Clinical trial NCT03796013
Conditions: Healthy Volunteers
Sponsor: Genentech, Inc.
Start date: 2019-01-10; Completion date: 2019-02-06
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study aims to demonstrate similarities between two different forms of entrectinib (A and C) when administered under fasted conditions in healthy subjects.

Detailed description:

Arms: arm 1: Participants first randomized to this arm will receive a single oral dose of entrectinib form A (reference form) under fasted conditions on Day 1 of each Period. This dose will be followed by a minimum 14-day washout period, after which participants will receive a single oral dose of entrectinib form C (test form) under fasted conditions on Day 1 of Period 2 (Periods 1 and 2 = 6 days). arm 2: Participants first randomized to this arm will receive a single oral dose of entrectinib form C (test form) under fasted conditions on Day 1 of each Period. This dose will be followed by a minimum 14-day washout period, after which participants will receive a single oral dose of entrectinib form A (reference form) under fasted conditions on Day 1 of Period 2 (Periods 1 and 2 = 6 days).
Interventions: intervention 1: Entrectinib Form A intervention 2: Entrectinib Form C
Intervention descriptions: intervention 1: Participants will receive a single oral dose of entrectinib form A under fasted conditions. intervention 2: Participants will receive a single oral dose of entrectinib form C under fasted conditions.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A RANDOMIZED, OPEN-LABEL, TWO-TREATMENT, TWO-
PERIOD, TWO-WAY CROSSOVER STUDY TO INVESTIGATE THE 
BIOEQUIVALENCE OF ENTRECTINIB POLYMORPH FORMS A 
AND C UNDER FASTED CONDITIONS IN HEALTHY SUBJECTS 
NCT Number: 
NCT03796013 
Document Date: 
Protocol Version 1: 05-Nov-2018 
 
 
 


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A RANDOMIZED, OPEN-LABEL, TWO-TREATMENT, TWO-PERIOD, TWO-WAY 
CROSSOVER STUDY TO INVESTIGATE THE BIOEQUIVALENCE OF 
ENTRECTINIB POLYMORPH FORMS A AND C UNDER FASTED CONDITIONS IN 
HEALTHY SUBJECTS 
 
 
 
 
 
Protocol GP41049 
 
Covance Study 8397015 
 
IND 120500 
 
 
for 
 
Genentech, Inc. 
1 DNA Way 
South San Francisco, California USA 94080-4990 
 
 
 
 
by 
 
Covance Early Clinical Segment 
3402 Kinsman Boulevard 
Madison, Wisconsin USA 53704 
 


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STUDY IDENTIFICATION 
Sponsor 
Genentech, Inc. 
 
1 DNA Way 
 
South San Francisco, California USA 94080-4990 
 
Sponsor’s Study Contact 
, PhD 
 
Clinical Pharmacologist 
 
Roche Innovation Centre, Welwyn 
 
Hexagon Place, 6 Falcon Way, Welwyn Garden City 
 
Hertfordshire, United Kingdom, AL7 1TW 
 
Sponsor’s Medical Monitor 
 
 
 
 
Roche Innovation Centre, Basel, Grenzacherstrasse 124 
 
Basel 4070, Switzerland 
 
Study Site 
Covance Clinical Research Unit 
 
1341 West Mockingbird Lane, Suite 200E 
 
Dallas, Texas USA 75247 
 
Principal Investigator 
, MD, CPI 
 
Covance Clinical Research Unit 
 
 
 
Study Institutional 
Review Board 
 
 
 USA 
 
 
Main Clinical Laboratory 
(Obtain information from Form FDA 1572) 
 
Bioanalytical Laboratory 
 
 
 
 
 USA 
 
 


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Protocol Biostatistician 
, MSc 
 
Covance Patient Solutions, Safety, and Data Sciences 
 
 
 
Protocol Pharmacokineticist 
 
 
Covance Clinical Pharmacology Services – Medical & Scientific 
Affairs 
 
 
 
Protocol Medical Writer 
, PhD 
 
Covance Patient Solutions, Safety, and Data Sciences 
 
 


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TABLE OF CONTENTS 
 
1 
SYNOPSIS ........................................................................................................................ 11 
2 
INTRODUCTION ............................................................................................................ 13 
2.1 
BACKGROUND .................................................................................................. 13 
2.1.1 
PHARMACOLOGY ........................................................................... 13 
2.1.2 
TOXICOLOGY AND SAFETY PHARMACOLOGY ...................... 13 
2.1.3 
PHARMACOKINETICS .................................................................... 14 
2.1.4 
CLINICAL PROGRAM ..................................................................... 15 
2.2 
STUDY RATIONALE ......................................................................................... 16 
2.3 
DOSE RATIONALE ............................................................................................ 16 
2.4 
BENEFIT:RISK ASSESSMENT ......................................................................... 16 
3 
STUDY OBJECTIVES AND CORRESPONDING ENDPOINTS ................................. 17 
3.1 
PRIMARY OBJECTIVE ...................................................................................... 17 
3.2 
SECONDARY OBJECTIVE ................................................................................ 17 
3.3 
PRIMARY ENDPOINTS ..................................................................................... 17 
3.4 
SECONDARY ENDPOINTS ............................................................................... 17 
4 
STUDY DESIGN.............................................................................................................. 17 
4.1 
DESCRIPTION OF THE STUDY ....................................................................... 17 
4.2 
RATIONALE FOR STUDY DESIGN ................................................................. 19 
4.3 
RATIONALE FOR SUBJECT POPULATION ................................................... 20 
4.4 
RATIONALE FOR EXPLORATORY ASSESSMENTS .................................... 20 
4.5 
RATIONALE FOR PHARMACOKINETIC SAMPLING SCHEDULE ............ 20 
5 
SUBJECT SELECTION ................................................................................................... 20 
5.1 
SCREENING PROCEDURES ............................................................................. 20 
5.2 
CHECK-IN PROCEDURES ................................................................................ 20 
5.3 
INCLUSION CRITERIA ...................................................................................... 21 
5.4 
EXCLUSION CRITERIA .................................................................................... 21 


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5.5 
REMOVAL OF SUBJECTS FROM STUDY PARTICIPATION ....................... 22 
6 
ASSESSMENT OF SAFETY ........................................................................................... 23 
7 
STUDY PROCEDURES .................................................................................................. 23 
7.1 
SCHEDULE OF STUDY ACTIVITIES .............................................................. 23 
7.2 
STUDY TREATMENT ........................................................................................ 26 
7.2.1 
DRUG SUPPLIES AND ACCOUNTABILITY ................................ 26 
7.2.2 
DOSE PREPARATION AND ADMINISTRATION ........................ 27 
7.3 
REMOVAL OF STUDY BLIND ......................................................................... 28 
7.4 
CONTRACEPTION ............................................................................................. 28 
7.5 
DIET, FLUID, AND ACTIVITY CONTROL ..................................................... 29 
7.6 
CONCOMITANT MEDICATIONS .................................................................... 30 
7.7 
PHARMACOKINETIC BLOOD SAMPLE COLLECTION AND PROCESSING
............................................................................................................................... 31 
7.8 
ANALYTICAL METHODOLOGY ..................................................................... 31 
7.9 
CLINICAL LABORATORY EVALUATIONS .................................................. 31 
7.10 
12-LEAD ELECTROCARDIOGRAMS .............................................................. 32 
7.11 
VITAL SIGNS ...................................................................................................... 32 
7.12 
HOW DO YOU FEEL? INQUIRY ...................................................................... 32 
7.13 
PHYSICAL EXAMINATIONS ........................................................................... 33 
7.14 
CLINIC DISCHARGE PROCEDURES .............................................................. 33 
7.15 
STUDY COMPLETION/EARLY TERMINATION PROCEDURES ................ 33 
8 
ADVERSE EXPERIENCES ............................................................................................ 33 
8.1 
SAFETY PARAMETERS AND DEFINITIONS ................................................ 33 
8.1.1 
ADVERSE EVENTS .......................................................................... 33 
8.1.2 
SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) .......................................................................... 34 
8.1.3 
ADVERSE EVENTS OF SPECIAL INTEREST (IMMEDIATELY 
REPORTABLE TO THE SPONSOR) ............................................... 35 


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8.2 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS .................................................................................................... 35 
8.2.1 
ADVERSE EVENT REPORTING PERIOD ..................................... 36 
8.2.2 
ELICITING ADVERSE EVENT INFORMATION .......................... 36 
8.2.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS ............... 37 
8.2.4 
ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS ........... 37 
8.3 
PROCEDURES FOR RECORDING ADVERSE EVENTS ................................ 38 
8.3.1 
RECORDING ADVERSE EVENTS ON THE CASE REPORT 
FORM ................................................................................................. 38 
8.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO 
SPONSOR............................................................................................................. 43 
8.4.1 
REPORTING REQUIREMENTS FOR FATAL OR LIFE-
THREATENING SERIOUS ADVERSE EVENTS ........................... 44 
8.4.2 
REPORTING REQUIREMENTS FOR ALL SERIOUS ADVERSE 
EVENTS ............................................................................................. 44 
8.4.3 
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR ........................................ 46 
8.4.4 
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS .......... 47 
8.5 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT 
REPORTING PERIOD ......................................................................................... 48 
8.5.1 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES .................................................................... 48 
9 
STATISTICAL ANALYSES ........................................................................................... 49 
9.1 
SAFETY AND TOLERABILITY ANALYSIS ................................................... 49 
9.2 
PHARMACOKINETIC ANALYSIS ................................................................... 49 
9.3 
INTERIM ANALYSIS ......................................................................................... 50 
9.4 
STATISTICAL ANALYSIS OF PHARMACOKINETIC DATA ....................... 50 
9.5 
STATISTICAL ANALYSES OF SAFETY DATA ............................................. 51 
9.6 
SAMPLE SIZE ..................................................................................................... 51 


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9.7 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 51 
10 
ADMINISTRATIVE ASPECTS ...................................................................................... 52 
10.1 
CHANGE IN PROTOCOL................................................................................... 52 
10.2 
INVESTIGATOR MEETING; SITE INITIATION ............................................. 52 
10.3 
DISCLOSURE ...................................................................................................... 52 
10.4 
MONITORING (CLINICAL RESEARCH ASSOCIATE) ................................. 52 
10.5 
INSTITUTIONAL REVIEW BOARD ................................................................. 53 
10.6 
INFORMED CONSENT ...................................................................................... 53 
10.7 
RECORDS ............................................................................................................ 53 
10.7.1 
ELECTRONIC CASE REPORT FORMS ......................................... 54 
10.7.2 
SOURCE DATA DOCUMENTATION ............................................. 54 
10.7.3 
USE OF COMPUTERIZED SYSTEMS ............................................ 55 
10.7.4 
STUDY MEDICATION ACCOUNTABILITY................................. 55 
10.7.5 
DISCLOSURE OF DATA .................................................................. 56 
10.7.6 
RETENTION OF RECORDS............................................................. 56 
10.8 
REFERENCE TO DECLARATION OF HELSINKI/BASIC PRINCIPLES ...... 57 
PRINCIPAL INVESTIGATOR AGREEMENT .......................................................................... 58 
SPONSOR AGREEMENT ........................................................................................................... 59 
REFERENCES ............................................................................................................................. 60 
APPENDIX A – CLINICAL LABORATORY EVALUATIONS ............................................... 61 
APPENDIX B – APPROXIMATE MAXIMUM BLOOD VOLUME COLLECTED ................ 62 
 
TABLE OF TABLES 
 
Table 7-1 
Schedule of Activities ........................................................................................... 24 
Table 7-2 
Pharmacokinetic Sampling Scheme (Periods 1 and 2) ......................................... 26 
Table 7-3 
Clinical Laboratory and Safety Assessment Windows ......................................... 26 
Table 7-4 
Study Drugs .......................................................................................................... 27 
Table 8-1 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
CTCAE ................................................................................................................. 37 


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Table 8-2 
Causal Attribution Guidance ................................................................................. 38 
 
TABLE OF FIGURES 
 
Figure 1 
Median Entrectinib Plasma Concentration versus Time Profile Following a  
Single 600-mg Dose to Healthy Volunteers Under Fed or Fasted Conditions ..... 14 
Figure 2 
Overview of Study Design .................................................................................... 18 
 


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ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last measurable 
concentration 
AUC0-∞ 
area under the concentration-time curve extrapolated to infinity 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
apparent systemic clearance 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CSR 
Clinical Study Report 
Ct 
last measurable concentration 
CV 
coefficient of variation 
CYP 
cytochrome P450 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HDYF? 
How do you feel? 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation/International Council for 
Harmonisation 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 


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IRB 
Institutional Review Board 
IUD 
intrauterine device 
λz 
apparent terminal elimination rate constant 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected through use of Fridericia’s formula  
R 
Reference 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedures 
T 
Test 
t1/2 
apparent terminal elimination half-life 
tmax 
time to maximum observed concentration 
UA 
urinalysis 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
apparent volume of distribution during the terminal elimination phase 
WBC 
white blood cell 
 


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1 SYNOPSIS 
Title of Study: 
A Randomized, Open-Label, Two-Treatment, Two-Period, Two-Way Crossover Study to 
Investigate the Bioequivalence of Entrectinib Polymorph Forms A and C under Fasted 
Conditions in Healthy Subjects 
Objectives: 
The primary objective of this study is: 
• 
To demonstrate bioequivalence between entrectinib polymorph Forms A and C 
under fasted conditions in healthy adult male and female subjects 
The secondary objective of this study is: 
• 
To explore the safety and tolerability of a single 200-mg oral dose of entrectinib 
polymorph Forms A and C in healthy adult male and female subjects 
Methodology/Study 
Design: 
This is a randomized, open-label, 2-treatment, 2-period, 2-way crossover study to 
demonstrate bioequivalence between entrectinib polymorph Forms A and C administered 
under fasted conditions in healthy male and female subjects. Potential subjects will be 
screened to assess their eligibility to enter the study within 27 days (Days -28 to -2) prior 
to study entry. Dosing will be on Day 1 of each period. Replacement subjects may be 
enrolled, only if deemed necessary by the Sponsor. Samples will be collected for analysis 
at specified timepoints. 
Number and General 
Description of Subjects: 
A total of 28 subjects will be enrolled in the study at a single clinical site to complete a 
minimum of 26 subjects. 
Diagnosis and Main 
Criteria for Inclusion: 
Healthy males and females, between 18 and 60 years of age, inclusive, within body mass 
index range of 18.0 to 32.0 kg/m2, inclusive, weighing at least 50 kg at Screening who 
are in good health, as determined by no clinically significant findings from medical 
history, 12-lead electrocardiogram (ECG), clinical laboratory evaluations, and vital 
signs. 
Test Product(s), Dose, 
and Mode of 
Administration: 
Subjects will receive the following 2 treatments in a randomized sequence. Each 
treatment will be dosed as 1 × 200-mg capsule administered orally with 240 mL of water 
after an overnight fast (minimum 8 hours): 
• 
Single 200-mg oral dose of entrectinib F06 capsule formulation Form A 
(Reference formulation) 
• 
Single 200-mg oral dose of entrectinib F06 capsule formulation Form C (Test 
formulation) 
Duration of Treatment: 
Planned Enrollment/Screening Duration:  approximately 4 weeks. 
Length of Each Confinement:  Subjects will be confined at the study site from the time of 
Check-in (Day -1) of each period until Clinic Discharge on Day 5. There will be at least 
a 14-day washout between doses in Periods 1 and 2. There will be a follow-up telephone 
call 12 to 14 days after the last dose of study drug (Period 2). 
Planned Study Conduct Duration:  approximately 8 weeks. 
Criteria for Evaluation:  
Safety 
Safety and tolerability assessments will include recording of adverse events, clinical 
laboratory evaluations, vital sign measurements, physical examinations, and ECGs. 
Criteria for Evaluation:  
Pharmacokinetics 
The following pharmacokinetic (PK) parameters will be derived from the plasma 
concentrations of entrectinib and M5 using the model independent approach:  maximum 
observed concentration (Cmax), time to maximum observed concentration (tmax), area 
under the concentration-time curve from Hour 0 to the last measurable concentration 
(AUC0-t), area under the concentration-time curve extrapolated to infinity (AUC0-∞), 
apparent terminal elimination rate constant (λz), apparent terminal elimination half-life 
(t1/2), apparent systemic clearance (entrectinib only, CL/F), and apparent volume of 
distribution during the terminal elimination phase (entrectinib only, Vz/F). 
Statistical Methods: 
Descriptive statistics (mean, median, minimum, maximum, standard deviation, geometric 
mean, and geometric coefficient of variation) will be calculated for all PK parameters 
and PK concentration data. 
The primary parameters for bioequivalence testing will be Cmax and AUC0-t of 


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entrectinib. A linear mixed model will be applied to analyze the log-transformed primary 
PK parameters. The model assumes fixed effects for treatment, period, and sequence, and 
a random effect for subject within sequence. Estimates of geometric mean ratios on the 
original scale, together with the corresponding 90% confidence intervals (CIs), will be 
derived for the comparisons between Test and Reference treatments. Bioequivalence will 
be concluded if the 90% CIs for the treatment ratios fall within the no-effect boundaries 
of 0.80 and 1.25. 
Descriptive statistics will be calculated on the safety parameters. No formal statistical 
analyses are planned. 
 


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2 INTRODUCTION 
2.1 BACKGROUND 
Entrectinib (RO7102122, formerly known as RXDX-101) is a potent and selective inhibitor of 
TRKA, TRKB, TRKC, ROS1, and ALK receptor tyrosine kinase. These kinases are 
overexpressed or dysregulated in a number of types of cancer with constitutive activity, making 
the growth of the cancer cells dependent on or “addicted” to the abnormal kinases.1,2 Therefore, 
these kinases represent attractive targets for anticancer therapy. 
 
Refer to the Investigator’s Brochure (IB)3 for detailed background information on entrectinib and 
for details on nonclinical and clinical studies. 
2.1.1 PHARMACOLOGY 
Entrectinib selectively inhibits TRKA/B/C, ROS1, and ALK tyrosine kinases at low nanomolar 
concentrations in vitro and is highly potent in inhibiting proliferation of tumor cell lines 
dependent on the expression of these kinases. Treatment of mice bearing different xenograft 
(TRKA- or ALK-dependent) or allograph (ROS1-dependent) tumors with 60 mg/kg entrectinib 
twice daily showed potent growth inhibition of TRKA-dependent tumors and even complete 
regression of ROS1- and ALK-dependent tumors. 
2.1.2 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 (GI) 
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. 
 


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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. 
2.1.3 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 (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 significant effect on oral bioavailability from clinical capsule formulations 
containing acidulant (Figure 1). 
 
Figure 1 
Median Entrectinib Plasma Concentration versus Time Profile Following a 
 
Single 600-mg Dose to Healthy Volunteers Under Fed or Fasted Conditions 
 
Source: Study RXDX-101-154 CSR Figure 14.3. 


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Entrectinib is highly protein bound (≥99%) and has a high apparent volume of distribution 
(approximately 600 L), indicating extensive distribution into body tissues. Data also suggest that 
entrectinib crosses the blood/brain barrier. 
 
Entrectinib is primarily cleared by metabolism, with the majority of a dose being recovered as 
metabolites in feces and very little elimination of parent drug or metabolites via the kidney. 
Based on in vitro incubations, cytochrome P450 (CYP) 3A4 is the primary enzyme responsible 
for the biotransformation of entrectinib, with lesser contributions from other CYPs and Phase II 
enzymes. The M5 metabolite (formed by demethylation) is a major circulating metabolite and is 
also pharmacologically active. 
 
In in vitro drug-drug interaction studies entrectinib exhibited potential to inhibit and induce the 
activities of CYP3A. A study on the interaction with transporters in vitro revealed that 
entrectinib is a poor P-glycoprotein (P-gp) substrate and has the potential to inhibit the 
transporters P-gp (MDR1), breast cancer resistance protein, and MATE1. 
2.1.4 CLINICAL PROGRAM 
The clinical program to date includes 10 healthy volunteer and 5 patient studies:  approximately 
300 healthy volunteers and approximately 400 patients have received one or more doses of 
entrectinib. In patients with NTRK, ROS1, or ALK fusion-positive locally advanced or 
metastatic extracranial solid tumors, antitumor activity has been broadly observed among TRK, 
ROS1, and ALK inhibitor-naïve patients treated with entrectinib, including patients with CNS 
involvement. Based upon particularly compelling clinical safety and efficacy data and an 
assessment of unmet medical need, entrectinib development has focused on 2 patient 
populations, NTRK fusion-positive solid tumors and ROS1 fusion-positive non-small cell lung 
cancer. 
 
In the 4 main entrectinib studies in oncology patients, the most common treatment-related 
adverse events (AEs) 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 AEs were reversible with dose modifications, and there was no evidence of 
cumulative toxicity, clinically significant hepatic toxicity, or clinically significant QTc 
prolongation. In single-dose clinical pharmacology studies, entrectinib doses up to 800 mg have 
been administered to healthy volunteers without significant safety findings. 


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2.2 STUDY RATIONALE 
Entrectinib can exist in 2 polymorphic forms (Forms A and C). 
 
 
 
 
 
 
 
 
 
 Therefore, the principal aim of this study is to compare the 
in vivo pharmacokinetic (PK) performance of 2 capsule formulations containing either 
polymorph Form A or C, 
 
 
2.3 DOSE RATIONALE 
The recommended dose of entrectinib for cancer patients is 600 mg once daily administered as 
3 × 200-mg capsules, and so a single-capsule dose of 200 mg is used for the current study. 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. 
2.4 BENEFIT:RISK ASSESSMENT 
There will be no therapeutic benefit for the healthy subjects 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 to healthy 
subjects has been characterized from previous clinical studies. There have been few AEs 
following entrectinib dosing in previous clinical studies in healthy volunteers and no specific 
safety concerns have been identified about the use of entrectinib in healthy volunteers. 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. 
 


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Overall, no significant safety concerns have been identified about the use of 200 mg entrectinib 
in healthy subjects. All subjects will be resident in the study center and remain under medical 
supervision following each study drug administration and will undergo a standard battery of 
safety assessments. Hence, the risks to participants in this study are considered acceptable. 
3 STUDY OBJECTIVES AND CORRESPONDING ENDPOINTS 
3.1 PRIMARY OBJECTIVE 
The primary objective of this study is: 
• To demonstrate bioequivalence between entrectinib polymorph Forms A and C under 
fasted conditions in healthy adult male and female subjects 
3.2 SECONDARY OBJECTIVE 
The secondary objective of this study is: 
• To explore the safety and tolerability of a single 200-mg oral dose of entrectinib 
polymorph Forms A and C in healthy adult male and female subjects 
3.3 PRIMARY ENDPOINTS 
The primary endpoints are: 
• The geometric mean ratios and associated 90% confidence intervals (CIs) of entrectinib 
and M5 metabolite PK parameters area under the concentration-time curve from Hour 0 
to the last measureable concentration (AUC0-t) and maximum observed concentration 
(Cmax) 
3.4 SECONDARY ENDPOINTS 
The secondary endpoints are: 
• Incidence and severity of AEs and incidence of abnormalities in laboratory safety tests, 
12-lead ECGs, and vital sign measurements 
4 STUDY DESIGN 
4.1 DESCRIPTION OF THE STUDY 
This is a randomized, open-label, 2-treatment, 2-period, 2-way crossover study to demonstrate 
bioequivalence between entrectinib polymorph Forms A and C administered under fasted 
conditions in healthy male and female subjects. In each treatment period, subjects will receive a 




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Subjects will be confined at the study site from the time of Check-in (Day -1) of each period 
until Clinic Discharge on Day 5 in each period. The site will attempt to contact all subjects who 
received at least 1 dose of entrectinib (including subjects who terminate the study early) 
approximately 12 to 14 days after the last study drug administration. A detailed list of 
assessments to be conducted in this study is included in Table 7-1. 
 
In this study, physical examinations, 12-lead ECGs, vital signs, How do you feel? (HDYF?) 
inquiries, and clinical laboratory evaluations (Appendix A) will be performed at specified times 
during the study (for specific timepoints and details on each study variable, refer to Section 7). 
After informed consent has been obtained but prior to initiation of study drug administration, 
only serious AEs (SAEs) caused by protocol-mandated interventions will be reported. After 
study drug administration on Day 1 of Period 1, all AEs, whether volunteered, elicited, or noted 
upon physical examination, will be recorded throughout the study (i.e., from Day 1 of Period 1 
until Early Termination [ET] or until the follow-up telephone call). A schedule of activities is 
presented in Table 7-1. 
 
The end of study is defined as the date of the last scheduled study procedure for the last 
participating subject. 
4.2 RATIONALE FOR STUDY DESIGN 
A crossover design will be used to reduce the residual variability as every subject acts as their 
own control. A single-dose, crossover design is the standard design to compare PK. Subjects will 
be randomized to 1 of 2 treatment sequences to minimize assignment bias. 
 
This study is an open-label investigation because the PK parameters are believed not to be 
subject to bias. The crossover design further minimizes the effect of inter-subject variability. 
Blood sampling up to 96 hours postdose will allow the PK parameters of entrectinib and 
metabolite M5 to be adequately characterized based on prior data. The 14-day washout between 
entrectinib doses is considered sufficient to prevent carryover effects of the treatments based on 
the entrectinib apparent terminal elimination half-life (t1/2) of approximately 20 to 30 hours and 
M5 t1/2 of approximately 40 hours. 
 
Doses will be administered in the fasted state for formulation comparison without the 
confounding effect of food. 


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4.3 RATIONALE FOR SUBJECT POPULATION 
Healthy adult male and female subjects were chosen for inclusion in this study because they are 
free of health problems that could otherwise make them more susceptible to drug toxicity or 
confound the interpretation of the study results, are not routinely using concomitant medications 
that could interact with the study drug, and can provide a standard basis for comparison 
(i.e., control) with less variability. 
4.4 RATIONALE FOR EXPLORATORY ASSESSMENTS 
Not applicable. 
4.5 RATIONALE FOR PHARMACOKINETIC SAMPLING SCHEDULE 
The PK sampling schedule has been selected on the basis of data from previous studies in which 
a single dose of entrectinib was administered to healthy volunteers. The frequent sampling 
schedule is designed to capture data at a sufficient number of timepoints to provide a detailed 
profile of the concentration-time curve, including Cmax, time to maximum observed concentration 
(tmax), and t1/2. 
5 SUBJECT SELECTION 
A total of 28 healthy volunteer male and female subjects who meet all the protocol inclusion 
criteria and none of the exclusion criteria will be enrolled into the study. 
5.1 SCREENING PROCEDURES 
Refer to Table 7-1 for procedures performed for all potential subjects at the Screening visit. 
5.2 CHECK-IN PROCEDURES 
Refer to Table 7-1 for procedures performed at Check-in (Day -1), when subjects will report to 
the study site. 
 
For subjects to continue their participation in the study, the drug and alcohol (as applicable) 
screen (and for females of childbearing potential, the pregnancy test) must be negative and the 
clinical laboratory evaluations must be within the normal laboratory range (unless deemed not 
clinically significant by the Investigator). In addition, continued compliance with concomitant 
medication and other restrictions will be verified. 


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5.3 INCLUSION CRITERIA 
Subjects who meet the following criteria may be included in the study: 
1. Males or females, between 18 and 60 years of age, inclusive, at Screening; 
2. Within body mass index (BMI) range 18.0 to 32.0 kg/m2, inclusive, and weighing at least 
50 kg at Screening; 
3. 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, 12-lead ECG, and laboratory safety 
test results; 
4. Clinical laboratory evaluations (including chemistry panel [fasted at least 8 hours], 
complete blood count [CBC], and urinalysis [UA]) within the reference range for the test 
laboratory, unless deemed not clinically significant by the Investigator. Congenital 
nonhemolytic hyperbilirubinemia (e.g., suspicion of Gilbert’s syndrome based on total 
and direct bilirubin) is acceptable. In case of borderline or questionable results, tests may 
be repeated to confirm eligibility; 
5. Negative test for selected drugs of abuse at Screening (does not include alcohol) and at 
Check-in (Day -1) of Period 1 (does include alcohol; Appendix A); 
6. Negative hepatitis panel (hepatitis B surface antigen and hepatitis C virus antibody) and 
negative human immunodeficiency virus (HIV) antibody screens (Appendix A); 
7. Females will not be pregnant or breastfeeding, and females of childbearing potential will 
agree to use highly-effective contraception as detailed in Section 7.4; 
8. Females of childbearing potential (Section 7.4) must agree to refrain from donating eggs 
during the treatment period and for 6 weeks after the final dose of study drug; 
9. Males will agree to use contraception as detailed in Section 7.4 and will refrain from 
sperm donation from Check-in (Day -1) of Period 1 and for 90 days after the final dose of 
study drug; 
10. Able to comprehend and willing to sign an Informed Consent Form (ICF) and to comply 
with the study protocol and study restrictions. 
5.4 EXCLUSION CRITERIA 
The following will exclude potential subjects from the study: 
1. History of GI surgery (e.g., gastric bypass) or other GI disorder (e.g. malabsorption 
syndrome) that might affect absorption of medicines from the GI tract (cholecystectomy 
will be allowed); 
2. 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 


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relevant. Ongoing chronic disorders that are not considered clinically significant are 
permissible, provided they are stable; 
3. Have a QT interval corrected through use of Fridericia’s formula (QTcF) >450 msec or 
concurrent use of medications that may prolong the QT interval. If the QTcF 
measurement is >450 msec, the ECG will be repeated 2 additional times and a triplicate 
average will be used to determine eligibility; 
4. Confirmed (e.g., 2 consecutive measurements) systolic blood pressure >140 or 
<90 mmHg, diastolic blood pressure >90 or <50 mmHg, or pulse rate >100 or <40 beats 
per minute; 
5. Clinically significant change in health status, as judged by the Investigator, or any major 
illness within 4 weeks prior to Screening, or clinically significant acute infection or 
febrile illness within 14 days prior to Screening; 
6. Any other ongoing condition, disease, or laboratory test result that the Investigator 
considers would render the subject unsuitable for the study, place the subject at undue 
risk, interfere with the ability of the subject to participate in or complete the study, or 
confound interpretation of study data; 
7. Use of moderate or potent inhibitors or inducers of CYP3A enzyme or the transporter 
P-gp within 28 days prior to Screening and during the entire study duration, or use of 
other prohibited medications within 14 days prior to Screening and during the entire 
study duration (see Section 7.6); 
8. Participation in any other clinical study involving an investigational medicinal product 
(IMP) or device within 30 days or 5 half-lives (if known), whichever is longer, before 
Screening; 
9. History of alcoholism, drug abuse, or addiction within 1 year prior to Screening; 
10. History of clinically significant hypersensitivity or severe allergic reaction to entrectinib 
or related compounds; 
11. Poor peripheral venous access; 
12. Donation or loss of over 500 mL of blood or donation of plasma from 3 months prior to 
Screening through Follow-up; 
13. Receipt of blood products within 2 months prior to Check-in (Day -1) of Period 1. 
5.5 REMOVAL OF SUBJECTS FROM STUDY PARTICIPATION 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. The Investigator may remove a subject from the study if, in the Investigator’s opinion, it 
is not in the best interest of the subject to continue the study. Subjects may be discontinued due 
to the following:  change in compliance with inclusion/exclusion criterion that is clinically 
relevant and affects subject safety, occurrence of AEs, occurrence of pregnancy, intake of 


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non-permitted concomitant medication that might affect subject safety or study 
assessments/objectives, etc. Notification of discontinuation will immediately be made to the 
Sponsor’s Study Monitor. In case of premature discontinuation of study participation, efforts will 
be made to perform all final study day assessments (see Section 7.15). The date the subject is 
withdrawn from the study and the reason for discontinuation will be recorded on the subject’s 
electronic Case Report Form (eCRF). All dropouts will be followed until resolution of all their 
AEs or until the unresolved AEs are judged by the Investigator to have stabilized or returned to 
baseline, as applicable. 
 
For subjects who are discontinued by the Investigator or who voluntarily withdraw prematurely 
from the study, replacement subjects will be enrolled only if deemed necessary by the Sponsor. 
Except for replacements, the subjects will be assigned a number by study site staff. Assignment 
of numbers will be in ascending order and no numbers will be omitted. Subject numbers will be 
used on all study documentation. Replacement subjects will be assigned a subject number by 
adding 100 or 1000 to the number of the subject they are replacing (e.g., Subject No. 105 
replaces Subject No. 005). 
 
The entire study may be discontinued at the discretion of the Investigator, Sponsor, or Sponsor’s 
Medical Monitor based on the occurrence of the following: 
• 
AEs unknown to date with respect to their nature, severity, and duration 
• 
Increased frequency, and/or severity, and/or duration of known AEs 
• 
Medical or ethical reasons affecting the continued performance of the 
study 
• 
Difficulties in the recruitment of subjects 
• 
Cancellation of drug development 
6 ASSESSMENT OF SAFETY 
Subjects will undergo safety monitoring during the study, including assessment of the nature, 
frequency, and severity of AEs throughout the study, and clinical laboratory safety testing and 
measurement of ECGs and vital signs at intervals. 
7 STUDY PROCEDURES 
7.1 SCHEDULE OF STUDY ACTIVITIES 
The schedule of activities is presented in Table 7-1. The PK sampling scheme is presented in 
Table 7-2. The clinical laboratory and safety assessment windows are presented in Table 7-3.


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Table 7-1 
Schedule of Activities 
 
Screening 
Periods 1 and 2 
Follow-Upa 
Study 
Procedures 
Days 
-28 to -2 
-1 
1 
2 
3 
4 
5 
12 to 14 
days after 
last dose 
Time (hours) 
relative to 
dosing 
 
Check-In Predose 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 12 24 36 48 72 
96/ 
Discharge/ 
ET 
Confined to the Study Site 
˂−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−˃  
Ambulatory (outpatient) Study 
Site Visits 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Previous Medication and 
Compliance with 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
Physical Examinationc 
X 
 
 
 
 
 
 
Height, Weight, and BMI 
X 
 
 
 
 
 
 
Single 12-Lead Safety ECG 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Vital Signsd 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
Chemistry Panel, CBC, and UAe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Drug and Alcohol Screene 
X 
X 
 
 
 
 
 
 
Hepatitis B, C, and HIV Screene 
X 
 
 
 
 
 
 
FSHe 
X 
 
 
 
 
 
 
Pregnancy Testf 
X 
X 
 
 
 
 
 
 
X 
AE Monitoring (HDYF? Inquiry)g 
 
 
˂−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−˃ 
Concomitant Medication 
Monitoring 
 
 
˂−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−˃  
Randomization (Period 1) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administrationh 
X 
 
 
 
 
 
Blood Sampling for Entrectinib 
and M5 PKi 
 
 
X 
 
X 
X X 
X X 
X X 
X X 
X 
X 
X 
X 
X 
 
AE = adverse event; BMI = body mass index; CBC = complete blood count (hematology); ECG = electrocardiogram; ET = Early Termination; 
FSH = follicle-stimulating hormone; HDYF? = how do you feel?; HIV = human immunodeficiency virus; PK = pharmacokinetic; UA = urinalysis. 


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a Telephone call. 
b Interim medical history only, only includes any medical history that occurred between the end of the Screening visit and the Check-in visit. 
c A routine physical examination on Day -1 of Period 1 and an abbreviated physical examination on Day -1 of Period 2 (Section 7.13). Symptom-driven physical 
examinations may be performed at other times at the Investigator’s discretion. 
d Vital signs include:  oral temperature, respiratory rate, and supine blood pressure and pulse rate. 
e Refer to Appendix A for details and a list of evaluations. Includes alcohol testing at Check-in (Day -1) only. The FSH test is for postmenopausal females only. 
f Females of childbearing potential only. 
g Adverse event checks with interspersed HDYF? inquiries. Adverse events are collected after administration of study drug. 
h There will be at least a 14-day washout between doses in Periods 1 and 2. 
i For PK blood samples collected during the study, also refer to Table 7-2. 


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Table 7-2 
Pharmacokinetic Sampling Scheme (Periods 1 and 2) 
Study 
Day 
Pharmacokinetic Sampling Timepoints 
(Hours) 
Window (+/-) 
Analytes (Matrix) 
Day 1 
Predose 
Any convenient 
time prior to dosing 
Entrectinib and M5 (plasma) 
0.5 
3 minutes 
Entrectinib and M5 (plasma) 
1 
5 minutes 
Entrectinib and M5 (plasma) 
2 
10 minutes 
Entrectinib and M5 (plasma) 
3 
10 minutes 
Entrectinib and M5 (plasma) 
4 
10 minutes 
Entrectinib and M5 (plasma) 
5 
10 minutes 
Entrectinib and M5 (plasma) 
6 
10 minutes 
Entrectinib and M5 (plasma) 
8 
10 minutes 
Entrectinib and M5 (plasma) 
12 
10 minutes 
Entrectinib and M5 (plasma) 
Day 2 
24 
10 minutes 
Entrectinib and M5 (plasma) 
36 
30 minutes 
Entrectinib and M5 (plasma) 
Day 3 
48 
30 minutes 
Entrectinib and M5 (plasma) 
Day 4 
72 
30 minutes 
Entrectinib and M5 (plasma) 
Day 5 
96 
30 minutes 
Entrectinib and M5 (plasma) 
 
Table 7-3 
Clinical Laboratory and Safety Assessment Windows 
Safety Assessment Timepointsa 
Window (+/-) 
Predose 
45 minutes 
0 to 8 hours postdose 
15 minutes 
12 to 36 hours postdose 
1 hour 
Days 3 to 5 
4 hours 
a Safety assessments may include vital signs, electrocardiograms, physical examinations, and clinical laboratory 
assessments. Not all safety assessments will be performed at each timepoint specified. 
7.2 STUDY TREATMENT 
The IMP for this study is entrectinib. 
7.2.1 DRUG SUPPLIES AND ACCOUNTABILITY 
The Sponsor or designee will provide the Investigator with adequate quantities of the study drugs 
(see Table 7-4). 


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Table 7-4 
Study Drugs 
Study Drug 
Entrectinib 
Entrectinib 
Formulationa 
Capsule F06 (Form A, Reference formulation) 
Capsule F06 (Form C, Test formulation) 
Strength 
200 mg 
200 mg 
Supplier 
Genentech 
Genentech 
Manufacturer 
Genentech 
Genentech 
a Specific ingredients/purity will be identified on the Certificate of Analysis (or equivalent) that is supplied with the 
study drug(s). 
 
The lot numbers for the study drugs will be provided to the study site by the 
supplier/manufacturer as soon as available. 
 
Study drugs will be stored at controlled room temperature (not above 25°C) under secure 
conditions. The study drugs will be transferred from the bulk supplies into the subject’s dose 
container by qualified study site employees. Each unit dose container will be appropriately 
labeled. 
 
The Investigator or designee will maintain an accurate record of the receipt of the test materials 
as shipped by the Sponsor or designee, including the date received. One copy of this receipt will 
be returned to the Sponsor when the contents of the test material shipment have been verified. In 
addition, an accurate drug disposition record will be kept, specifying the amount dispensed to 
each subject and the date of dispensation. This drug accountability record will be available for 
inspection at any time. At the completion of the study, the original drug accountability record 
will be available for review by the Sponsor upon request. 
 
If deemed appropriate by the Sponsor, sufficient samples will be randomly selected from the 
supply provided by the Sponsor or designee and retained by the study site to meet the retention 
requirements described in the United States (US) Title 21 Code of Federal Regulations (CFR) 
320.38 and 320.63. 
 
At the completion of the study, all unused drug supplies (except for retention supplies, if 
appropriate) will be returned to the Sponsor or designee or disposed of by the study site, per the 
Sponsor’s or designee’s written instructions. 
7.2.2 DOSE PREPARATION AND ADMINISTRATION 
Each unit dose will be prepared by qualified clinical staff based on the study randomization that 
will be provided by a Covance Biostatistician. 
 
The assigned treatment will be administered on Day 1 of each period: 


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Treatment A: Entrectinib F06 capsule formulation Form A (Reference formulation) 
Treatment C: Entrectinib F06 capsule formulation Form C (Test formulation) 
 
Each dose will be administered orally with approximately 240 mL of room temperature water 
after an overnight fast (minimum 8 hours). A hand and mouth check will be performed to verify 
that the dose administered was swallowed. Subjects will be instructed not to crush, split, or chew 
the entrectinib capsules. Subjects will continue to fast for at least 4 hours following entrectinib 
dosing. 
 
Water (except water provided with entrectinib dosing) will be restricted 1 hour prior to and 
1 hour after each entrectinib administration, but will be allowed ad libitum at all other times. 
 
Doses of entrectinib will be separated by a washout period of at least 14 days. 
 
Appropriate unit doses, as described above, will be administered to consecutively numbered 
subjects. Although the timing of events requires that each subject will be consistently 
administered the appropriate dose at specific times, the exact dose time of consecutive subjects 
may be staggered to obviate the need to have all subjects on precisely the same study schedule. 
For each dose, the subject’s actual time will be recorded in the source documents and transcribed 
into the eCRFs. 
7.3 REMOVAL OF STUDY BLIND 
Not applicable; this is an open-label study and will not be blinded. 
7.4 CONTRACEPTION 
Postmenopausal is defined as at least 12 months without a period (i.e., amenorrhea) in a female 
at least 45 years of age and documented by a serum follicle-stimulating hormone [FSH] level 
consistent with postmenopausal status (i.e., ≥40 IU/L) in the absence of a reversible medical 
iatrogenic cause. Surgically sterile is defined as permanently sterile via hysterectomy, bilateral 
oophorectomy, and/or bilateral salpingectomy by reported medical history and/or medical 
records for at least 90 days prior to Screening. 
 
Females who are not postmenopausal or surgically sterile are of childbearing potential and must 
agree to use one of the following examples of highly-effective contraception (failure rate of <1% 
per year) from the time of signing the informed consent or 10 days prior to Check-in (Day -1) of 
Period 1 and for 6 weeks after the final dose of study drug: 


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• Bilateral tubal ligation 
• Bilateral tubal occlusion (Essure) 
• Vasectomized male partner 
• Hormonal contraceptives that inhibit ovulation 
• Hormone-releasing intrauterine device (IUD) 
• Copper IUD 
 
Male subjects will either be surgically sterile with documented azoospermia (confirmed by 
reported medical history and/or medical records) for at least 90 days prior to Screening, or will 
be required to use the following approved method of contraception from Check-in (Day -1) of 
Period 1 and for 90 days after the final dose of study drug: 
• Male condom with spermicide 
 
For subjects who are exclusively in same-sex relationships or are abstinent (when this is in line 
with the preferred and usual lifestyle of the subject), contraceptive requirements do not apply. If 
a subject who is in a same-sex relationship or abstinent at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception, as described 
previously. 
 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. If a male subject cannot provide proof 
of sterilization by medical records, the subject must agree to either true abstinence or a method 
of birth control, as outlined above. 
 
Male subjects (including men who have had vasectomies) whose partners are currently pregnant 
should use a barrier method with spermicide for the duration of the study through Follow-up. 
This is to ensure that the fetus is not exposed to the drug in the ejaculate. 
7.5 DIET, FLUID, AND ACTIVITY CONTROL 
Subjects will refrain from use of tobacco- or nicotine-containing products (including, but not 
limited to, cigarettes, e-cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine 
lozenges, and nicotine gum) within 6 months prior to Check-in (Day -1) of Period 1 and during 
the entire study. 
 
Subjects will abstain from consuming alcohol- or caffeine-containing foods and beverages for 
72 hours prior to Check-in (Day -1) of Period 1 and during the entire study, unless deemed 
acceptable by the Investigator. 


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Subjects will abstain from consuming grapefruit- or Seville orange-containing foods and 
beverages for 7 days prior to Check-in (Day -1) of Period 1 and during the entire study, unless 
deemed acceptable by the Investigator. 
 
Subjects will refrain from strenuous exercise from 48 hours prior to Check-in (Day -1) of 
Period 1 and during the period of confinement at the study site 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). 
 
With the exception of dosing, as applicable, while confined at the study site, subjects will receive 
a standardized diet at scheduled times that do not conflict with other study-related activities. 
 
See Section 7.2.2 for diet and fluid restrictions in regards to dose administration. 
 
Subjects will remain ambulatory or seated upright for 4 hours following entrectinib 
administration, except as necessitated by the occurrence of an AE(s) and/or study procedures. 
7.6 CONCOMITANT MEDICATIONS 
Subjects should not take any prescription or over-the-counter medication, vitamins, or minerals 
from 14 days prior to Screening and during the study, unless the Investigator has given prior 
consent. The following categories of medication are specifically prohibited from 28 days prior to 
Screening and during the study: 
• Moderate or potent inhibitors or inducers of CYP3A enzyme 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 
anti-depressants, anti-psychotics, sedatives, and stimulants 
 
Acetaminophen (paracetamol) up to 2 g per day, medications to treat AEs, hormonal 
contraceptives, and hormone replacement therapy are allowed throughout the study. Ondansetron 
is permitted as a treatment for nausea for individual subjects at the discretion of the Investigator. 
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 prior to Screening. 
 


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The administration of any other concomitant medications during the study is prohibited without 
prior approval of the Investigator, unless its use is deemed necessary in a medical emergency. 
Any medication taken by a subject during the course of the study, including the name, strength, 
frequency of dosing, and reason for its use, will be documented in the source documents and the 
eCRF. 
7.7 PHARMACOKINETIC BLOOD SAMPLE COLLECTION AND PROCESSING 
Blood samples for PK analysis of entrectinib and M5 levels will be collected via an indwelling 
catheter and/or via direct venipuncture using Vacutainer or equivalent evacuated collection 
tubes. Blood samples will be collected at the timepoints listed in Table 7-2. 
 
Processing, storage, and shipping instructions for these PK blood samples are presented in a 
separate laboratory manual. 
 
After the plasma samples collected in the study are analyzed for entrectinib and M5 
concentrations, any residual samples may be used for analysis such as metabolite profiling and 
identification, interacting drug concentration measurements, ex vivo protein binding, or 
development of PK or pharmacodynamic assays. Residual PK samples will be destroyed no later 
than 5 years after the final Clinical Study Report (CSR) 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 in writing 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. Sample 
retention may be detailed in the laboratory manual. 
7.8 ANALYTICAL METHODOLOGY 
Plasma concentrations of entrectinib and M5 will be determined using a validated liquid 
chromatography tandem mass spectrometry bioanalytical procedure by an external vendor. 
7.9 CLINICAL LABORATORY EVALUATIONS 
Clinical laboratory evaluations (including chemistry panel [fasted at least 8 hours], CBC, and 
UA) will be collected at the timepoints listed in Table 7-1. 
 
Screens for a hepatitis panel and HIV antibody will be performed at Screening. A drug screen for 
selected drugs of abuse (not including alcohol) will be performed at Screening and repeated (but 
including an alcohol breath test) at Check-in (Day -1). A serum qualitative pregnancy test 


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(females of childbearing potential only) and FSH test (postmenopausal females only) will be 
performed at the timepoints specified in Table 7-1. 
7.10 
12-LEAD ELECTROCARDIOGRAMS 
A single 12-lead ECG will be obtained at the timepoints specified in Table 7-1. 
 
To minimize variability in autonomic tone and heart rate, subjects will rest quietly and in a 
supine position for at least 5 minutes prior to recording the ECG. Blood draws, other procedures, 
activity, and environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and between ECG recordings to minimize variability due to 
the effects of activity and stress on cardiac electrophysiology. Whenever possible, ECG tracings 
for each subject should be obtained from the same type of machine throughout the study. 
 
When 12-lead ECGs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained as close as possible 
to the scheduled blood draw, but prior to the blood draw. 
7.11 
VITAL SIGNS 
Vital signs (including oral temperature, respiratory rate, and supine blood pressure and pulse 
rate) will be obtained at the timepoints specified in Table 7-1. 
 
Supine blood pressure and pulse rate will be obtained after the subject has been supine for at 
least 5 minutes. When vital signs are scheduled at the same time as blood draws, the blood draws 
will be obtained at the scheduled timepoint and the vital signs will be obtained as close as 
possible to the scheduled blood draw, but prior to the blood draw. 
7.12 
HOW DO YOU FEEL? INQUIRY 
Subjects will be asked a non-leading HDYF? question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the timepoints specified in 
Table 7-1. Subjects will also be encouraged to voluntarily report AEs occurring at any other time 
during the study. See Section 8.3 and Section 8.4 for reporting requirements for AEs and SAEs, 
respectively. 


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7.13 
PHYSICAL EXAMINATIONS 
A routine or abbreviated physical examination will be performed at the timepoints specified in 
Table 7-1. Symptom-driven physical examinations may be performed at other times at the 
Investigator’s discretion. 
 
A routine physical examination will consist of an assessment of general appearance; skin; 
thorax/lungs; abdomen; lymph nodes; head, ears, eyes, nose, throat, and neck (including 
thyroid); and cardiovascular, musculoskeletal, and neurological systems. An abbreviated 
physical examination will consist of an assessment of general appearance, skin, thorax/lungs, 
cardiovascular system, and abdomen. 
7.14 
CLINIC DISCHARGE PROCEDURES 
Refer to Table 7-1 for procedures performed on the day of discharge. 
7.15 
STUDY COMPLETION/EARLY TERMINATION PROCEDURES 
Refer to Table 7-1 for procedures performed at Follow-up or ET. 
8 ADVERSE EXPERIENCES 
8.1 SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and AEs of 
special interest (AESIs), 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. The Sponsor or its designee is responsible for 
reporting relevant SAEs to the competent authority, other applicable regulatory authorities, and 
participating Investigators, in accordance with the International Conference on 
Harmonisation/International Council for Harmonisation (ICH) guidelines, Food and Drug 
Administration (FDA) regulations, European Clinical Trials Directive (Directive 2001/20/EC), 
and/or local regulatory requirements. 
 
Certain types of events require immediate reporting to the Sponsor, as outlined in Section 8.4. 
8.1.1 ADVERSE EVENTS 
According to the ICH Guideline for Good Clinical Practice (GCP), an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution. An AE can therefore be any of the following: 


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• 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) 
• 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) 
8.1.2 SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE TO THE 
SPONSOR) 
An SAE is any AE that meets any of the following criteria: 
• Is fatal (i.e., the AE actually causes or leads to death) 
• Is life-threatening (i.e., the AE, in the view of the Investigator, places the subject at 
immediate risk of death); this does not include any AE that had it occurred in a more 
severe form or was allowed to continue might have caused death 
• Requires or prolongs inpatient hospitalization 
• Results in persistent or significant disability/incapacity (i.e., the AE 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) 
 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(e.g., rated as mild, moderate, or severe, according to National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE]); the event itself may be of relatively 
minor medical significance (such as severe headache) without any further findings. An event 
should be considered “serious” only if it meets the regulatory criteria outlined in the 
above-mentioned paragraph outlining seriousness criteria. 


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Seriousness (not severity) serves as the guide for defining regulatory reporting obligations. 
 
Severity, seriousness, and causality need to be independently assessed for each AE recorded on 
the eCRF. 
 
Serious AEs are required to be reported by the Investigator to the Sponsor via the Covance 
Project Manager immediately (i.e., no more than 24 hours after learning of the event; see 
Section 8.4.2 for reporting instructions). 
8.1.3 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 
via the Covance Project Manager immediately (i.e., no more than 24 hours after learning of the 
event; see Section 8.4.2 for reporting instructions). Adverse events of special interest for this 
study are as follows: 
• Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either 
an elevated bilirubin or clinical jaundice, as defined by Hy’s Law (see Section 8.3.1.6); 
• Suspected transmission of an infectious agent by the study drug as defined below: 
o 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. The term applies only when a 
contamination of the study drug is suspected. 
• All grades syncope events 
• Grade ≥2 congestive cardiac failure 
• Grade ≥2 QT prolongation 
• Grade ≥3 cognitive disturbances (including confusion, mental status changes, 
hallucinations, or memory loss) 
8.2 METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS 
The Investigator is responsible for ensuring that all AEs (as defined in Section 8.1) are recorded 
on the AE eCRF and reported to the Sponsor via the Covance Project Manager in accordance 
with protocol instructions (see Section 8.4.2). 


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For each AE recorded on the AE eCRF, the Investigator will make an assessment of seriousness 
(see Section 8.1.2 for seriousness criteria), severity, and causality (see Sections 8.2.3 and 8.2.4). 
8.2.1 ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each subject contact. All AEs, whether reported by 
the subject or noted by study personnel, will be recorded in the subject’s medical record and on 
the AE eCRF. 
 
After informed consent has been obtained but prior to initiation of study drug administration, 
only SAEs caused by a protocol-mandated intervention (e.g., discontinuation of medications) 
will be reported (see Section 8.4.2 for instructions for reporting SAEs). After initiation of study 
drug administration, all AEs will be reported until 28 days after the final dose. 
 
Instructions for reporting AEs that occur after the AE reporting period are provided in 
Section 8.5. 
 
The Investigator is not required to actively monitor subjects after the study has ended or for AEs 
after the end of the AE reporting period (defined as 28 days after the final dose of study drug). 
However, the Sponsor should be notified if the Investigator becomes aware of any death, other 
SAEs, or AESIs occurring after the end of the AE reporting period that are believed to be related 
to prior study drug treatment. The Sponsor should also be notified if the Investigator becomes 
aware of the development of cancer or a congenital anomaly/birth defect in a subsequently 
conceived offspring of a female subject exposed to study drug (or the female partner of a male 
subject exposed to study drug). 
8.2.2 ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all subject evaluation timepoints. 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?” 


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8.2.3 ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The AE severity grading scale for the NCI CTCAE (version 5.0) will be used for assessing AE 
severity. Table 8-1 will be used for assessing AE severity for AEs that are not specifically listed 
in the NCI CTCAE. 
 
Table 8-1 
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 livinga 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily 
livingb,c 
4 
Life-threatening consequences or urgent intervention indicatedd 
5 
Death related to adverse eventd 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the 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 an SAE (see Section 8.4.2 for 
reporting instructions), per the definition of SAE in Section 8.1.2. 
d Grade 4 and 5 events must be reported as SAEs (see Section 8.4 for reporting instructions), per the definition of 
SAE in Section 8.1.2. 
8.2.4 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 AE 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 8-2): 
• 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 


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• 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 
Table 8-2 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug based on 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. 
Investigators should apply facts, evidence, or rationales based on scientific principles and clinical 
judgment to support a causal/contributory association with a study drug. 
NO 
Adverse events will be considered related, unless they fulfill the criteria as specified below. 
Evidence exists that the adverse event has an etiology other than the study drug (e.g., pre-existing 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). 
Note:  The Investigator’s assessment of causality for individual adverse event reports is part of the study 
documentation process. Regardless of the “Yes” or “No” causality assessment for individual adverse event 
reports, the Sponsor will promptly evaluate all reported serious adverse events against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to Investigators and 
applicable regulatory authorities. Attribution of serious adverse events will be reviewed on an ongoing 
basis, and may be changed as additional clinical data emerges (e.g., reversibility of adverse event, 
new clinical findings in subject with adverse event, effects of re-treatment, and adverse events in 
other subjects). 
8.3 PROCEDURES FOR RECORDING ADVERSE EVENTS 
8.3.1 RECORDING ADVERSE EVENTS ON THE CASE REPORT FORM 
Investigators should use correct medical terminology/concepts when recording AEs on the AE 
eCRF. Colloquialisms and abbreviations should be avoided. 
 
All AEs should be recorded on the AE eCRF page. If the AE qualifies as an SAE or non-serious 
AESI, the Investigator should record all case details that can be gathered immediately (i.e., 
within 24 hours after learning of the event) on a paper Clinical Trial SAE/AESI Reporting Form. 
The completed paper Clinical Trial SAE/AESI Reporting Form and safety fax coversheet should 
be emailed to Roche Safety Risk Management via the Covance Project Manager within 24 hours 
of learning of the event (see Section 8.4.2). The AE and SAE eCRF should also be completed 
within this timeframe. It is important that the information on the SAE Reporting Form and AE 
and SAE eCRF is consistent and identical. 


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Only 1 AE term should be recorded in the event field on the AE eCRF. 
8.3.1.1 DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
If known, a diagnosis should be recorded on the AE 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 AE eCRF. If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced by 1 AE report 
based on the single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
8.3.1.2 ADVERSE EVENTS THAT ARE SECONDARY TO OTHER EVENTS 
In general, AEs 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 AE that is separated in time from the initiating event 
should be recorded as an independent event on the AE 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. 
• If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
• If dizziness leads to a fall and subsequent fracture, all 3 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 AEs should be recorded separately on the AE eCRF if it is unclear as to whether the events 
are associated. 
8.3.1.3 PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
timepoints. Such events should only be recorded once in the AE eCRF. The initial severity 
(intensity or grade) of the event will be recorded at the time the event is first reported. If a 


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persistent AE becomes more severe, the most extreme severity should also be recorded on the 
AE 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 8.4.2 for 
reporting instructions). The AE eCRF should be updated by changing the event from 
“non-serious” to “serious,” providing the date that the event became serious, and by completing 
all data fields related to SAEs. 
 
A recurrent AE is one that resolves between subject evaluation timepoints and subsequently 
recurs. Each recurrence of an AE should be recorded as a separate event on the AE eCRF. 
8.3.1.4 ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be reported 
as an AE 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 AE. 
 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 times the upper limit of normal [ULN] associated with cholestasis), 
only the diagnosis (i.e., cholestasis) should be recorded on the AE eCRF. 
 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the AE 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 AE. For 
example, an elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
 


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Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the AE eCRF (see Section 8.3.1.3 for details on recording persistent 
AEs). 
8.3.1.5 ABNORMAL VITAL SIGN VALUES 
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported as an 
AE 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 AE. 
 
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 AE eCRF. 
 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the AE eCRF (see Section 8.3.1.3 for details on recording persistent 
AEs). 
8.3.1.6 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 the occurrence of either of the following as an AE: 
• 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 AE eCRF (see Section 8.3.1) and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event), either as an SAE or an 
AESI (see Section 8.4.2). 


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8.3.1.7 DEATHS 
All deaths that occur during the protocol-specified AE reporting period (see Section 8.2.1), 
regardless of relationship to study drug, will be recorded on the AE eCRF as well as on the paper 
Clinical Trial SAE Reporting Form and immediately reported to the Sponsor via the Covance 
Project Manager (see Section 8.4.2 for reporting instructions). 
 
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 AE eCRF. Generally, only 1 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 AE 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 AE reporting period should be reported as described in Section 8.5. 
8.3.1.8 PRE-EXISTING MEDICAL CONDITIONS 
A pre-existing 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 
page. 
 
A pre-existing medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study. When recording such events on an AE 
eCRF, it is important to convey the concept that the pre-existing condition has changed by 
including applicable descriptors (e.g., “accelerated worsening of headaches”). 
8.3.1.9 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any AE that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as an SAE (per the definition of SAE in 
Section 8.1.2) except as outlined below. 
 
An event that leads to hospitalization under the following circumstances should not be reported 
as an AE or SAE: 
• Hospitalization for respite care 
• Hospitalization for a pre-existing condition, provided that all of the following criteria are 
met: 


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o 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 
o The subject has not experienced an AE 
 
An event that leads to hospitalization under the following circumstances is not considered to be 
an SAE but should be reported as an AE instead: 
• Hospitalization that was necessary because of the subject’s requirement for outpatient 
care outside of normal outpatient clinic operation hours 
8.4 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 via the Covance Project Manager; 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 (see Section 8.4.2) after 
learning of the event, regardless of relationship to study drug: 
• SAEs (see Section 8.4.2 for further details) 
• AESIs (see Section 8.1.3 for further details) 
• Pregnancies (see Section 8.4.2.3 for further details) 
• Accidental overdoses or medication errors (see Section 8.4.3 for details on reporting 
requirements) 
 
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately via the Covance Project Manager (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 
• 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 SAEs to the local health 
authority and Institutional Review Board (IRB)/Ethics Committee (EC). 


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8.4.1 REPORTING REQUIREMENTS FOR FATAL OR LIFE-THREATENING 
SERIOUS ADVERSE EVENTS 
Any life-threatening (e.g., imminent risk of death) or fatal AE that is attributed to study drug by 
the Investigator will be telephoned to the Medical Monitor immediately, followed by completion 
of the paper Clinical Trial SAE Reporting Form within 24 hours of learning of the event as 
described in Section 8.4.2. 
 
Medical Monitor: 
 
 
F. Hoffmann-La Roche AG 
 
 (Office Telephone No.) 
 
 (Mobile Telephone No.) 
8.4.2 REPORTING REQUIREMENTS FOR ALL SERIOUS ADVERSE EVENTS 
8.4.2.1 EVENTS THAT OCCUR PRIOR TO STUDY DRUG INITIATION 
After informed consent has been obtained but prior to initiation of study drug, only SAEs caused 
by protocol-mandated intervention should be reported. The paper Clinical Trial SAE/AESI 
Reporting Form provided to the Investigator should be completed and submitted to the Sponsor 
via the Covance Project Manager 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 below. 
 
The Covance Project Manager to receive the Investigator-generated SAE reports: 
Name:  
, RN, BSN, CCRC 
Email Address:  
 
 (Office Telephone No.) 
 (Mobile Telephone No.) 
8.4.2.2 EVENTS THAT OCCUR AFTER STUDY DRUG INITIATION 
After initiation of study drug, SAEs and AESIs will be reported until 28 days after the final dose 
of study drug. Investigators should record all case details that can be gathered immediately on a 
paper Clinical Trial SAE/AESI Reporting Form. The paper Clinical Trial SAE/AESI Reporting 
Form should be completed and submitted to the Sponsor (via the Covance Project Manager) 
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 in 
Section 8.4.2.1. All information will also need to be entered into the AE eCRF. 
 


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Relevant follow-up information should be submitted to Roche Safety Risk Management via the 
Covance Project Manager on an updated paper Clinical Trial SAE/AESI Reporting Form as soon 
as it becomes available and/or upon request. Any updates to the paper Clinical Trial SAE/AESI 
Reporting Form must also be updated in electronic data capture (EDC) on the AE eCRF. 
8.4.2.3 REPORTING REQUIREMENTS FOR PREGNANCIES 
8.4.2.3.1 
PREGNANCIES IN FEMALE SUBJECTS 
Female subjects of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 28 days after the final dose of 
study drug. A paper Clinical Trial Pregnancy Reporting Form should be completed by the 
Investigator immediately (i.e., no more than 24 hours after learning of the pregnancy) and 
emailed to Roche Safety Risk Management via the Covance Project Manager (see Section 8.4.2 
for reporting instructions). Pregnancy should not be recorded on the AE 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 SAEs 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 AE eCRF. In addition, the Investigator will submit a paper Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. 
8.4.2.3.2 
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 28 days after the final dose of study drug. A 
paper Clinical Trial Pregnancy Reporting Form should be completed by the Investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and emailed to Roche 
Safety Risk Management via the Covance Project Manager (see Section 8.4.2 for reporting 
instructions). 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. 


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8.4.2.3.3 
CONGENITAL ANOMALIES/BIRTH DEFECTS AND ABORTIONS 
Any congenital anomaly/birth defect in a child born to a female subject exposed to the study 
drug or the female partner of a male subject exposed to the study drug should be classified as an 
SAE, recorded on the AE eCRF, and reported to the Sponsor immediately via the Covance 
Project Manager (i.e., no more than 24 hours after learning of the event; see Section 8.4.2). Any 
abortion should be reported in the same fashion (as the Sponsor considers abortions to be 
medically significant events). 
8.4.3 REPORTING REQUIREMENTS FOR 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 AEs, but may result in AEs. Each AE associated with a 
special situation should be recorded separately on the AE eCRF. If the associated AE 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 8.4.2). For entrectinib, AEs associated with 
special situations should be recorded as described below for each situation: 
• Accidental overdose:  Enter the AE term. Check the “Accidental overdose” and 
“Medication error” boxes. 
• Medication error that does not qualify as an overdose:  Enter the AE term. Check the 
“Medication error” box. 
• Medication error that qualifies as an overdose:  Enter the AE term. Check the “Accidental 
overdose” and “Medication error” boxes. 
 
In addition, all special situations associated with entrectinib, regardless of whether they result in 
an AE, should be recorded on the AE eCRF and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event). Special situations should be recorded as 
described below: 
• Accidental overdose:  Enter the drug name and “accidental overdose” as the event term. 
Check the “Accidental overdose” and “Medication error” boxes. 


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• 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 the completion 
of 2 AE eCRF pages, one to report the accidental overdose and one to report the headache. The 
“Accidental overdose” and “Medication error” boxes would need to be checked on both eCRF 
pages. 
8.4.4 FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS 
8.4.4.1 INVESTIGATOR FOLLOW-UP 
The Investigator should follow each AE 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 SAEs considered to be related to 
study drug or trial-related procedures until a final outcome can be reported. During the study 
period, resolution of AEs (with dates) should be documented on the AE 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. 
8.4.4.2 SPONSOR FOLLOW-UP 
For SAEs, AESIs, 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. 


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8.5 ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT REPORTING 
PERIOD 
At the Follow-up/ET visit, the Investigator should instruct each subject to report to the 
Investigator any subsequent AEs that the subject’s personal physician believes could be related 
to prior study drug treatment or study procedures. The Sponsor should be notified if the 
Investigator becomes aware of any SAE that occurs after the end of the AE reporting period 
(defined as 28 days after the final dose of study drug) if the event is believed to be related to 
prior study drug treatment. 
 
These events should be reported through the use of the AE eCRF. However, if the EDC system is 
not available, the Investigator should report these events directly to the Sponsor or its designee, 
by faxing or by scanning and emailing the paper Clinical Trial SAE/AESI Reporting Form using 
the below fax number or email address provided to Investigators. 
 
Genentech US Drug Safety 
Email Address: 
us_drug.safety@gene.com 
Fax No.: 
 
(650) 225-4682 
8.5.1 EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, 
INSTITUTIONAL REVIEW BOARDS, AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and AESIs against cumulative product experience 
to identify and expeditiously communicate possible new safety findings to Investigators, IRBs, 
ECs, and applicable health authorities based on applicable legislation. 
 
To determine reporting requirements for single AE 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. 
 


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The IRB will be notified by the investigative site in writing (e.g., email) within the timeframe 
required per local IRB regulations for when a reportable AE is first recognized or reported. In 
addition, a copy of the written confirmation or summary of the AE, as submitted to the Sponsor, 
will also be submitted to the IRB within that same timeframe from when the AE is first 
recognized or reported. The IRB Serious and Unexpected AE Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the AE. 
9 STATISTICAL ANALYSES 
The Safety Population will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 postdose safety assessment. 
 
The PK Population will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 evaluable postdose PK sample. 
 
Baseline is defined as the last result prior to the first dose of study drug on Day 1 of Period 1. As 
necessary, baseline will be further defined in the Statistical Analysis Plan (SAP). 
9.1 SAFETY AND TOLERABILITY ANALYSIS 
Safety will be assessed by a review of AEs, vital signs, clinical laboratory assessments, and 
ECGs. Clinical laboratory assessments, vital signs (including oral temperature, respiratory rate, 
and supine blood pressure and pulse rate), and ECGs will be listed by subject number and 
scheduled time. Changes from baseline will be summarized, as appropriate. 
 
Verbatim descriptions of AEs will be coded according to current Medical Dictionary for 
Regulatory Activities version 21.1 (or higher) guidelines. Adverse events will be summarized. 
Enrollment and discontinuations from the study will be summarized overall. Demographics and 
baseline characteristics such as age, sex, and BMI will be summarized overall. 
9.2 PHARMACOKINETIC ANALYSIS 
The following PK parameters will be derived from the plasma concentrations of entrectinib and 
M5 using the model independent approach:5 
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
AUC0-t 
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 


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AUC0-∞ 
area under the concentration-time curve extrapolated to infinity, 
calculated using the formula: 
AUC0-∞ = AUC0-t + 
z
t
λ
C  
where Ct is the last measurable concentration and λz is the apparent 
terminal elimination rate constant 
λz 
apparent terminal elimination rate constant, where λz is the 
magnitude of the slope of the linear regression of the log 
concentration versus time profile during the terminal phase 
t1/2 
apparent terminal elimination half-life (whenever possible), where 
t1/2 = (ln2)/λz 
CL/F 
apparent systemic clearance, calculated as dose/AUC0-∞ 
(entrectinib only) 
Vz/F 
apparent volume of distribution during the terminal elimination 
phase, calculated as (CL/F)/λz (entrectinib only) 
 
Pharmacokinetic calculations will be performed, if appropriate, using commercial software such 
as Phoenix WinNonlin (Certara Inc., version 6.4 or higher). 
 
Other parameters may be added, as appropriate. Final PK parameters reported will be detailed in 
the SAP. 
 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. Other data handling 
procedures will be detailed in the SAP. 
9.3 INTERIM ANALYSIS 
There will not be any interim analysis for this study. 
9.4 STATISTICAL ANALYSIS OF PHARMACOKINETIC DATA 
Descriptive statistics (mean, median, minimum, maximum, standard deviation, geometric mean, 
and geometric coefficient of variation [CV]) will be calculated for all PK parameters and PK 
concentration data. 
 
Plasma concentrations of entrectinib and its active metabolite M5, and derived plasma PK 
parameters, will be listed and summarized by treatment using descriptive statistics. Individual 
and mean concentration versus time profiles will be plotted. 
 


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The primary parameters for bioequivalence testing will be Cmax and AUC0-t of entrectinib. A 
linear mixed model will be applied to analyze the log-transformed primary PK parameters. The 
model assumes fixed effects for treatment, period, and sequence, and a random effect for subject 
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. Bioequivalence will be concluded if the 90% CIs for the treatment ratios fall within 
the no-effect boundaries of 0.80 and 1.25. 
 
All calculations will be performed using SAS version 9.4 or greater. 
 
Specification of PK parameters for analysis; statistical level of significance to be used; criteria 
for study termination; procedures for accounting for missing, unused, or spurious data; 
procedures for reporting deviations from the original statistical plan; and selection of subjects to 
be included in the analyses population(s) will be presented in the CSR and/or SAP, as 
appropriate. 
9.5 STATISTICAL ANALYSES OF SAFETY DATA 
Descriptive statistics will be calculated for the safety parameters. No formal statistical analyses 
are planned. 
9.6 SAMPLE SIZE 
A total of 28 subjects will be enrolled to ensure that 26 subjects complete the study and have 
evaluable PK data from both treatment periods. 
 
In a previous study (Study RXDX-101-15), the within-subject CVs for entrectinib AUC0-∞ and 
Cmax following administration of a single dose of entrectinib were estimated to be 20% and 16%, 
respectively. Assuming a true ratio of 1.05 between the geometric means of Test and Reference 
treatments, and a within-subject CV of 21%, 26 evaluable subjects are needed to ensure there is 
at least 90% probability that the 90% confidence limits for the treatment ratios fall within the 
no-effect boundaries of 0.80 and 1.25 for each of the 2 primary PK parameters (AUC0-∞ and 
Cmax). 
9.7 QUALITY CONTROL AND QUALITY ASSURANCE 
Quality control and quality assurance will be performed according to Covance Standard 
Operating Procedures (SOPs) or per client request and as applicable according to the contract 
between Covance and the Sponsor. 


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10 ADMINISTRATIVE ASPECTS 
10.1 
CHANGE IN PROTOCOL 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator. 
 
There will be no alterations in the protocol affecting subject safety without the express written 
approval of the Sponsor, Investigator, and the IRB (see Form FDA 1572). 
10.2 
INVESTIGATOR MEETING; SITE INITIATION 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with the 
Investigator(s) and appropriate clinical staff to familiarize the Investigator and clinical staff with 
the materials necessary for conducting the clinical study. 
10.3 
DISCLOSURE 
All information provided regarding the study, as well as all information collected and 
documented during the course of the study, will be regarded as confidential. The Investigator 
agrees not to disclose such information in any way without prior written permission from the 
Sponsor. 
 
Any publication of the results, either in part or in total (e.g., articles in journals or newspapers, 
oral presentations, abstracts) by the Investigator(s) or their representative(s), shall require prior 
notification and review, within a reasonable timeframe, by the Sponsor, and cannot be made in 
violation of the Sponsor’s confidentiality restrictions or to the detriment of the Sponsor’s 
intellectual property rights. 
10.4 
MONITORING (CLINICAL RESEARCH ASSOCIATE) 
The Sponsor will designate a Sponsor’s Study Monitor who will be responsible for monitoring 
this clinical trial. The Sponsor’s Study Monitor will monitor the study conduct, proper eCRF and 
source documentation completion and retention, and accurate study drug accountability. To this 
end, the Sponsor’s Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. It is essential that the Sponsor’s Study 
Monitor have access to all documents, including study data, subject medical records, and eCRFs, 
at any time these are requested. In turn, the Sponsor’s Study Monitor will adhere to all 
requirements for subject confidentiality as outlined in the ICF. The Investigator and 
Investigator’s staff will be expected to cooperate with the Sponsor’s Study Monitor, to be 


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available during a portion of the monitoring visit to answer questions, and to provide any missing 
information. 
10.5 
INSTITUTIONAL REVIEW BOARD 
In accordance with 21 CFR 56, the protocol, advertisement, and ICF will be reviewed and 
approved by the IRB. The Sponsor will supply relevant material for the Investigator to submit to 
the IRB for the protocol’s review and approval. Verification of the IRB unconditional approval 
of the protocol and the written ICF statement will be transmitted to the Investigator. 
 
The IRB will be informed by the Investigator of subsequent protocol amendments and of serious 
and unexpected AEs. Approval for protocol amendments will be transmitted in writing to the 
Investigator. If requested, the Investigator will permit audits by the IRB and regulatory 
inspections by providing direct access to source data and documents. 
 
The Investigator will provide the IRB with progress reports at appropriate intervals (not to 
exceed 1 year) and a Study Progress Report following the completion, termination, or 
discontinuation of the Investigator’s participation in the study. 
10.6 
INFORMED CONSENT 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the protocol) 
by the IRB and will be acceptable to the Sponsor. 
 
The Investigator or designee will explain the nature of the study and the action of the test 
product. The subjects will be informed that participation is voluntary and that they can withdraw 
from the study at any time. In accordance with 21 CFR 50, the informed consent process shall be 
documented by the use of a written ICF approved by the IRB and signed by the subject prior to 
protocol-specific procedures being performed. 
 
The subject will sign 2 copies of the ICF. One copy will be given to the subject, and the other 
will be maintained with the subject’s records. 
10.7 
RECORDS 
The results from Screening and data collected during the study will be recorded in the subject’s 
eCRF. To maintain confidentiality, the subjects will be identified only by numbers. 
 


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The completed eCRFs will be transferred to the Sponsor or designee. Copies of each eCRF will 
be retained by the Investigator. All source documents, records, and reports will be retained by the 
study site in accordance with 21 CFR 312.62(c). 
 
All primary data, or copies thereof (e.g., laboratory records, eCRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report, will be 
retained in the study site archives. 
10.7.1 ELECTRONIC CASE REPORT FORMS 
Electronic Case Report Forms are to be completed using the Medidata RAVE EDC system. The 
site will receive training and have access to a manual for appropriate eCRF completion. 
Electronic Case Report Forms will be submitted electronically to Covance and should be handled 
in accordance with instructions from Genentech/Covance. All eCRFs should be completed by 
designated, trained examining personnel as appropriate. 
 
The results from Screening and data collected during the study will be recorded in the subject’s 
eCRF. To maintain confidentiality, the subjects will be identified only by numbers. The 
Investigator will ensure the accuracy, completeness, legibility, and timeliness of the data 
reported in the eCRF by providing an electronic signature. The completed eCRFs will be 
transferred to the Sponsor or designee. 
 
In addition, at the end of the study, the Investigator will receive subject data for the site in a 
readable format (e.g., a compact disc) that must be kept with the study records. 
10.7.2 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, subject diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated 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 the pharmacy, 
laboratories, and medico-technical departments involved in a clinical trial. Source documents 


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that are required to verify the validity and completeness of data entered into the eCRFs must 
never be obliterated or destroyed. To facilitate source data verification and review, the 
Investigator and institution(s) must provide the Sponsor direct access to applicable source 
documents and reports for trial-related monitoring, Sponsor audits, and IRB/EC review. The 
study site must also allow inspection by applicable health authorities. 
10.7.3 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 FDA requirements pertaining to 
computerized systems used in clinical research. An acceptable computerized data collection 
system (for clinical research purposes) would be one that (1) allows data entry only by 
authorized individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (e.g., modification of file); (3) protects the database 
from tampering; and (4) ensures data preservation. 
 
In collaboration with the Study Monitor, Genentech’s or Covance’s Quality Assurance group 
may assist in assessing whether electronic records generated from computerized medical record 
systems used at study sites can serve as source documents for the purposes of this protocol. If a 
site’s computerized medical record system is not adequately validated for the purposes of clinical 
research (as opposed to general clinical practice), applicable hardcopy source documents must be 
maintained to ensure that critical protocol data entered into the eCRFs can be verified. 
10.7.4 STUDY MEDICATION ACCOUNTABILITY 
The recipient of study medication will acknowledge receipt by returning the appropriate 
documentation form indicating shipment content and condition. Damaged supplies will be 
replaced. Accurate records of all study drug received at, dispensed from, returned to, and 
disposed of by the study site should be recorded by using the Drug Inventory Log. 
 
Study drug will either be disposed of at the study site according to the study site’s institutional 
SOP or returned to Genentech with the appropriate documentation, as determined by the 
Sponsor. If the study site is able to destroy study drug, the method of destruction must be 
documented. Genentech must evaluate and approve the study site’s drug destruction SOP prior to 
the initiation of drug destruction by the study site. 


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10.7.5 DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the ICF (or separate authorization to use and disclose personal 
health information) signed by the subject or 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 the analyses, data derived from exploratory 
biomarker specimens will generally not be provided to study Investigators or subjects unless 
required by law. The aggregate results of any conducted research will be available in accordance 
with the effective Sponsor policy on study data publication. 
 
Data generated by this study must be available for inspection upon request by representatives of 
the US FDA and other regulatory agencies, national and local health authorities, Genentech 
monitors/representatives and collaborators, and the IRB/EC for the study site, if 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 CSRs and other summary reports 
will be provided upon request. 
10.7.6 RETENTION OF RECORDS 
The US FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP require that 
records and documents pertaining to the conduct of this study and the distribution of 
investigational drug, including eCRFs, ICFs, laboratory test results, and medication inventory 
records, must be retained by the Investigator for 2 years after the last marketing application 
approval in an ICH region or after at least 2 years have elapsed since formal discontinuation of 
clinical development of the study drug. All state and local laws for retention of records also 
apply. No records should 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. For studies conducted outside the US under a US 
Investigational New Drug (IND), the Investigator must comply with the record retention 
requirements set forth in the US FDA IND regulations and the relevant national and local health 
authorities, whichever is longer. 
 


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All primary data, or copies thereof (e.g., laboratory records, eCRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report will be 
retained in the study site archives. 
10.8 
REFERENCE TO DECLARATION OF HELSINKI/BASIC PRINCIPLES 
The study procedures outlined in this protocol will be conducted in accordance with the US CFR 
governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), IND Application (21 CFR 312), and Applications 
for FDA Approval to Market a New Drug (21 CFR 314), as appropriate. As such, these sections 
of US Title 21 CFR, along with the applicable ICH Guidelines, are commonly known as GCP, 
which are consistent with the Declaration of Helsinki. 






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REFERENCES 
1. Weinstein IB and Joe AK. Mechanisms of disease:  Oncogene addiction--a rationale for 
molecular targeting in cancer therapy. Nat Clin Pract Oncol 2006;3:448-57. 
2. Weinstein IB and Joe AK. Oncogene addiction. Cancer Res 2008;68:3077-80. 
3. Entrectinib (RXDX-101). Investigator’s Brochure. Ignyta, Inc. Edition 008. Apr2018. 
4. RXDX-101-15:  A 2-Part, Open-Label, Randomized, 2-Period, Single-Dose, Study to 
Assess the Relative Bioavailability of 2 Entrectinib Formulations Under Fasting 
Conditions and the Effect of Food on the Entrectinib F06 Formulation in Healthy Adult 
Male Subjects. 
5. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York, NY:  Marcel Dekker, Inc., 
1982. 
 


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APPENDIX A – CLINICAL LABORATORY EVALUATIONS 
Chemistry Panel (Fasted at least 
8 hours): 
Complete Blood Count: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatine kinase/Creatine phosphokinase 
Glucose 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Triglycerides 
Uric acid 
 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity 
Protein 
Urobilinogen 
Microscopic exam including 
bacteria, casts, crystals, epithelial 
cells, RBCs, and WBCs (if 
protein, leukocyte esterase, nitrite, 
or blood is positive) 
Drug Screen: 
Other Tests: 
 
Including but not limited to the 
following: 
Alcohol (ethanol)a 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids (THC) 
Cocaine (metabolite) 
Methadone 
Opiates 
Phencyclidine 
Cotinineb 
Hepatitis B virus core antibodyb 
Hepatitis B surface antigenb 
Hepatitis C virus antibodyb 
Human immunodeficiency virus antibodyb 
Pregnancy test (females of childbearing potential only; serum qualitative) 
Follicle-stimulating hormone (postmenopausal females only)b 
 
a Alcohol breath testing will be performed at Check-in (Day -1) only. 
b Measured at the Screening visit only. 
 
 


Clinical Protocol 
Covance Study 8397015 
CONFIDENTIAL 
Protocol GP41049 
 
 
Final:  5 November 2018 
Page 62 of 62 
CPET Protocol Template, Version 11.0:  30 April 2018 
APPENDIX B – APPROXIMATE MAXIMUM BLOOD VOLUME COLLECTED 
Note:  Additional samples may be drawn for safety purposes. 
 
 
Sample Volume 
(mL) 
Number of 
Samples 
Total Volume 
(mL) 
Serology 
7.0 
1 
7.0 
Chemistry Panel (includes serum pregnancy and 
FSH) 
8.5 
5 
42.5 
CBC (hematology) 
4.0 
5 
20.0 
PK Samples 
4.0 
30 
120 
Total 
189.5 
CBC = complete blood count; FSH = follicle-stimulating hormone; PK = pharmacokinetic. 
 

SAP_001.pdf: 
 
 
 
Official Title: 
A RANDOMIZED, OPEN-LABEL, TWO-TREATMENT, TWO- 
PERIOD, TWO-WAY CROSSOVER STUDY TO INVESTIGATE THE 
BIOEQUIVALENCE OF ENTRECTINIB POLYMORPH FORMS A 
AND C UNDER FASTED CONDITIONS IN HEALTHY SUBJECTS 
NCT Number: 
NCT03796013 
Document Date: 
SAP Version 1: 31-Jan-2019 
 


 
Final V1: 31 January 2019                                                                                                                        Page 1 of 17 
  
STATISTICAL ANALYSIS PLAN 
A RANDOMIZED, OPEN-LABEL, TWO-TREATMENT, TWO-PERIOD, TWO-WAY  
CROSSOVER STUDY TO INVESTIGATE THE BIOEQUIVALENCE OF 
ENTRECTINIB POLYMORPH FORMS A AND C UNDER FASTED CONDITIONS IN 
HEALTHY SUBJECTS 
 
 
 
Statistical Analysis Plan Status: Final V1 
Statistical Analysis Plan Date: 31 January 2019  
Study Drug: Entrectinib  
Sponsor Reference No.: GP41049 
Covance Study No: 8397015 
 
Clinical Phase I 
 
 
Sponsor: 
 
Genentech, Inc. 
1 DNA Way 
South San Francisco,  
California USA 94080-4990 
Study Site: 
Covance Clinical Research Unit  
1341 West Mockingbird Lane, Suite 200E 
Dallas, Texas USA 75247 
 
 
 
 
 
Sponsor Signatory: 
 
Statistician 
Principal Investigator: 
, MD, CPI 
Covance Clinical Research Unit 
 
 
 
 
 
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Statistical Analysis Plan                                      
  CONFIDENTIAL 
Covance Clinical Study No. 8397015 
 
               Sponsor Reference No. GP41049 
Final V1: 31 January 2019                                                                                                                    Page 3 of 17 
  
 
2  TABLE OF CONTENTS 
1 
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ............................................... 2 
2 
TABLE OF CONTENTS ................................................................................................................ 3 
3 
ABBREVIATIONS......................................................................................................................... 4 
4 
INTRODUCTION........................................................................................................................... 6 
5 
STUDY OBJECTIVES ................................................................................................................... 6 
 
Primary objective ..................................................................................................................... 6 
5.1
 
Secondary objective ................................................................................................................. 6 
5.2
6 
STUDY ENDPOINTS .................................................................................................................... 6 
 
Primary Endpoints ................................................................................................................... 6 
6.1
 
Secondary Endpoints ............................................................................................................... 7 
6.2
7 
STUDY DESIGN ............................................................................................................................ 7 
8 
TREATMENTS .............................................................................................................................. 8 
9 
SAMPLE SIZE JUSTIFICATION ................................................................................................. 8 
10 DEFINITION OF ANALYSIS POPULATIONS ........................................................................... 9 
11 STATISTICAL METHODOLOGY ............................................................................................... 9 
 General .................................................................................................................................... 9 
11.1
 
Definition of Baseline and Change from Baseline ...................................................... 10 
11.1.1
 
Repeat and Unscheduled Readings ............................................................................. 10 
11.1.2
 Demographics and Subject Disposition ................................................................................. 10 
11.2
 Prior and Concomitant Medications ...................................................................................... 10 
11.3
 Pharmacokinetic Assessment ................................................................................................ 10 
11.4
 
Pharmacokinetic Analysis ........................................................................................... 10 
11.4.1
 
Presentation of Pharmacokinetic Data ......................................................................... 13 
11.4.2
 
Presentation of Pharmacokinetic Parameters .............................................................. 14 
11.4.3
 
Pharmacokinetic Statistical Methodology ................................................................... 14 
11.4.4
 Safety and Tolerability Assessments ..................................................................................... 15 
11.5
 
Adverse Events ............................................................................................................ 15 
11.5.1
 
Clinical Laboratory Parameters ................................................................................... 15 
11.5.2
 
Vital Signs ................................................................................................................... 15 
11.5.3
 
Electrocardiogram ....................................................................................................... 16 
11.5.4
 
Other Assessments ...................................................................................................... 16 
11.5.5
 
Safety and Tolerability Statistical Methodology ......................................................... 16 
11.5.6
12 INTERIM ANALYSES ................................................................................................................ 16 
13 CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES .................... 16 
14 DATA PRESENTATION ............................................................................................................. 16 
13.1 Insufficient Data for Presentation ............................................................................................ 16 
15 REFERENCES .............................................................................................................................. 17 
 
 
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Statistical Analysis Plan                                      
  CONFIDENTIAL 
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               Sponsor Reference No. GP41049 
Final V1: 31 January 2019                                                                                                                    Page 4 of 17 
  
 
3  ABBREVIATIONS 
Abbreviations pertain to the SAP only (not the TFLs). 
ADaM 
Analysis Data Model 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve extrapolated to infinity 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last 
measurable concentration 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent systemic clearance 
Cmax 
maximum observed concentration 
CSR 
Clinical Study Report 
Ct 
last measurable concentration 
CV 
coefficient of variation 
CVW 
within-subject coefficient of variation 
ECG 
electrocardiogram 
ICH 
International Conference on Harmonisation 
λz 
apparent terminal elimination rate constant 
MRAUC 
metabolite ratio based on AUC0-∞  
NC 
not calculated 
NR 
no result 
PK 
pharmacokinetic 
QTcB 
QTc calculated using the Bazett correction 
QTcF 
QTc calculated using the Fridericia correction  
R 
Reference formulation 
R2 
adjusted coefficient for determination of exponential fit 
SAP 
Statistical Analysis Plan 
T 
Test formulation 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
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               Sponsor Reference No. GP41049 
Final V1: 31 January 2019                                                                                                                    Page 5 of 17 
  
 
tmax 
time to maximum observed concentration 
tlast 
time of last measurable concentration 
t1/2 
apparent terminal elimination half-life  
Vz/F 
apparent volume of distribution during the terminal elimination 
phase 
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Statistical Analysis Plan                                      
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               Sponsor Reference No. GP41049 
Final V1: 31 January 2019                                                                                                                    Page 8 of 17 
  
 
Eligible subjects will be admitted to the study site on the day prior to entrectinib dosing (Check-
in [Day -1] of Period 1) to collect baseline data and to familiarize the subjects with study 
procedures that will be used during the rest of the study. On Day 1 of Period 1, subjects will be 
randomly assigned to 1 of 2 treatment sequences (i.e., TR or RT) according to a pre-specified 
randomization scheme based on the order of study enrollment. The assigned treatments will be 
administered under fasted conditions on Day 1 of each period. Doses of entrectinib will be 
separated by a washout period of at least 14 days.  
8  TREATMENTS 
The following is a list of the study treatment abbreviations and ordering that will be used in the 
TFLs. 
Study Treatment Name 
Abbreviation 
Treatment Order on TFLs 
Single 200-mg oral dose of entrectinib 
F06 capsule formulation Form C (Test) 
Form C  
1 
Single 200-mg oral dose of entrectinib 
F06 capsule formulation Form A 
(R f
)
Form A  
2 
The following is a list of the study treatment sequence abbreviations and ordering that will be 
used in the baseline TFLs. 
Study Treatment Sequence 
Abbreviation 
Treatment Sequence 
Order on TFLs 
Single 200-mg oral dose of entrectinib F06 
capsule formulation Form C (Test) /Single 
200-mg oral dose of entrectinib F06 capsule 
formulation Form A (Reference) 
Form C / Form A  
 
1 
Single 200-mg oral dose of entrectinib F06 
capsule formulation Form A (Reference) 
/Single 200-mg oral dose of entrectinib F06 
capsule formulation Form C (Test) 
Form A / Form C  
 
2 
9  SAMPLE SIZE JUSTIFICATION 
A total of 28 subjects will be enrolled to ensure that 26 subjects complete the study and have 
evaluable PK data from both treatment periods. 
In a previous study (Study RXDX-101-15), the within-subject coefficients of variation (CV) for 
entrectinib area under the concentration-time curve extrapolated to infinity (AUC0-∞) and Cmax 
following administration of a single dose of entrectinib were estimated to be 20% and 16%, 
respectively. Assuming a true ratio of 1.05 between the geometric means of Test and Reference 
treatments, and a within-subject CV of 21%, 26 evaluable subjects are needed to ensure there is 
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Statistical Analysis Plan                                      
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               Sponsor Reference No. GP41049 
Final V1: 31 January 2019                                                                                                                    Page 9 of 17 
  
 
at least 90% probability that the 90% CI for the treatment ratios fall within the no-effect 
boundaries of 0.80 and 1.25 for each of the 2 primary PK parameters (AUC0-∞ and Cmax). 
10  
DEFINITION OF ANALYSIS POPULATIONS 
The Safety Population will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 postdose safety assessment. 
The PK Population will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 evaluable postdose PK sample. A subject may be excluded from the PK summary 
statistics and statistical analysis if the subject has an AE of vomiting that occurs at or before 2 
times median time to maximum observed concentration.  
All protocol deviations that occur during the study will be considered prior to database lock for 
their severity/impact and will be taken into consideration when subjects are assigned to analysis 
populations. Details of subject assignment to the analysis populations will be listed. 
The All Subjects Population will be consistent with the Safety Population.  
11  
STATISTICAL METHODOLOGY 
 General 
11.1
Data listings will be provided for the All Subjects Population. Summary statistics and statistical 
analyses will be performed for subjects included in the relevant analysis populations 
(Safety/PK).  
For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation, median, minimum, maximum, and number. For log-normal data (e.g. the PK 
parameters: area under the concentration-time curves [AUCs] and Cmax) the geometric mean and 
geometric CV will also be presented. For categorical data, frequency count and percentages will 
be presented. Data listings will be provided for all subjects up to the point of withdrawal, with 
any subjects excluded from the relevant population highlighted. For the calculation of summary 
statistics and statistical analysis, unrounded data will be used.  
Missing values will not be imputed, with the possible exception of missing PK predose 
concentrations, as detailed in Section 11.4.2. 
Data analysis will be performed using SAS® Version 9.4. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1, and CDISC ADaM Implementation Guide 
Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilized to ensure 
compliance with CDISC standards. 
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               Sponsor Reference No. GP41049 
Final V1: 31 January 2019                                                                                                                    Page 10 of 17 
  
 
 Definition of Baseline and Change from Baseline  
11.1.1
Period specific baseline for each parameter is defined as the last value measured prior to dosing 
in each period, including repeat (vital signs and ECGs) and unscheduled (clinical laboratory 
parameters) readings (see Section 11.1.2 for definitions of repeat and unscheduled readings).  
Mean change from period specific baseline is the mean of all individual subjects’ change from 
baseline values. Each individual change from baseline will be calculated by subtracting the 
individual subject’s baseline value from the value at the timepoint. The individual subject’s 
change from baseline values will be used to calculate the mean change from baseline using a 
SAS procedure such as Proc Univariate. 
 Repeat and Unscheduled Readings 
11.1.2
Repeat readings occur when the original vital signs or ECG result requires confirmation. Repeat 
readings are labelled as ‘Repeat’ in the listings and replace the original readings in all summaries 
and changes from baseline presentations and calculations. Prior to dosing, all readings taken in 
addition to the original reading are defined as predose repeats. Postdose repeat readings are 
defined as readings collected within 15 minutes of the actual time of the original reading.  
With the exception of predose results described above, unscheduled readings for vital signs or 
ECGs are defined as readings collected >15 minutes from the actual time of the original reading. 
Unscheduled readings are labelled as ‘Unscheduled’ in the listings. Because unscheduled 
readings are not associated with any scheduled timepoint, they are excluded from all summaries 
(with the exception that they may be used as baseline, as stated in Section 11.1.1). 
 Demographics and Subject Disposition 
11.2
The demographic variables age, sex, race, ethnicity, body weight, height, and body mass index 
will be summarized and listed. Subject disposition will be summarized and listed. 
 Prior and Concomitant Medications 
11.3
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (Version September 2018 Enhanced Dictionary Version B3 format [or higher if 
version is updated during the study]). Prior and concomitant medications will be listed 
separately. 
 Pharmacokinetic Assessment 
11.4
 Pharmacokinetic Analysis 
11.4.1
The following PK parameters will be determined where possible from the plasma concentrations 
of entrectinib and M5 using non-compartmental methods performed using Phoenix WinNonlin 
(Certara USA, Inc., Version 6.4 or higher): 
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Final V1: 31 January 2019                                                                                                                    Page 11 of 17 
  
 
Parameter 
Definition 
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
tlast 
time of last measurable concentration 
AUC0-t 
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-∞ 
area under the concentration-time curve extrapolated to infinity, calculated 
using the formula: 
AUC0-∞ = AUC0-t + (Ct/λz) 
where Ct is the last measurable concentration and λz is the apparent 
terminal elimination rate constant  
λz 
apparent terminal elimination rate constant, where λz is the magnitude of 
the slope of the linear regression of the log concentration versus time 
profile during the terminal phase 
t1/2 
apparent terminal elimination half-life (wherever possible), where 
t1/2 = natural log(ln)2/λz 
CL/F 
apparent systemic clearance, calculated as dose/AUC0-∞ (entrectinib only) 
Vz/F 
apparent volume of distribution during the terminal elimination phase, 
calculated as CL/F/λz (entrectinib only) 
MRAUC 
metabolite ratio based on AUC0-∞ (M5 only) 
Additional PK parameters may be determined where appropriate. 
The PK analysis will, where possible, be carried out using actual postdose times recorded in the 
raw data. If actual times are missing, nominal times may be used with sponsor approval.  
Concentrations will be used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
The Cmax, tmax, and tlast will be obtained directly from the plasma concentration-time profiles.   
For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest tmax will be reported.  
The metabolic ratios (MRAUC) will be calculated as follows: 
drug
parent
AUC
metabolite
AUC
MR
0
0
AUC





 
 
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The AUC0-t or other common partial area may be used to determine metabolite ratios (MRAUC) if 
AUC0-∞ cannot be reliably calculated for the majority of subjects. 
11.4.1.1 Criteria for Handling Concentrations that are Missing or Below the Limit of 
Quantification in Pharmacokinetic Analysis 
 
Concentration values that are below the limit of quantification (BLQ) will be set to zero, 
with defined exceptions as follows; 
o 
Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ 
values following the last quantifiable concentration in a profile will be set to 
missing for the purposes of PK analysis. 
o 
If there are late positive concentration values following 2 BLQ concentration 
values in the apparent terminal phase, these values will be evaluated. If these 
values are considered to be anomalous, they will be set to missing. 
o 
If an entire concentration-time profile is BLQ, the profile will be excluded from 
the PK analysis. 
o 
If a predose concentration is missing, these values may be set to zero. 
11.4.1.2 Criteria for the Calculation of an Apparent Terminal Elimination Half-Life 
Number of Data Points 
 
At least 3 data points will be included in the regression analysis and preferably should 
not include Cmax. 
Goodness of Fit 
 
When assessing terminal elimination phases, the adjusted coefficient for determination 
of exponential fit (R2 adjusted) will be used as a measure of the goodness of fit of the 
data points to the determined line.  
 
Regression-based parameters (i.e., λz, t1/2, AUC0-∞, CL/F, Vz/F, MRAUC) will only be 
calculated if the R2 adjusted value of the regression line is ≥0.7. 
Period of Estimation 
 
The time period used for the estimation of t1/2, where possible, will be over at least 2 
half-lives.  
 
Where an elimination half-life is estimated over a time period of <2 half-lives, it will be 
flagged in the data listings at the discretion of the Pharmacokineticist, and the robustness 
of the value should be discussed in the study report. 
Calculation of AUC 
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 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive plasma concentrations above the lower limit of quantification, with at least 1 
of these concentrations following Cmax. 
 
For any partial AUC determination (where applicable), nominal time will generally be 
used for the end of the interval. Actual times for partial AUC intervals may be used at the 
discretion of the Pharmacokineticist.  
 
The AUC0- values (and related parameters [CL/F, Vz/F, MRAUC]) where the percentage 
extrapolation is less than 30% will be reported. Any AUC0- values (and related 
parameters) where the percentage extrapolation is ≥30% will be reported and flagged but 
excluded from descriptive statistics.   
Anomalous Values 
 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in the raw data 
and study report. 
 
Embedded BLQ values may be considered anomalous depending on the route of 
administration and the characteristics of the drug. 
 
If a PK profile has a quantifiable predose value that is >5% of its respective Cmax value, 
all concentrations and PK parameters for the given PK profile may be excluded from the 
summary statistics of PK tables and statistical analysis at the discretion of the 
Pharmacokineticist. 
 
Presentation of Pharmacokinetic Data 
11.4.2
11.4.2.1  Presentation of Pharmacokinetic Concentration Data 
 
The following rules will be applied if there are values that are BLQ or if there are missing 
values (e.g., no result [NR]) in a plasma concentration data series to be summarized. 
o For the calculation of summary statistics, BLQ values will be set to zero. 
o If an embedded BLQ value is considered anomalous within the concentration-time 
profile, this value will be excluded from the summary statistics. 
o Where there is NR, these will be set to missing. 
o If there are <3 values in the data series, only the minimum, maximum and number 
will be presented. The other summary statistics will be denoted as not calculated 
(NC). A BLQ is considered a value. 
o If all the values are BLQ, then the arithmetic mean, arithmetic standard deviation, 
median, min and max will be presented as zero, and the geometric mean and 
geometric CV will be denoted as NC. 
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where mse is the residual error from the mixed model.  
Residual plots will be produced to assess the adequacy of the model. 
 
Safety and Tolerability Assessments  
11.5
 Adverse Events 
11.5.1
A baseline sign and symptom is defined as an AE that starts after the subject has provided 
written informed consent and that resolves prior to the first dosing occasion, or an AE that starts 
prior to the first dosing occasion and does not increase in severity after dosing. A 
treatment-emergent AE (TEAE) is defined as an AE that occurs postdose or that is present 
predose and becomes more severe postdose.  
Any AEs occurring during administration of the Period 1 Day 1 dose up to the dose 
administration in Period 2 will be assigned to Period 1. Any AEs occurring during administration 
of the Period 2 Day 1 dose and postdose from Period 2 Day 1 to Follow-up will be assigned to 
Period 2. All AEs will be listed. The TEAEs will be summarized by treatment, severity rated 
based on National Cancer Institute Common Terminology Criteria for Adverse Events, and 
relationship to the study drug. The frequency (the number of TEAEs, the number of subjects 
experiencing a TEAE, and the percentage of subjects experiencing a TEAE) of TEAEs will be 
summarized by treatment, and by Medical Dictionary for Regulatory Activities system organ 
class and preferred term. The summary and frequency TEAE tables will be presented for all 
causalities and for those TEAEs considered related to the study drug (those that have a 
relationship of suspected). Any severe or serious AEs or any AEs of special interest (AESIs) or 
deaths will be tabulated. For any AEs that change severity ratings the AE will be included only 
once under the maximum severity rating in the summaries. 
    Clinical Laboratory Parameters 
11.5.2
All chemistry, hematology, and urinalysis data outside the clinical reference ranges will be listed 
by parameter and treatment.  
All other laboratory assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
 Vital Signs 
11.5.3
Vital sign values outside the clinical reference ranges will be flagged on the individual subject 
data listings.  
The vital signs data will be summarized by treatment, together with changes from baseline. 
Figures of mean vital signs and mean change from baseline profiles will be presented by 
treatment. 
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 Electrocardiogram 
11.5.4
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the QT 
interval calculated using the Bazett correction (QTcB), the QT interval calculated using the 
Fridericia correction (QTcF), the PR, RR, and QT intervals, QRS duration, and heart rate.  
Values for ECG parameters outside the clinical reference ranges will be flagged on the individual 
subject data listings. 
The ECG data will be summarized by treatment, together with changes from baseline. Figures of 
mean ECG data and mean change from baseline profiles will be presented by treatment.  
An outlier analysis will be performed including all individual postdose measurements (not the 
mean data), including all repeat and unscheduled readings. The frequency of subjects with a 
maximum increase from baseline in QTcB and QTcF intervals will be summarized for each 
treatment according to the following categories: >30, >60, and ≤30 ms. All incidences of >30 
and >60 ms will be flagged on the listing. In addition, the frequency of subjects with QTcB and 
QTcF postdose values will be summarized for each treatment, according to the following 
categories: >450, >480, >500, and ≤450 ms. All incidences of >450, >480, and >500 ms will be 
flagged on the listing.  
 Other Assessments 
11.5.5
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
Medical history data will be presented. 
 Safety and Tolerability Statistical Methodology 
11.5.6
No inferential statistical analyses are planned. 
12  
INTERIM ANALYSES 
Interim statistical analyses will be performed on the PK parameter results (Table 14.2.1-1 only). 
13  
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
There were no changes from the protocol-specified statistical analyses. 
14  
DATA PRESENTATION 
13.1 Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious AEs occurred for this study.” 
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15  
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
3. Statistical Approaches to Establishing Bioequivalence.  Rockville, MD: US Dept of Health 
and Human Services, Food and Drug Administration; Center for Drug Evaluation and 
Research (CDER); January 2001. 
4. Keene ON.  The log transformation is special.  Statistics in Medicine 1995; 14: 811-819. 
5. Brown H, Prescott R.  Applied Mixed Models in Medicine.  Wiley, 1999; Ch 7. 
 
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