Clinical trial NCT06258174
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2021-09-28; Completion date: 2021-12-22
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose of this study is to compare two different formulations (mixtures) of pirtobrutinib (LOXO-305) in healthy participants. This study will compare how much of each formulation gets into the blood stream and how long it takes the body to remove it. Information about any side effects that may occur will be collected. The study will last up to 65 days.

Detailed description:

Arms: arm 1: Period 1: Participants received a reference formulation (R) of oral pirtobrutinib 200 milligrams (mg) on day 1.

Period 2: Participants received a test formulation (T) of oral pirtobrutinib 200 mg on day 8.

There was a washout period of 7 days between the doses of pirtobrutinib. arm 2: Period 1: Participants received a test formulation (T) of oral pirtobrutinib 200 mg on day 1.

Period 2: Participants received a reference formulation (R) of oral pirtobrutinib 200 mg on day 8.

There was a washout period of 7 days between the doses of pirtobrutinib.
Interventions: intervention 1: Pirtobrutinib
Intervention descriptions: intervention 1: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol LOXO-BTK-21050 (J2N-OX-JZNV) Version 1.0 
A Phase I, Open-Label, Randomized, 2-Way Crossover Study to Compare the PK of 
Pirtobrutinib (LOXO-305) Tablets
NCT06258174
Approval date: 31-Aug-2021


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SAP_001.pdf: 
Statistical Analysis Plan LOXO-BTK-21050 (J2N-OX-JZNV) Version 1.0 
A Phase I, Open-Label, Randomized, 2-Way Crossover Study to Compare the PK of 
Pirtobrutinib (LOXO-305) Tablets
NCT06258174
Approval date: 21-Oct-2021


TITLE PAGE 
Statistical Analysis Plan 
A Phase I, Open-Label, Randomized, 2-Way Crossover Study to Compare 
the PK of Pirtobrutinib (LOXO-305) Tablets 
SAP Status: Sponsor Final 
SAP Version: 1.0 
SAP Date: 21OCT2021 
Investigational Medicinal Product: Pirtobrutinib 
Protocol Reference: LOXO-BTK-21050 
Labcorp Drug Development Study: 8478595 
Sponsor: 
Loxo Oncology, Inc., 
a wholly owned subsidiary of Eli Lilly and 
Company’701 Gateway Boulevard, Suite 
420 
South San Francisco, CA 94080 
USA 
Coordinating Investigator Study Site: 
Labcorp Clinical Research Unit Inc. 
3402 Kinsman Boulevard 
Madison, WI 53704 
USA 
Up to 2 additional sites in the United States 
may be utilized. 
Coordinating Investigator: 
 MD 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
PPD


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF IN-TEXT TABLES AND FIGURES ......................................................................... 3 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1. Primary Objective ........................................................................................................... 6 
2.2. Secondary Objective ....................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 7 
3.1. Primary Endpoints ........................................................................................................... 7 
3.2. Secondary Endpoints ....................................................................................................... 7 
4. STUDY DESIGN................................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION ........................................................................................ 9 
6. STUDY TREATMENTS ....................................................................................................... 9 
7. DEFINITIONS OF POPULATIONS .................................................................................. 10 
7.1. All Subjects Population ................................................................................................. 10 
7.2. Safety Population .......................................................................................................... 10 
7.3. Pharmacokinetic Population ......................................................................................... 10 
8. STATISTICAL METHODOLOGY .................................................................................... 11 
8.1. General .......................................................................................................................... 11 
8.1.1. Handling of Data Quality Issues Such as Missing Data and Protocol Deviations 
Due to Coronavirus Disease 2019 and Related Restrictions ............................................ 11 
8.1.2. Calculation of the Summary Statistics ................................................................... 12 
8.1.3. Repeat and Unscheduled Readings ........................................................................ 13 
8.1.4. Definitions of Baseline and Change from Baseline ............................................... 13 
8.2. Subject Disposition and Population Assignment .......................................................... 13 
8.3. Screening Demographics and Baseline Characteristics ................................................ 14 
8.4. Prior and Concomitant Medication ............................................................................... 14 
8.5. Pharmacokinetic Assessments ...................................................................................... 14 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 14 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 16 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 17 


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8.6. Safety and Tolerability Assessments ............................................................................ 18 
8.6.1. Adverse Events ....................................................................................................... 18 
8.6.2. Clinical Laboratory Parameters .............................................................................. 19 
8.6.3. Vital Signs Parameters ........................................................................................... 20 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 20 
8.6.5. Other Assessments ................................................................................................. 20 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 20 
9. INTERIM ANALYSES ....................................................................................................... 20 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 20 
11. REFERENCES .................................................................................................................. 21 
12. APPENDICES ................................................................................................................... 22 
Appendix 1: 
Document History ................................................................................ 22 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1: 
Presentation of Study Treatments in TFLs ........................................................... 10 
Table 2: 
Presentation of Study Treatment Sequences in TFLs ........................................... 10 
 
Figure 1: 
Study Design ........................................................................................................... 8 
 


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LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
%AUCextrap 
percentage of AUC0-inf due to extrapolation from the last quantifiable 
concentration to infinity 
ADaM 
Analysis Data Model 
AE 
adverse event 
AUC0-t 
area under the concentration-time curve from hour 0 to the time of the 
last quantifiable concentration 
AUC0-24 
area under the concentration-time curve from hour 0 to 24 hours 
postdose 
AUC0-inf 
area under the concentration-time curve from hour 0 extrapolated to 
infinity 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent systemic clearance 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019 
CRU 
Clinical Research Unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
Geom CV 
geometric CV 
Geom Mean 
geometric mean 
GLSM 
geometric least square mean 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation 
λz 
apparent terminal elimination rate constant 
λz Lower 
start of exponential fit 
λz N 
number of data points included in the log-linear regression 
λz Span Ratio 
time period over which λz was determined as a ratio of t1/2 


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λz Upper 
end of exponential fit 
ln 
natural log 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRTinf 
mean residence time based on AUC0-inf 
NA 
Not applicable 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R 
reference 
R2-adj 
adjusted coefficient for determination of exponential fit 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDV 
source document verification 
T 
test 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tmax 
time of the maximum observed concentration 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODrug 
World Health Organization Drug Dictionary  


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1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 
dated 31 August 2021) and electronic case report form (eCRF).  
This SAP describes the planned analysis of the pharmacokinetic (PK), safety, and tolerability 
data from this study. A detailed description of the planned TFLs to be presented in the 
clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of information about this 
study (eg, objectives, study design) is given to help the reader’s interpretation.  
This SAP must be finalized prior to the first subject enrollment (the point of enrollment 
occurs at the time of subject number allocation). Additionally, the SAP and TFL shells should 
be finalized prior to any programming activities commencing.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Loxo Oncology, Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E3 guideline Structure and Content of Clinical Study 
Reports, ICH E8 guideline General Considerations for Clinical Trials, and ICH E9 guideline 
Statistical Principles for Clinical Trials.1,2,3  
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
2.1. Primary Objective  
The primary objective of the study is to assess the relative bioavailability of a pirtobrutinib 
tablet lot with a slower dissolution profile (T) relative to the pirtobrutinib tablet lot currently 
used in the clinical setting (R) following single doses of pirtobrutinib, as assessed by 
pirtobrutinib PK in healthy adult subjects. 
2.2. Secondary Objective  
The secondary objective of the study is to assess the safety and tolerability of single doses of 
pirtobrutinib when administered as a test tablet lot and a reference tablet lot in healthy adult 
subjects. 


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3. STUDY ENDPOINTS  
3.1. Primary Endpoints 
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of pirtobrutinib (as appropriate): 
● Area under the concentration-time curve from hour 0 to 24 hours postdose (AUC0-24) 
● Area under the concentration-time curve from hour 0 to the time of the last quantifiable 
concentration (AUC0-t) 
● Area under the concentration-time curve from hour 0 extrapolated to infinity (AUC0-inf) 
● Percentage of AUC0-inf due to extrapolation from the last quantifiable concentration to 
infinity (%AUCextrap) 
● Apparent systemic clearance (CL/F) 
● Apparent terminal elimination half-life (t1/2) 
● Maximum observed concentration (Cmax) 
● Time of the maximum observed concentration (tmax) 
● Apparent terminal elimination rate constant (λz) 
● Apparent volume of distribution during the terminal phase (Vz/F) 
3.2. Secondary Endpoints 
Safety and tolerability will be assessed by monitoring adverse events (AEs), performing 
physical examinations and clinical laboratory evaluations, measuring vital signs, and 
recording 12-lead electrocardiograms (ECGs). 
4. STUDY DESIGN  
This is a Phase 1, open-label, randomized, 2-way crossover study to compare the PK of 
2 different lots of pirtobrutinib after a single oral dose in healthy adult subjects. 
A single oral dose of pirtobrutinib will be administered as test lot tablets (T2-L [T]) or 
reference lot tablets (T2-PR [R]). The 2 treatment sequences will be TR and RT. Subjects 
will be randomly assigned to 1 of the 2 treatment sequences, according to a randomization 
scheme issued by Labcorp Drug Development. Up to 28 healthy adult male and female 
subjects (women of non-childbearing potential only) will be enrolled. Replacement subjects 
may be enrolled only if deemed necessary by the Sponsor. Every attempt will be made to 
enroll at least 3 subjects of each sex in the study. 


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In Treatment T, a single oral dose of 200 mg pirtobrutinib (2 × 100 mg) as test lot tablets will 
be administered in the morning on Day 1 or Day 8 (according to the randomization scheme), 
following a fast of at least 10 hours prior to and 4 hours after dosing. Water will be restricted 
for 1 hour prior to and 1 hour after dosing with the exception of water administered for dose 
administration. 
In Treatment R, a single oral dose of 200 mg pirtobrutinib (2 × 100 mg) as reference lot 
tablets will be administered in the morning on Day 1 or Day 8 (according to the 
randomization scheme), following a fast of at least 10 hours prior to and 4 hours after dosing. 
Water will be restricted for 1 hour prior to and 1 hour after dosing with the exception of water 
administered for dose administration. 
Blood samples for the analysis of plasma concentrations of pirtobrutinib and for future 
potential and/or exploratory analysis will be collected from predose through 168 hours 
postdose for Treatment R and Treatment T. 
There will be a washout period of 7 days between the doses of pirtobrutinib administered in 
Treatments R and T. 
A schematic of the study design is presented in Figure 1.  
Figure 1: Study Design  
 
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an informed consent form (ICF). Note that enrolled subjects are defined as those subjects 
who are assigned to receive a dose of study drug; this definition excludes screen failure 
subjects. Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
Subjects who are determined to be screen failures are permitted to be re-screened if the 
Investigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number. A minimum of 7 days must elapse between date of screen failure and date of 
re-screening. 


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To assess their eligibility to enter the study, potential subjects will be screened within 40 days 
(Days -41 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 15 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. Subjects will be dosed on Day 1 and Day 8. A 
follow-up phone call will occur for all subjects who received at least 1 dose of study drug 
(including subjects who are terminated early) 7 days (± 2 days) after EOT or ET. The 
duration of participation is expected to be approximately 65 days (Screening through 
follow-up phone call). 
In this study, physical examinations, 12-lead ECGs, vital sign measurements, How Do You 
Feel? inquiries, clinical chemistry panel, coagulation parameters, hematology panel, 
urinalysis, and recording of concomitant medications will be performed at specified times 
during the study. 
Adverse events and serious AEs (SAEs) will be collected beginning at informed consent. 
Adverse events will be reported throughout the study (ie, from signing of the ICF until End of 
Study [EOS], or until ET if the subject discontinues from the study and does not complete a 
follow-up phone call), either as subject medical history (if the event is reported as beginning 
prior to signing of the ICF or if the event occurs prior to study drug administration on Day 1 
and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs 
(if the event occurs after signing of the ICF but prior to study drug administration on Day 1 
and is assessed as related to study procedures by the Investigator [or designee], or if the event 
occurs after study drug administration on Day 1 through EOT or ET regardless of relationship 
to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug by 
the Investigator (or designee) are to be reported. All SAEs that develop from the time of ICF 
signing until EOS (or ET, if the subject discontinues from the study and does not complete a 
follow-up phone call) are to be reported. 
Study completion is defined as the time of the last subject’s follow-up phone call. 
5. SAMPLE SIZE JUSTIFICATION  
Up to 28 healthy adult male and female subjects (women of non-childbearing potential only) 
will be enrolled. This is a relative bioavailability study; however, a total of 28 evaluable 
subjects (14 subjects per treatment sequence) will provide at least 
 power to have the 
respective 90% confidence intervals (CIs) for the geometric mean ratios for Cmax and AUC 
values between test and reference lot tablets are within the interval of 80.00% to 125.00%, 
assuming a 
and that the expected ratio of 
means is 1.05 (or 0.95). Based on PK results of LOXO-BTK-20009, 
 
 Replacement subjects may be enrolled only if deemed necessary by the Sponsor. Every 
attempt will be made to enroll at least 3 subjects of each sex in the study. 
6. STUDY TREATMENTS  
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 1.  
CCI
CCI
CCI


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Table 1: 
Presentation of Study Treatments in TFLs  
Study Treatment 
Abbreviation 
Order in 
TFLs 
200 mg pirtobrutinib reference lot tablets  
R 
1 
200 mg pirtobrutinib test lot tablets  
T 
2 
All TFLs will be based on actual treatments (eg, if subject was assigned to receive reference 
but was wrongfully dosed with test treatment they would be summarized and listed under test 
treatment). 
The study treatment sequence names, abbreviations, and ordering to be used in the TFLs are 
presented in Table 2.  
Table 2: 
Presentation of Study Treatment Sequences in TFLs 
Study Treatment Sequence 
Abbreviation 
Order in TFLs 
200 mg pirtobrutinib reference lot tablets / 200 mg pirtobrutinib 
test lot tablets 
R/T 
1 
200 mg pirtobrutinib test lot tablets / 200 mg pirtobrutinib 
reference lot tablets 
T/R 
2 
The summaries will be based on planned treatment sequences and listings will be based on 
actual treatment sequences (eg, if subject was assigned to receive reference in Period 1 and 
test treatment in Period 2 (sequence ‘R/T’) but was wrongfully dosed with test treatment in 
Period 1 and discontinued before start of Period 2, they would be summarized under ‘R/T’ 
treatment sequence and listed under ‘T’ treatment sequence).   
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those due to coronavirus disease 2019 (COVID-19) and 
related restrictions (see Section 8.1.1), will be considered prior to database lock for their 
importance and taken into consideration when assigning subjects to populations.  
7.1. All Subjects Population  
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
7.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study treatment 
(pirtobrutinib). Subjects will be classified into groups based on actual treatment received.  
7.3. Pharmacokinetic Population  
The PK population will include all subjects who received a dose of study treatment 
(pirtobrutinib), have at least 1 quantifiable plasma concentration, and for whom at least 1 PK 


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parameter can be computed. The impact of protocol deviations on the PK population will be 
evaluated on a case-by-case basis.    
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they complete the scheduled EOS phone call (rather than ET visit). Any subject who 
discontinues the study will be identified accordingly in the listings. Summaries and statistical 
analyses will include the subjects assigned to the relevant population based on data type.  
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if a new version is issued during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if a new version is issued 
during the study) and CDISC ADaM Implementation Guide Version 1.2(or higher if a new 
version is issued during the study). Pinnacle 21 Community Validator Version 2.2.0 (or 
higher if a new version is issued during the study) will be utilized to ensure compliance with 
CDISC standards.  
For all statistical analyses, the hypothesis testing will be 2-sided and carried out on 0.05 
significance level, unless specifically stated otherwise.  
Where reference is made to ‘valid’ data, this refers to non-missing data which meet the 
predetermined criteria (eg, are not flagged for exclusion).  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, and changes from baseline.  
All figures will be produced on linear-linear or discrete-linear scales, as applicable, unless 
specifically stated otherwise. 
Any protocol deviations and data issues (eg missing data, out of protocol window) that occur 
during the study, including those due to COVID-19 and related restrictions (see 
Section 8.1.1), will be considered prior to database lock for their severity and impact on the 
analyses. 
8.1.1. Handling of Data Quality Issues Such as Missing Data and Protocol Deviations 
Due to Coronavirus Disease 2019 and Related Restrictions 
Due to COVID-19 and related restrictions, there is a high risk for impact to data integrity, 
with the recognized potential for: 
● Missed visits, caused by, for example,: 


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o Subject unable to travel to site due to restrictions, the need to quarantine, or 
COVID-19 infection 
o Subject unwilling to go to site due to fear of COVID-19 infection 
o Site postponing subject’s visit due to investigator not being available (eg, if they 
have been dispatched to hospital handling COVID-19 infections) 
● Site unable to replenish supply of investigational product 
● Incomplete data entry by sites due to limited resources to support study or no access to 
source documents or to eCRF 
● Outstanding source document verification (SDV) due to sponsor or country restrictions 
on remote SDV, or no or limited access to site(s) for on-site visits 
● Unanswered queries. 
Any protocol deviations and data issues (eg missing data, out of protocol window) that occur 
during the study, including those due to COVID-19 and related restrictions (see 
Section 8.1.1), will be considered prior to database lock for their severity and impact on the 
analyses. If needed, appropriate statistical methods will be applied as a mitigating action (eg, 
data might be categorized into 2 analysis groups, with and without COVID-19 and related 
restrictions impact); however, this will exclude any imputations of the missing values. Any 
mitigating actions will be agreed with Loxo Oncology, Inc. in advance and identified in the 
CSR. 
8.1.2. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum.  
● In general, as early termination data are not associated with any scheduled timepoint, 
they will be excluded from all calculations of summary statistics. Exceptions may be 
made where justified.  
● Postdose repeats and unscheduled assessments will not be included in calculations of 
summary statistics. 
For categorical data the following rules will be applied:  
● For ordered categorical data (eg, AE severity), all categories between the possible 
minimum and maximum categories will be included, even if n = 0 for a given category.  


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● For non-ordered categorical data (eg, race), only those categories for which there is at 
least 1 subject represented will be included; unless specifically stated otherwise.  
● Missing values will not be imputed, unless specifically stated otherwise. A ‘missing’ 
category will be included for any parameter for which information is missing. This will 
ensure that the population size totals are consistent across different parameters.  
8.1.3. Repeat and Unscheduled Readings  
For vital signs and 12-lead ECG data only, any predose value recorded in addition to the 
original value or a postdose value recorded within 15 minutes of the original value will be 
defined as a repeat value; any postdose value recorded more than 15 minutes after the 
original value will be defined as an unscheduled value. For all other data types (eg, laboratory 
parameters), any value recorded in addition to the original value will be defined as an 
unscheduled value.  
The original scheduled value will be used in all calculations post dose. In the event of any 
repeats or unscheduled measurements taken pre-dose the values will be considered when 
determining the baseline value.  
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 8.1.4).  Post dose repeats and ET measurements will also be excluded from all 
calculations with the exception of the baseline derivation (see Section 8.1.4). 
8.1.4. Definitions of Baseline and Change from Baseline  
The baseline will be defined as the last value recorded prior to dosing in each period. In 
general, baseline will be the predose value collected on Day 1 for period 1 and on Day 8 for 
period 2, respectively. For clinical chemistry, baseline for period 2 will be the value collected 
on Day 7 in period 1. If the date/time of the value is incomplete or missing, it will be 
excluded from the baseline calculation, unless the incomplete date/time indicates the value 
was recorded prior to dosing in each period.  
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the postdose timepoint.  
The summary statistics for change from baseline will be derived from individual subjects’ 
values (eg, mean change from baseline will be the mean of the individual changes from 
baseline for all subjects, rather than difference between the mean value at the postdose 
timepoint and mean value at baseline).  
See Section 8.1.3 for more detail on handling repeat and unscheduled readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  


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A summary table by treatment sequence will be provided, based on the safety population.  
8.3. Screening Demographics and Baseline Characteristics  
The screening demographics and baseline characteristics including age, sex, race, ethnicity, 
height, body weight, and body mass index will be listed.  
A summary table by treatment sequence will be provided, based on the safety population.  
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that starts during or after the first dose or starts but 
does not end prior to the first dose.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version September 2021 (or later if a new 
version is issued during the study; see the data management plan [DMP] for more details). 
Prior and concomitant medications will be listed.  
8.5. Pharmacokinetic Assessments  
8.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma 
concentrations of pirtobrutinib using noncompartmental methods in validated software 
program Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Parameter 
Unitsa 
Definition 
AUC0-t 
h*ng/mL 
area under the concentration-time curve from hour 0 to the 
time of the last quantifiable concentration (tlast)b 
AUC0-24 
h*ng/mL 
area under the concentration-time curve from hour 0 to 
24 hours postdose  
AUC0-inf 
h*ng/mL 
area under the concentration-time curve from hour 0 
extrapolated to infinityc 
%AUCextrap 
% 
percentage of AUC0-inf due to extrapolation from the last 
quantifiable concentration to infinity 
Cmax 
ng/mL 
maximum observed concentration 
tmax 
h 
time of the maximum observed concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent systemic clearance 
MRTinf 
h 
mean residence time (based on AUC0-inf) 
Vz/F 
L 
apparent volume of distribution during the terminal phase  
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
  parameters) and dose units used in the study. 
b The AUC will be calculated using the linear trapezoidal rule for increasing and decreasing concentrations. 
c Based on the last observed quantifiable concentration. 


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Additional PK parameters may be determined where appropriate. 
The PK analysis will be carried out where possible using actual blood sampling times 
postdose. If an actual time is missing, the sample concentration result will be treated as 
missing unless there is scientific justification to include the result using the nominal time. 
The parameters Cmax and tmax will be obtained directly from the concentration-time profiles. If 
Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax. 
8.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz for their calculation (eg, AUC0-inf, t1/2, CL/F, and Vz/F) will only be 
calculated if the R2-adj value of the regression line is ≥0.7. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (ie, the difference between 
λz Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of 
the t1/2 values will be discussed in the CSR. 
8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive concentrations above the lower limit of quantification. If there are only 
3 consecutive concentrations, at least 1 should follow Cmax.  
The AUC0-inf values where the percentage extrapolation is less than 30% will be reported. 
The AUC0-inf values where the percentage extrapolation is greater than 30% will be listed but 
excluded from descriptive statistics. 


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If AUC0-inf cannot be determined reliably for all subjects and/or treatments, an alternative 
AUC measure, such as AUC to a fixed timepoint or AUC0-t, may be used in the statistical 
comparison of treatments. 
8.5.1.3. Criteria for Handling Concentration Below the Limit of Quantification or 
Missing Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQ concentrations will be treated as 
missing. The following rules apply to the specific situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the 
profile will be deemed to have terminated and any further quantifiable concentrations 
will be set to missing for the calculation of the PK parameters, unless they are 
considered to be a true characteristic of the profile of the drug. 
● If a predose plasma concentration is missing, it will be set to 0 by default within 
Phoenix WinNonlin. 
8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value in the first treatment period will be considered 
anomalous and set to missing for the PK analysis. A missing predose concentration will be 
set to 0 by default in Phoenix WinNonlin. 
If the predose concentration is >5% of Cmax in the second treatment period, all PK 
concentration and parameter data will be excluded from the summary statistics and statistical 
analysis for that period. 
8.5.2. Presentation of Pharmacokinetic Data 
All PK concentrations and parameters will be listed.  
Summary tables, arithmetic mean (+ standard deviation [SD]) figures, overlaying individual 
figures by treatment, and individual figures with treatments overlaid will be provided for 
plasma PK concentrations. All figures will be produced on both linear-linear and linear-
logarithmic scales. The +SD bars will only be displayed on the linear-linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Summary statistics (n, Mean, SD, CV, 
minimum, median, maximum, geometric mean [Geom Mean] and geometric CV [Geom CV]) 
will be calculated for plasma pirtobrutinib PK parameters. Individual values and geometric 
means of PK parameters will be plotted.    


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A subject may be excluded from the PK summary statistics and statistical analysis when the 
subject has an AE of vomiting that occurs on or before 2 times the median tmax.    
Individual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 
For plasma concentration data the following rules will apply: 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
● Arithmetic mean or median values that are BLQ will be presented as 0. 
● If any BLQ results (treated as 0) are in a series of summarized data, geometric mean 
and CV of geometric mean will be reported as not calculated. 
For PK parameters the following rule will apply: 
● Geometric mean and CV will not be calculated for tmax. 
8.5.3. Pharmacokinetic Statistical Methodology  
A statistical analysis will be conducted to investigate the relative bioavailability of 200 mg 
pirtobrutinib test lot tablets (test treatment) versus 200 mg pirtobrutinib reference lot tablets 
(reference treatment).  
The hypothesis testing will be 2-sided and carried out on 0.1 significance level. 
The natural log (ln)-transformed4 AUC0-t, AUC0-inf, and Cmax (only for plasma pirtobrutinib) 
will be analyzed using a mixed model.5 The model will include planned treatment sequence, 
period, and actual treatment as fixed effects, and subject within planned treatment sequence 
as a random effect. 
For each PK parameter separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the test and reference treatments, and corresponding 90% CI will 
be calculated; these values will then be back-transformed to give the geometric least square 
mean (GLSM), geometric mean ratio (GMR), and corresponding 90% CI.  
It will be concluded that the test treatment is bioequivalent to the reference treatment if, for 
all tested PK parameters, the 90% CI for GMR is completely contained within the predefined 
interval of (80.00%, 125.00%).6 This procedure is equivalent to Schuirmann’s7 two one-sided 
tests at the 0.05 level of significance.  
Additionally, the pooled estimate (across treatments) of the within-subject CV will be 
calculated, and residual plots will be produced to assess the adequacy of the model(s) fitted.  
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis  
proc mixed data = <data in>; 


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  by parcat1n parcat1 pkday paramn param; 
  class trtan aperiod trtseqp usubjid; 
  model lpk = trtan aperiod trtseqp / cl residual ddfm = kr; 
  lsmeans trtan / cl pdiff = control('1') alpha = 0.1; 
  random intercept / subject = usubjid(trtseqp);  
  ods output lsmeans = <data out>;   
  ods output diffs = <data out>; 
  ods output covparms = <data out>; 
run; 
8.6. Safety and Tolerability Assessments  
8.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 24.1 (or higher if a new version is issued during the study; see the DMP for more 
details). All AEs will be assigned a severity grade using Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0 (or higher if a new version is issued during the study; 
see the protocol for more details).  
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose, or starts prior to the first dose and increases in severity after the first dose.  
A treatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment, as determined by the investigator.  
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
last associated dose for TEAEs only.  
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment  
● Treatment-related TEAEs by severity and treatment  
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  


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For the AE data the following rules will apply:  
● For the derivation of treatment-emergent status (applicable to all AEs): If the start 
date/time of an AE is incomplete or missing, an AE will be assumed to be a TEAE, 
unless the incomplete start date/time or the end date/time indicates an AE started prior 
to the first dose.  
● For the derivation of treatment-related status (applicable to TEAEs only): If the study 
treatment relationship for a TEAE is missing, that TEAE will be counted under the 
‘missing’ category.  
● For the derivation of onset time (applicable to TEAEs only): If the start date/time of a 
TEAE is missing, onset time will not be calculated. If the start date/time of a TEAE is 
incomplete, where possible, the minimum possible onset time will be calculated and 
presented in ‘≥DD:HH:MM’ format (eg, if the date/time of the last associated dose is 
01MAY2019/08:00 and recorded start date/time of a TEAE is 03MAY2019, then the 
minimum possible onset time will be calculated by assuming a TEAE started at the first 
hour and minute of 03MAY2019 [03MAY2019/00:00], thus will be presented as onset 
time ≥01:16:00 in the listing). If the start date of a TEAE is the same as the date of the 
last associated dose but the start time of a TEAE is missing, an onset time will be 
presented as ‘≥00:00:01’. Any clock changes will be accounted for in the derivation.  
● For the derivation of duration (applicable to all AEs): If the end date/time of an AE is 
missing, duration will not be calculated. If the start or end date/time of an AE is 
incomplete, where possible, the maximum possible duration will be calculated and 
presented in ‘≤DD:HH:MM’ format (eg, if the start of an AE date/time is 
01MAY2019/08:00 and its recorded end date/time is 03MAY2019, then the maximum 
possible duration will be calculated by assuming an AE ended at the last hour and 
minute of 03MAY2019 [03MAY2019/23:59], thus will be presented as 
duration ≤02:15:59 in the listing). Any clock changes will be accounted for in the 
derivation.  
● For the calculation of TEAE summary statistics: If the severity of a TEAE is missing, 
that TEAE will be counted under the ‘missing’ category. 
● For the calculation of TEAE summary statistics: If a subject experienced multiple 
TEAEs with the same preferred term for the same treatment, this will be counted as 
1 TEAE for that treatment under the maximum severity recorded.  
8.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters and their changes from baseline, will be listed, as 
applicable; any value outside the clinical reference range will be flagged, and whether the out 
of range value was deemed clinically significant or not clinically significant will be indicated. 
Separate listings will be provided for any parameter for which there is any individual subject 
value outside the respective clinical reference range. 


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Summary tables by treatment and timepoint will be provided for clinical chemistry, 
hematology, and coagulation parameters, and their changes from baseline, as applicable.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, all calculations, and presentation in the figures, <x, ≤x, >x and ≥x 
values will be set to x i.e. will be considered equal to the lower or upper limit of 
quantification, respectively.  
8.6.3. Vital Signs Parameters  
All vital signs parameters and their changes from baseline, will be listed, as applicable; any 
value outside the clinical reference range will be flagged, and whether the out of range value 
was deemed clinically significant or not clinically significant will be indicated.  
Summary tables by treatment and timepoint will be provided for oxygen saturation, 
respiratory rate, oral body temperature, systolic blood pressure, diastolic blood pressure, and 
pulse rate, and their changes from baseline, as applicable.  
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters will be listed; any value outside the clinical reference range will 
be flagged, and whether the out of range value was deemed clinically significant or not 
clinically significant will be indicated.  
Summary tables by treatment and timepoint will be provided for all 12-lead ECG parameters. 
QT interval corrected for heart rate using Fridericia’s formula (QTcF) values that are > 450 
msec and increase from baseline > 30 msec will be flagged in the data listing.  
8.6.5. Other Assessments  
Medical history and physical examination will be listed.  Medical history will not be coded 
per MedDRA, and will be presented as reported (verbatim) on the eCRFs. Any physical 
examination abnormalities reported will also be flagged as clinically significant or not 
clinically significant as indicated.  
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.  
9. INTERIM ANALYSES  
No interim analyses are planned.   
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  


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11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
2. ICH. ICH Harmonised Tripartite Guideline: General considerations for clinical trials (E8). 
17 July 1997.  
3. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
4. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
5. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
6. 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. 
7. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm. 1987;15(6):657-680. 


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12. APPENDICES 
Appendix 1: 
Document History 
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
NA = not applicable