within the same system organ 
class. 
Relatedness will be determined by the investigator. 
If the study is halted, a temporary halt will be submitted to the Medicines and Healthcare 
products Regulatory Agency (MHRA) and ethics committee (EC) in the form of a 
substantial amendment.  The study may be resumed or terminated; however, it will not 
be resumed until a further substantial amendment to resume the study is submitted and 
approved by MHRA and EC. 
In addition, subjects must permanently discontinue study treatment if they experience 
any of the following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the subject's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the subject 
 
Pregnancy 
 
Concurrent illness or requirement for prohibited medication 
 
Experiencing a serious or severe adverse event including but not limited to: 
o corrected QT interval by Fridericia’s formula (QTcF) interval of >500 msec 
or increase in QTcF interval of >60 msec from baseline (confirmed 
following a repeat ECG) 
o ALT concentration >3 × the upper limit of the reference range 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
For a subject who withdraws because of an IMP-related adverse event, every effort will 
be made to ensure the subject completes follow-up procedures.  Any subject withdrawn 
or discontinuing the study prematurely because of an IMP-related adverse event or 
termination of the study will be considered to have completed the study, and will not be 
replaced.  Subjects who discontinue study treatment may be replaced at the discretion of 
the Sponsor and the investigator to ensure a minimum of 12 evaluable subjects in each 
study part.   
A subject is considered evaluable if they have sufficient data to ensure the primary 
objective of the relevant study part is met. 
4.6.2 
Subject Discontinuation from the Study 
Subjects have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a subject from the study at any 
time. 

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Reasons for subject discontinuation from the study may include, but are not limited to, 
the following: 
 
Subject withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Subject non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for subject discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a subject requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.   
For a subject who withdraws because of an IMP-related adverse event, every effort will 
be made to ensure the subject completes follow-up procedures.  Any subject withdrawn 
or discontinuing the study prematurely because of an IMP-related adverse event or 
termination of the study will be considered to have completed the study, and will not be 
replaced.  Subjects who discontinue study treatment may be replaced at the discretion of 
the Sponsor and the investigator to ensure a minimum of 12 evaluable subjects in each 
study part.   
A subject is considered evaluable if they have sufficient data to ensure the primary 
objective of the relevant study part is met. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects 
 
Subject enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the Sponsor and investigator without consultation with the MHRA 
and EC.  The end of the trial must be notified to the MHRA and EC immediately and at 
the latest within 15 days after the study is terminated, clearly explaining the reasons.  A 
description of follow up measures taken for safety reasons if applicable will also be 
provided. 

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If the study is abandoned prior to commencement of any protocol activities, the Principal 
Investigator or Sponsor must notify the EC and MHRA by letter outlining the reasons for 
abandonment of the trial. 
If it becomes necessary to consider termination of the study after dosing has begun, 
dosing may be suspended pending discussion between the investigator and Sponsor. 
Dosing will be stopped immediately on safety grounds. 
The study may be terminated or suspended at the request of the MHRA or EC. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all subjects have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN  
Entrectinib is not approved, and clinical development is ongoing.  The safety plan for 
volunteers in this study is based on clinical experience with entrectinib in completed and 
ongoing studies.  The anticipated important safety risks for entrectinib are described in 
the entrectinib IB. 
Several measures will be taken to ensure the safety of subjects participating in this 
study.  Eligibility criteria have been designed to exclude subjects at higher risk for 
toxicities.  Subjects will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.   
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 

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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.8 for more 
information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
subject at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs subject hospitalization (see Section 5.3.5.9) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the subject's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
subject or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 

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Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 
for reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
All grades of syncope 
 
Congestive heart failure ıGrade 2 
 
QT prolongation ıGrade 2 
 
Cognitive disturbances ıGrade 3 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.6) 
 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a subject exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 

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5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each subject contact.  All 
adverse events, whether reported by the subject or noted by study personnel, will be 
recorded in the subject's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until the Follow-up phone 
call (12 to 14 days after the final dose of study drug). 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all subject evaluation time points.  Examples of 
non-directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events  
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

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Table 3 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by subjects who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse events in Section 5.2.2.
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 4): 

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction,
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the subject or use of concomitant medications known to
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the
occurrence of the event

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Table 4 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the subject's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 

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 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
subject evaluation time points.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between subject evaluation time points 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
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cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the Adverse 
Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 

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 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.4) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).   
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.9 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   

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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The subject has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of subject requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.10 
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
entrectinib, adverse events associated with special situations should be recorded as 
described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 

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In addition, all special situations associated with entrectinib, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 

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 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information 
Medical Monitor contact information: 
Medical Monitors: 
 (Primary) 
 
 (Secondary) 
Telephone Nos.: 
 (Western Europe) 
 
 (Western Europe) 
 
 (Western Europe)   
  
5.4.2 
Reporting Requirements for Serious Adverse Events, Adverse 
Events of Special Interest 
5.4.2.1 
Events that Occur Prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the Follow-up phone call (12 to 14 days after the final dose 
of study drug).  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   

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Instructions for reporting serious adverse events that occur 14 days after the final dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Subjects 
Female subjects will be instructed to immediately inform the investigator if they become 
pregnant during the study or within 44 days after the final dose of study drug.  A paper 
Clinical Trial Pregnancy Reporting Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
subject, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the subject should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.   
5.4.3.2 
Pregnancies in Female Partners of Male Subjects 
Male subjects will be instructed through the ICF to immediately inform the investigator if 
their partner becomes pregnant during the study or within 104 days after the final dose 
of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the pregnancy), either by faxing or by scanning and emailing the form 
using the fax number or email address provided to investigators.  Attempts should be 
made to collect and report details of the course and outcome of any pregnancy in the 
partner of a male subject exposed to study drug.  When permitted by the site, the 
pregnant partner would need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  If the 
authorization has been signed, the investigator should submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  An investigator who is contacted by the male subject or his 
pregnant partner may provide information on the risks of the pregnancy and the possible 
effects on the fetus, to support an informed decision in cooperation with the treating 
physician and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Sections 5.4.2 and 5.6). 

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If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 and 5.6).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female subject exposed to study 
drug or the female partner of a male subject exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 and 5.6). 
5.5 
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the subject 
is lost to follow-up, or the subject withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.  
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the subject's medical record to facilitate source data 
verification.  
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
12 to 14 days after the final dose of study drug [the Follow-up phone call]), if the event is 
believed to be related to prior study drug treatment.  These events should be reported 

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through use of the Adverse Event eCRF.  However, if the EDC system is not available, 
the investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, ECs, and applicable health 
authorities based on applicable legislation. 
Suspected unexpected serious adverse reactions (SUSARs) are adverse events that are 
believed to be related to an IMP and are both unexpected (i.e., the nature or severity is 
not expected from the information provided in the IB) and serious.  SUSARs are subject 
to expedited reporting to the MHRA, EMA, and EC. 
It is the responsibility of the Sponsor to determine whether a reported serious adverse 
event fits the classification of a SUSAR and to notify the investigator of their decision as 
soon as possible. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
 
Entrectinib IB 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.  Reporting requirements will also be based on the 
investigator's assessment of causality and seriousness, with allowance for upgrading by 
the Sponsor as needed. 
It is the responsibility of the Sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible. 
Where expedited reporting is required, the following procedures should be followed. 
Fatal or life-threatening SUSARs 
It is the responsibility of the Sponsor to report fatal or life-threatening SUSARs to the 
MHRA and EMA as soon as possible, but no later than 7 calendar days after they first 
became aware of the reaction.  Any additional relevant information should be sent within 
8 days of the report.  This responsibility may be delegated to the pharmacovigilance 
provider. 

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The Sponsor is required to notify the EC of other SUSARs as soon as possible, but no 
later than 7 calendar days after they first became aware of the reaction.  Any additional 
relevant information should be sent within 8 days of the report. 
Other SUSARs 
It is the responsibility of the Sponsor to report other SUSARs to the MHRA and EMA as 
soon as possible, but no later than 15 calendar days after they first became aware of the 
reaction.  This responsibility may be delegated to the pharmacovigilance provider. 
The investigator is required to notify the EC of other SUSARs as soon as possible, but 
no later than 15 calendar days after they first became aware of the reaction. 
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of an IMP or that would be 
sufficient to consider changes in the IMPs administration or in the overall conduct of the 
study, for instance: 
 
an increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important 
 
Serious adverse events that occur after the subject has completed the clinical study 
where the Sponsor considers them to be a SUSAR 
 
new events related to the conduct of the study or the development of the IMPs and 
likely to affect the safety of the subjects, such as: 
o a serious adverse event which could be associated with the study 
procedures and which could modify the conduct of the study 
o a major safety finding from a newly completed animal study (such as 
carcinogenicity) 
o any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same IMPs in another 
 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary objective of this study is to explore the relative bioavailability of entrectinib 
from two multi-particulate formulations (film-coated mini-tablets), and from two 
entrectinib capsule formulations.  A linear mixed model will be applied to analyze the 
log-transformed primary pharmacokinetic parameters, AUC0-inf and Cmax and descriptive 
statistical summaries will be provided (e.g., mean, median, standard deviation, minimum, 
maximum and n).  Additional statistics will be provided for PK-related data including 
coefficient of variation, geometric mean, geometric coefficient of variation (CV%), and 
geometric n (i.e., the number of subjects with an observation that were included in the 
natural logarithmic transformation).  Subjects will be grouped according to treatment 
actually received and subjects with sufficient data to enable estimation of key 
parameters will be included in the analysis. 

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6.1 
DETERMINATION OF SAMPLE SIZE 
It is planned that total of 15 subjects will be enrolled in Part 1 and 16 subjects will be 
enrolled in Part 2 of the study to achieve 12 evaluable subjects in each part.  Subjects 
who withdraw from the study may be replaced at the discretion of the Sponsor and 
investigator to ensure that in each part 12 subjects complete the study and have 
evaluable pharmacokinetic data from all treatment periods. 
The sample size has been chosen to ensure that the ratios of the geometric means for 
the pharmacokinetic parameters of entrectinib can be estimated with sufficient precision.  
In a previous study (Study RXDX-101-15) the within-subject coefficients of variation for 
AUC0-inf and Cmax following administration of a single dose of entrectinib were estimated 
to be 20% and 16%, respectively.  Based on a coefficient of variation of 20%, with 
12 evaluable subjects it is estimated that the lower and upper bounds of the 90% CIs of 
the ratio will be within 1.25x of the corresponding point estimates for each of the two 
entrectinib pharmacokinetic parameters (AUC0-inf and Cmax). 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of subjects who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race, height, weight, and 
BMI) will be summarized using means, standard deviations, medians, and ranges for 
continuous variables and proportions for categorical variables, as appropriate.  
Summaries will be presented overall and by treatment for each study part separately. 
Demographic and baseline characteristics will be recorded at screening.  
6.4 
SAFETY ANALYSES 
The safety analysis population will consist of all subjects who received at least one dose 
of study drug, with subjects grouped according to treatment received.  
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded as mild, 
moderate, or severe (Section 5.3.3). 
Summary tables will be presented by treatment.  If a subject has more than one episode 
of a particular event, only one episode (the most severe or the strongest causal 
relationship to study drug) will be counted.  A subject with more than one different 
adverse event within a particular body system will only be counted once in the total 
number of subjects experiencing adverse events for the body system.  Similarly, a 

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subject who experiences an adverse event in more than one body system will only be 
counted once in the total number of subjects experiencing adverse events in all body 
systems. 
6.5 
PHARMACOKINETIC ANALYSES 
Plasma concentrations of entrectinib and its active metabolite M5 will be listed and 
summarized by treatment using descriptive statistics.  Individual and mean concentration 
versus time profiles will be plotted.  
The plasma pharmacokinetics of entrectinib and M5 will be summarized by estimating 
the following parameters (as appropriate for data collected): 
 
tmax: the time to maximum plasma concentration  
 
Cmax: the maximum observed plasma concentration 
 
AUC0-t: the area under the concentration-time curve from Hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal rule for increasing 
concentrations and the logarithmic rule for decreasing concentrations 
 
AUC0-inf: area under the concentration-time curve extrapolated to infinity 
 
AUC%extrap: the percentage of AUC0-inf accounted for by extrapolation of the 
apparent elimination slope from Ct to infinity  
 
Z: apparent terminal elimination rate constant  
 
t1/2: apparent terminal elimination half-life (whenever possible) 
 
Vz/F: apparent volume of distribution base on area for oral dose 
 
CL/F: apparent clearance following oral dosing 
 
MPR: metabolite to parent ratio of AUC0-inf, where appropriate 
 
Frel: relative bioavailability for AUC0-inf, where appropriate 
The primary parameters for analysis will be Cmax and AUC0-inf of entrectinib and M5.  A 
linear mixed model will be applied to analyze the log-transformed primary 
pharmacokinetic parameters.  The model assumes fixed effects for treatment, period, 
and sequence, and a random effect for subject nested within sequence.  Estimates of 
geometric mean ratios on the original scale, together with the corresponding 90% CIs, 
will be derived for the comparisons between test and reference treatments. 
6.6 
OTHER ANALYSES 
Palatability questionnaire data will be listed and summarized using descriptive statistics. 
6.7 
INTERIM ANALYSES 
No interim analyses are planned; Part 1 and Part 2 will be analyzed separately.  

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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data.  The sites will be responsible for data capture into the EDC 
system.  In the event of discrepant data, the CRO will request data clarification from the 
site, which the site will resolve electronically in the EDC system. 
The CRO will produce a Data Management Plan that describes the quality checking to 
be performed on the data.  Laboratory data will be sent directly to the CRO, using the 
CRO's standard procedures to handle and process the electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO's data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor's 
standard procedures will be used to handle and process the electronic transfer of these 
data.   
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO's standard procedures.  
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of an EDC system.  The site will receive training 
for appropriate eCRF completion.  eCRFs will be submitted electronically and should be 
handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive subject data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which subject data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 

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instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
subject files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Source Document Identification List.  This includes any protocol 
data to be entered directly into the eCRFs (i.e., no prior written or electronic record of the 
data) and considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ICFs, laboratory test results, and medication inventory records, 
must be retained by the Principal Investigator for 15 years after completion or 
discontinuation of the study or for the length of time required by relevant national or local 
health authorities, whichever is longer.  After that period of time, the documents may be 
destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 

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8.
ETHICAL CONSIDERATIONS
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a US 
Investigational New Drug (IND) Application will comply with US FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample ICF will be provided to the site.  The Sponsor or its designee 
must review and approve any proposed deviations from the Sponsor's sample ICF or 
any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before EC submission.  The final IRB/ECapproved Consent Forms must be provided to 
the Sponsor for health authority submission purposes according to local requirements. 
If applicable, the ICF will contain separate sections for any optional procedures.  The 
investigator or authorized designee will explain to each subject the objectives, methods, 
and potential risks associated with each optional procedure.  Subjects will be told that 
they are free to refuse to participate and may withdraw their consent at any time for any 
reason.  A separate, specific signature will be required to document a subject's 
agreement to participate in optional procedures.  Subjects who decline to participate will 
not provide a separate signature. 
The Consent Forms must be signed and dated by the subject or the subject's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each subject shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
subject to participate.  The final revised EC-approved Consent Forms must be provided 
to the Sponsor for health authority submission purposes. 
Subjects must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
EC policy) during their participation in the study.  For any updated or revised Consent 
Forms, the case history or clinical records for each subject shall document the informed 

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consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the subject or the subject's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each subject's study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the subject, and relevant 
supporting information must be submitted to the EC by the Principal Investigator and 
reviewed and approved by the EC before the study is initiated.  In addition, any subject 
recruitment materials must be approved by the EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the EC.  Investigators are also responsible for 
promptly informing the EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and EC.  Investigators may receive written IND safety reports or 
other safety-related communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their EC and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number.  This means that 
subject names are not included in data sets that are transmitted to any Sponsor location. 
Subject medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) signed by the subject, unless permitted or 
required by law. 
Medical information may be given to a subject's personal physician or other appropriate 
medical personnel responsible for the subject's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
subjects unless required by law.  The aggregate results of any conducted research will 

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be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities; Sponsor monitors, 
representatives, and collaborators; and the EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.5). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, ICFs, and documentation of EC and governmental approval.  In addition, 
at the end of the study, the investigator will receive the subject data, including an audit 
trail containing a complete record of all changes to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on subject safety and 
data integrity to the Sponsor and to the EC in accordance with established EC policies 
and procedures.  The Sponsor will review all protocol deviations and assess whether 
any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 

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Protocol GP41341     Report Number 1100283
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9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by Genentech. 
The study will be conducted at a single-center:  Quotient Sciences, Mere Way, 
Ruddington Fields, Ruddington, Nottingham, NG11 6JS, UK.  
Central facilities will be used for certain study assessments throughout the study (e.g., 
clinical laboratory tests and pharmacokinetic analyses) as specified in Section 4.5.  
Monitoring will be performed by 
 
, United Kingdom. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website: 
www.roche.com/roche global policy on sharing of clinical study information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in subjects involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in subjects involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
Entrectinib—Genentech, Inc. 
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proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Quotient Sciences.  Substantial 
protocol amendments will be submitted to the EC and to regulatory authorities in 
accordance with local regulatory requirements. 
Approval must be obtained from the EC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to subjects or changes that involve logistical or administrative aspects 
only (e.g., change in Medical Monitor or contact information). 

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10. 
REFERENCES 
EMA – Guidance on the investigation of bioequivalence. 20 January 2010. 
Entrectinib Investigator Brochure Version 8 April 2018; Addendum 2, November 2018. 
FDA Guidance: Food effect, bioavailability and fed bioequivalence studies. 2002. 

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Appendix 1  
Schedule of Activities 

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Appendix 1: Schedule of Activities 
  
Entrectinib—Genentech, Inc. 
67/Protocol GP41341, Version 1 – 02 April 2019 
Study Procedures 
Screen. 
Study days in each period 
Follow
-upa 
Days 
-28 
to -2 
-1 
1 
2 
3 
4 
5 
13 to 
15 
Time relative to study drug 
dosing 
 
 
Pre-
dose  
 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
36 
48 
72 
96 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECG 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
x 
 
Vital signsg 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
x 
 
Laboratory safety testsb 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Urine drug screen 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon monoxide breath test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/hepatitis screen 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
AE monitoring 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medication 
monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Report: entrectinib - F. Hoffmann-La Roche Ltd
Protocol GP41341     Report Number 1100283
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Appendix 1: Schedule of Activities 
  
Entrectinib—Genentech, Inc. 
68/Protocol GP41341, Version 1 – 02 April 2019 
Study Procedures 
Screen. 
Study days in each period 
Follow
-upa 
Days 
-28 
to -2 
-1 
1 
2 
3 
4 
5 
13 to 
15 
Time relative to study drug 
dosing 
 
 
Pre-
dose  
 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
36 
48 
72 
96 
 
Study drug administration 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for entrectinib 
and M5 pharmacokineticse 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Palatability questionnaire 
 
 
 
 
x f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the clinic 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Ambulatory clinic visits 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
a: Telephone call 
b: Hematology, serum biochemistry, coagulation, and urinalysis; FSH at screening. Samples should be obtained following a fast of at least 8 
hours.   
c: Serum pregnancy test for all women at screening; urine test on Day -1 of each period.  
d: A complete physical examination at screening, a limited, symptom-directed physical examination on Day -1 of each treatment period.  
Symptom-driven physical examinations may be performed at other times at the investigator’s discretion. 
e: Permissible time windows for pharmacokinetic sampling and other assessments are: pre-dose, any convenient time prior to dosing; 
0.5 to 1 hour, ±0.1 hour; 2 to 8 hours, ±0.25 hour, 12 to 36 hours, ±1 hour, 48 to 96 hours, ±4 hour 
f: Multi-particulate formulation treatment periods in Part 1 only 
g: Pulse rate, systolic and diastolic blood pressure and oral temperature.  
 
 

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Appendix 2  
Schedule of Pharmacokinetic Samples 
Visita 
Time pointa 
Sample Type 
Day 1  
Predose -0.5 h 
Entrectinib and M5 PK (plasma) 
 
0.5 h post-dose 
Entrectinib and M5 PK (plasma) 
 
1.0 
Entrectinib and M5 PK (plasma) 
 
2.0 
Entrectinib and M5 PK (plasma) 
 
3.0 
Entrectinib and M5 PK (plasma) 
 
4.0 
Entrectinib and M5 PK (plasma) 
 
5.0 
Entrectinib and M5 PK (plasma) 
 
6.0 
Entrectinib and M5 PK (plasma) 
 
8.0 
Entrectinib and M5 PK (plasma) 
 
12.0 
Entrectinib and M5 PK (plasma) 
Day 2 
24.0 
Entrectinib and M5 PK (plasma) 
 
36.0 
Entrectinib and M5 PK (plasma) 
Day 3 
48.0 
Entrectinib and M5 PK (plasma) 
Day 4 
72.0 
Entrectinib and M5 PK (plasma) 
Day 5 
96.0 
Entrectinib and M5 PK (plasma) 
PK  pharmacokinetic. 
a Visit and time points are applicable to all periods in both study parts. 
Permissible time windows are: -0.5 hour, any convenient time prior to dosing; 
0.5 to 1 hours, ±0.1 hours; 2 to 8 hours, ±0.25 hour; 12 to 36 hours, ±1 hours; 48 to 
96 hours, ±4 hours 
 

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Appendix 3  
Palatability Questionnaire 
To be completed immediately after taking the multi-particulate with yoghurt. 
Please indicate your answer to the following questions by making a mark on the 
line. 
 
Overall, how did you like taking the multi-particulate in yoghurt? 
 
I did not like it 
I liked it very much 
 
How gritty/lumpy did the multi-particulate in yoghurt feel in your mouth 
(gritty/lumpy means you can feel “bits” in the sample)? 
 
Very gritty/lumpy 
Very smooth 
 
How did you like the feeling of the multi-particulate in yoghurt in your mouth? 
 
I did not like it 
I liked it very much 
 
How did you like the taste/flavour of the multi-particulate in yoghurt? 
 
I did not like it 
I liked it very much 
 

Clinical Study Report: entrectinib - F. Hoffmann-La Roche Ltd
Protocol GP41341     Report Number 1100283
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PRS006 T1 v10.1                                   Sponsor/Quotient Confidential  
 
Protocol Non-Substantial Amendment Number: 02, GP41341 (QSC201525), Version 1.0 
04 JUL 2019 
Page 2 of 6 
Reason for Change: 
The purpose of this protocol amendment is to clarify a typographical error in the current 
version of the Clinical Study Protocol (Version 1.0, dated 02 Apr 2019). The Schedule of 
Activities indicates that a pregnancy test should be performed at the Day 5 return visit; 
however, the footnote and text in Section 4.5.5 of the protocol do not reference a pregnancy 
test on Day 5.  
Genentech have confirmed that this is a typographical error and that pregnancy tests are not 
required on Day 5. The Schedule of Activities will be updated to remove the pregnancy test 
on Day 5. 
A minor formatting update will also be made to the footnotes of the Schedule of Activities.  
As these changes do not significantly affect the scientific value of the trial, or the safety or 
physical or mental integrity of the subjects of the trial, this amendment is considered to be 
non-substantial.  
Section to be Changed: 
Appendix 1: Schedule of Activities 
Revised Schedule of Activities: 

Clinical Study Report: entrectinib - F. Hoffmann-La Roche Ltd
Protocol GP41341     Report Number 1100283
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PRS006 T1 v10.1                                                                                Sponsor/Quotient Confidential  
 
Protocol Non-Substantial Amendment Number: 02, GP41341 (QSC201525), Version 1.0 
04 JUL 2019 
Page 3 of 6 
From: Appendix 1: Schedule of Activities 
Study Procedures 
Screen. 
Study days in each period 
Follow
-upa 
Days 
-28 
to -2 
-1 
1 
2 
3 
4 
5 
13 to 
15 
Time relative to study drug 
dosing 
Pre-
dose  
 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
36 
48 
72 
96 
Informed consent 
x 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
x 
x 
Height and weight 
x 
12-lead safety ECG 
x 
x 
x 
x 
x 
x 
Vital signsg 
x 
x 
x 
x 
x 
x 
Laboratory safety testsb 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Urine drug screen 
x 
x 
Alcohol breath test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon monoxide breath test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/hepatitis screen 
x 
Pregnancy testc 
x 
x 
x 
AE monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medication 
monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Report: entrectinib - F. Hoffmann-La Roche Ltd
Protocol GP41341     Report Number 1100283
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PRS006 T1 v10.1                                                                                Sponsor/Quotient Confidential  
 
Protocol Non-Substantial Amendment Number: 02, GP41341 (QSC201525), Version 1.0 
04 JUL 2019 
Page 4 of 6 
Study Procedures 
Screen. 
Study days in each period 
Follow
-upa 
Days 
-28 
to -2 
-1 
1 
2 
3 
4 
5 
13 to 
15 
Time relative to study drug 
dosing 
 
 
Pre-
dose  
 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
36 
48 
72 
96 
 
Study drug administration 
x 
Blood sampling for entrectinib 
and M5 pharmacokineticse 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Palatability questionnaire 
 
 
 
 
x f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the clinic 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Ambulatory clinic visits 
x 
x 
x 
a: Telephone call 
b: Hematology, serum biochemistry, coagulation, and urinalysis; FSH at screening. Samples should be obtained following a fast of at least 8 
hours.   
c: Serum pregnancy test for all women at screening; urine test on Day -1 of each period.  
d: A complete physical examination at screening, a limited, symptom-directed physical examination on Day -1 of each treatment period.  
Symptom-driven physical examinations may be performed at other times at the investigator’s discretion. 
e: Permissible time windows for pharmacokinetic sampling and other assessments are: pre-dose, any convenient time prior to dosing; 
0.5 to 1 hour, ±0.1 hour; 2 to 8 hours, ±0.25 hour, 12 to 36 hours, ±1 hour, 48 to 96 hours, ±4 hour 
f: Multi-particulate formulation treatment periods in Part 1 only 
g: Pulse rate, systolic and diastolic blood pressure and oral temperature.  
 
 
 

Clinical Study Report: entrectinib - F. Hoffmann-La Roche Ltd
Protocol GP41341     Report Number 1100283
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PRS006 T1 v10.1                                                                                Sponsor/Quotient Confidential  
 
Protocol Non-Substantial Amendment Number: 02, GP41341 (QSC201525), Version 1.0 
04 JUL 2019 
Page 5 of 6 
To: Appendix 1: Schedule of Activities 
Study Procedures 
Screen. 
Study days in each period 
Follow
-upa 
Days 
-28 
to -2 
-1 
1 
2 
3 
4 
5 
13 to 
15 
Time relative to study drug 
dosing 
Pre-
dose  
 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
36 
48 
72 
96 
Informed consent 
x 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
x 
x 
Height and weight 
x 
12-lead safety ECG 
x 
x 
x 
x 
x 
x 
Vital signsg 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
x 
 
Laboratory safety testsb 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Urine drug screen 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon monoxide breath test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/hepatitis screen 
x 
Pregnancy testc 
x 
x 
x 
AE monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medication 
monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Report: entrectinib - F. Hoffmann-La Roche Ltd
Protocol GP41341     Report Number 1100283
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PRS006 T1 v10.1                                                                                Sponsor/Quotient Confidential  
 
Protocol Non-Substantial Amendment Number: 02, GP41341 (QSC201525), Version 1.0 
04 JUL 2019 
Page 6 of 6 
Study Procedures 
Screen. 
Study days in each period 
Follow
-upa 
Days 
-28 
to -2 
-1 
1 
2 
3 
4 
5 
13 to 
15 
Time relative to study drug 
dosing 
 
 
Pre-
dose  
 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
36 
48 
72 
96 
 
Study drug administration 
x 
Blood sampling for entrectinib 
and M5 pharmacokineticse 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Palatability questionnaire 
 
 
 
 
x f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the clinic 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Ambulatory clinic visits 
x 
x 
x 
a: Telephone call 
b: Hematology, serum biochemistry, coagulation, and urinalysis; FSH at screening. Samples should be obtained following a fast of at least 
8 hours.   
c: Serum pregnancy test for all women at screening; urine test on Day -1 of each period.  
d: A complete physical examination at screening, a limited, symptom-directed physical examination on Day -1 of each treatment period.  
Symptom-driven physical examinations may be performed at other times at the investigator’s discretion. 
e: Permissible time windows for pharmacokinetic sampling and other assessments are: pre-dose, any convenient time prior to dosing; 
0.5 to 1 hour, ±0.1 hour; 2 to 8 hours, ±0.25 hour, 12 to 36 hours, ±1 hour, 48 to 96 hours, ±4 hour 
f: Multi-particulate formulation treatment periods in Part 1 only 
g: Pulse rate, systolic and diastolic blood pressure and oral temperature.