Clinical trial NCT04035473
Conditions: Solid Tumor
Sponsor: Athenex, Inc.
Start date: 2015-08-01; Completion date: 2019-03-27
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a multicenter, open-label, 2-stage study with a 2-treatment period crossover design. Eligible participants are adults with cancer for whom weekly therapy with IV paclitaxel at a dose of 80 mg/m2 over 1 hour is indicated.

Stage 1 will consist of an initial cohort (Cohort 1) up to 6 evaluable participants who will receive a dosing regimen of Oraxol consisting of a 15-mg oral HM30181AK-US tablet plus an oral paclitaxel dose of 205 mg/m2, both administered once daily for 3 consecutive days. The stages and cohorts are further described in the "Study Design - Stages and Cohorts" table below. An interim analysis of pharmacokinetic (PK) data from Cohort 1 will be conducted to determine if the administered regimen would appear likely to achieve bioequivalence(BE) (AUC0-∞), if tested in a greater number of participants in Stage 2. If it appears unlikely that the selected regimen will meet the criteria for BE based on AUC0-∞ data, a second cohort (Cohort 2) of up to 6 evaluable participants may be enrolled in Stage 1, and the dose of paclitaxel in Oraxol may be adjusted by a maximum of +/- 25%. If Cohort 2 is enrolled, a second interim analysis will be conducted.

After the interim analysis/analyses (depending on the outcomes), a decision will be made by consensus of the Data Safety and Monitoring Board(DSMB), Kinex, Zenith Technology, and the Principal Investigator as to what dose should be administered in Stage 2. The DSMB will consist of a clinical oncologist, an ethicist, an independent statistician, and additional members, as deemed necessary. A DSMB charter will describe the planned evaluations and decision points used to determine the dose for Stage 2. An additional 18 to 42 evaluable participants will be enrolled into Stage 2 based on the Stage 1 results (AUC0-∞). Thus a total of up to 54 evaluable participants could potentially be enrolled in this study (6 each from Stage 1, Cohorts 1 and 2, and up to 42 participants in Stage 2).

Detailed description:
Stage 1 will consist of an initial cohort (Cohort 1) up to 6 evaluable participants who will receive a dosing regimen of Oraxol consisting of a 15-mg oral HM30181AK-US tablet plus an oral paclitaxel dose of 205 mg/m2, both administered once daily for 3 consecutive days. The stages and cohorts are further described in the "Study Design - Stages and Cohorts" table below. An interim analysis of pharmacokinetic (PK) data from Cohort 1 will be conducted to determine if the administered regimen would appear likely to achieve bioequivalence (BE) (AUC0-∞), if tested in a greater number of participants in Stage 2. If it appears unlikely that the selected regimen will meet the criteria for BE based on AUC0-∞ data, a second cohort (Cohort 2) of up to 6 evaluable participants may be enrolled in Stage 1, and the dose of paclitaxel in Oraxol may be adjusted by a maximum of +/- 25%. If Cohort 2 is enrolled, a second interim analysis will be conducted.

After the interim analysis/analyses (depending on the outcomes), a decision will be made by consensus of the Data Safety and Monitoring Board(DSMB), Kinex, Zenith Technology, and the Principal Investigator as to what dose should be administered in Stage 2. The DSMB will consist of a clinical oncologist, an ethicist, an independent statistician, and additional members, as deemed necessary. A DSMB charter will describe the planned evaluations and decision points used to determine the dose for Stage 2. An additional 18 to 42 evaluable participants will be enrolled into Stage 2 based on the Stage 1 results (AUC0-∞). Thus a total of up to 54 evaluable participants could potentially be enrolled in this study (6 each from Stage 1, Cohorts 1 and 2, and up to 42 participants in Stage 2).

Arms: arm 1: The treatment sequences will be:

A Oraxol (paclitaxel + HM30181) on Days 1, 2, and 3 of Treatment Period 1 followed by IV paclitaxel on Day 1 of Treatment Period 2 B IV paclitaxel on Day 1 of Treatment Period 1 followed by Oraxol on Days 1, 2, and 3 of Treatment Period 2 arm 2: The treatment sequences will be:

A IV paclitaxel on Day 1 of Treatment Period 1 followed by Oraxol on Days 1, 2, and 3 of Treatment Period 2 B Oraxol (paclitaxel + HM30181) on Days 1, 2, and 3 of Treatment Period 1 followed by IV paclitaxel on Day 1 of Treatment Period 2
Interventions: intervention 1: HM30181 methanesulfonate monohydrate plus oral paclitaxel capsules
Intervention descriptions: intervention 1: HM30181 methanesulfonate monohydrate plus oral paclitaxel capsules

Oral paclitaxel capsules

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol_Amendment 05 
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Kinex Pharmaceuticals, Inc. 
FINAL (v6.0):  09 Nov 2017  
Confidential 
i 
 
REVISION HISTORY 
Revisions to KX-ORAX-002 Version 5.0 05 Jul 2017 (Amendment 04 protocol) 
Current Version and Date:  v6.0_09 Nov 2017 (Amendment 05) 
Change 
Rationale 
Affected Protocol Sections 
Revised eligibility criteria at 
Screening/Baseline for hemoglobin, 
from ≥100 g/L to ≥90 g/L 
A lower threshold of 90 g/L 
hemoglobin is acceptable in 
terms of participant safety and 
will facilitate enrollment. 
• 
Synopsis / Inclusion Criteria 
• 
Section 8.3.1 
Made the provision that the study may 
be conducted internationally. 
Additional sites may be added 
outside of New Zealand. 
• 
Synopsis / Sites 
• 
Section 5 
• 
Section 8.3 
• 
Section 8.4.2.4 
Provided a general reference to Health 
Authority(ies) and Ethics Committees. 
Because the study may extend 
to countries outside of New 
Zealand; editorial.  
• 
List of Abbreviations and Definition 
of Terms 
• 
Section 10.1 
• 
Section 11.1 
• 
Section 11.3 
• 
Section 11.6 
• 
Section 11.10 
• 
Section 11.11 
Deleted reference to a CRO 
(Pharmaceuticol Ltd). 
Correction. 
• 
Section 5 
 
 
 


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Revisions to KX-ORAX-002 Version 4.0 13 May 2017 (Amendment 03 protocol) 
Current Version and Date:  v5.0_05 July 2017 (Amendment 04) 
Change 
Rationale 
Affected Protocol Sections 
Added to inclusion criteria GGT 
values (<10 x ULN at Screening) to 
demonstrate adequate liver function. 
Preliminary data suggest that 
subjects who receive Oraxol 
with screening GGT ≥10 x 
ULN may be at increased risk 
for early onset of severe 
neutropenia or serious adverse 
events. 
• 
Synopsis/Inclusion Criteria #5 
• 
Section 8.3.1/Inclusion Criteria #5 
 
 
 


Clinical Study Protocol_Amendment 05 
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Revisions to KX-ORAX-002 Version 3.0 (Amendment 02 protocol) 
Current Version and Date:  v4.0_13 May 2017 
Change 
Rationale 
Affected Protocol Sections 
Per the Sponsor Protocol Clarification 
Letter, added new text that it is 
acceptable to place a pre-emptive 
PICC line in patients with difficult 
venous access if problems arise when 
taking blood from the peripheral IV 
catheter during PK sampling. 
Clarification. 
• 
Section 8.5.1.4.1 
Added new text that subject is eligible 
when alkaline phosphatase (ALP) >5 x 
ULN if liver or bone metastasis are 
present and the major fraction of ALP 
is from bone metastasis, at the 
discretion of the Investigator. 
Clarification. 
• 
Synopsis/Inclusion Criteria 
• 
Section 8.3.1 
Added a column to the schedules for 
Days 6-8 of the IV paclitaxel 
treatment period to differentiate from 
treatment and PK sampling on Days 
1-5.  For both sequences, the entire IV 
paclitaxel treatment period includes 
Days 1-8. 
Clarification. 
• 
Table 10/footnote b 
• 
Table 11/footnote b 
Vital signs, concomitant medications, 
and adverse events that were to be 
collected on Days 6-8 of the IV 
paclitaxel treatment period will be 
assessed at the next visit. 
Because there is no PK 
sampling on Days 6-8, 
collection of these parameters 
required participants to remain 
at the site for an additional 3 
days.  Removal of these 
increases participants’ comfort. 
• 
Table 10 
• 
Table 11 
Removed designated study day for the 
Final Visit on the Schedules of 
Assessments. 
Clarification; footnote c already 
describes when the Final Visit 
can occur. 
• 
Table 10 
• 
Table 11 
Revised language related to data 
collection and data management. 
Clarification. 
• 
Section 8.6.1 
• 
Section 8.6.2 
• 
Section 11.4 
Removed reference to “CRF”. 
Clarification; this is an EDC 
study. 
• 
Throughout document 
Made minor spelling, punctuation, and 
definition corrections. 
Administrative. 
• 
Throughout document 
 
 


Clinical Study Protocol_Amendment 05 
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Revisions to KX-ORAX-002 Version 2.0 (Amendment 01 protocol) 
Current Version and Date:  v3.0_26 Jan 2017 
Change 
Rationale 
Affected Protocol Sections 
Revised description of delayed 
treatment/dose interruption by 
extending the allowed delay from 
2 weeks to 3 weeks. 
To provide scheduling 
flexibility. 
• 
Synopsis 
- Study Design 
- Duration of Study Participation 
• 
Section 8.1 
• 
Section 8.1.2.1 
• 
Section 8.4.1.3 
• 
Table 10/footnote b 
• 
Table 11/footnote b 
Supplemented description of the PK 
analyses. 
Clarification. 
• 
Synopsis/PK Analyses 
• 
Section 8.7.1.7.1 
Revised language related to sample 
size. 
Clarification based on interim 
analysis of data from the first 
6 participants in the study. 
• 
Synopsis/Sample Size Rationale 
• 
Section 8.7.2 
Stipulated that subjects whose Oraxol 
dosing is temporarily suspended may 
be re-enrolled at a later time. 
Clarification. 
• 
Section 8.1 
Revised Section heading for Adverse 
Events Assessments to remove ‘Other 
Events of Interest’; stipulated that 
laboratory AEs considered serious 
should be reporting using SAE 
reporting procedures. 
Revised description of other events of 
interest. 
Clarification; other events of 
interest are noted in the 
following subsection. 
 
 
 
Clarification. 
• 
Section 8.5.1.5.1 
 
 
 
 
 
 
• 
Section 8.5.1.5.2 
Revised where instructions for SAE 
reporting will be located (investigator 
file, not the safety management plan). 
Clarification. 
• 
Section 8.5.4.1 
Removed reference to exposure to 
study drug through breastfeeding in 
section heading. 
Revised language relating to 
pregnancy reporting. 
Text does not have language 
related to exposure through 
breastfeeding. 
 
Clarification. 
• 
Section 8.5.4.2 
Specified that the Oraxol IB should be 
used for SAE determination in the 
context of expedited reporting. 
Clarification. 
• 
Section 8.5.4.4 
Revised language related to reporting 
other events of interest associated with 
overdose or medication error. 
Clarification. 
• 
Section 8.5.4.3.1 
Revised language related to reporting 
treatment-emergent significant 
laboratory abnormality. 
Clarification. 
• 
Section 8.5.4.3.2 


Clinical Study Protocol_Amendment 05 
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Revisions to KX-ORAX-002 Version 2.0 (Amendment 01 protocol) 
Current Version and Date:  v3.0_26 Jan 2017 
Change 
Rationale 
Affected Protocol Sections 
Provided criteria for excluding 
participants from analyses if they 
vomit. 
Clarification for the PK 
Analysis Set. 
• 
Section 8.7.1.2 
Revised description of the safety 
analysis set. 
Clarification to align with 
definition in Section 8.7.1.2. 
• 
Section 8.7.1.8 
Revised the Sponsor (medical) 
signatory. 
Administrative. 
• 
Protocol Signature Page 
 
 
 


Clinical Study Protocol_Amendment 05 
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Revisions to KX-ORAX-002 Version 1.0 (original protocol) 
Current Version and Date:  v2.0_23 Jan 2016 
Change 
Rationale 
Affected Protocol Sections 
Additional wording to describe 
procedures for participants 
experiencing unacceptable toxicities 
during the Treatment Phase.  
Unacceptable toxicities for which 
study treatment may be delayed are 
provided in Appendix 2.  Clarified that 
grades discussed in Appendix 2 are 
based on CTCAE v4.03. 
Instructions are provided allowing 
participants who experience 
unacceptable toxicity following 
Oraxol treatment during this study to 
be enrolled in Study KX-ORAX-003 
with dose reduction as allowed in that 
protocol, if considered appropriate by 
the Investigator.   
Investigator request for 
clarification concerning clinical 
management of toxicity. 
• 
Synopsis / Study Design - Stages 
and Cohorts  
• 
Section 8.1 
• 
Section 8.1.2.1 
• 
Appendix 2 
Additional wording to describe 
procedures for managing anaphylaxis 
and severe hypersensitivity reactions 
or minor infusion reactions if they 
occur after IV paclitaxel infusion and 
if PK sampling should continue.  If the 
infusion is slowed or interrupted, the 
PK sampling will be modified.  
Appendix 3 describes the changes to 
the PK sampling times. 
Investigator request for 
clarification on management of 
toxicity associated with IV 
paclitaxel infusion and PK 
sampling in participants with 
infusion reactions. 
• 
Synopsis / PK sampling timepoints 
table (added footnote) 
• 
Section 8.1.2.1 
• 
Section 8.5.1.4.1, Table 4 footnote b 
• 
Appendix 3 
Additional instructions for 
management of nausea or vomiting 
after Oraxol treatment for doses 
subsequent to the first dose.  
Directions are provided in the event 
there is vomiting within 4 hours 
postdose Oraxol on PK sampling days. 
Investigator request for 
clarification on the use of 
premedication and PK 
management of participants 
who vomit following Oraxol 
treatment. 
• 
Section 8.1.2.1 
• 
Section 8.5.1.4.1, Tables 6, 7, 8 
footnote b 
Inclusion Criteria #4:  Adequate 
hematologic status at 
Screening/Baseline, value for absolute 
neutrophil count (ANC) revised from 
≥1.0 x 109/L to ≥1.5 x 109/L. 
Typographical correction. 
• 
Synopsis / Inclusion Criteria 
• 
Section 8.3.1 
Inclusion Criteria #4:  Adequate 
hematologic status at 
Screening/Baseline, value for 
hemoglobin (Hgb) revised from 
9.0 g/L to ≥100 g/L. 
Typographical correction. 
• 
Synopsis / Inclusion Criteria 
• 
Section 8.3.1 


Clinical Study Protocol_Amendment 05 
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Revisions to KX-ORAX-002 Version 1.0 (original protocol) 
Current Version and Date:  v2.0_23 Jan 2016 
Change 
Rationale 
Affected Protocol Sections 
Participants who use warfarin are 
excluded from the study with the 
exception of those who are receiving 
warfarin and are otherwise eligible and 
who may be appropriately managed 
with low molecular weight heparin, in 
the opinion of the investigator.  They 
may be enrolled in the study provided 
they are switched to low molecular 
weight heparin at least 7 days prior to 
receiving study treatment. 
Investigator request for 
clarification on allowed use of 
anticoagulants. 
• 
Synopsis / Exclusion Criteria 
• 
Section 8.3.2 
• 
Section 8.4.7.2 
Revised the chemical name of 
paclitaxel 
Standardization of chemical 
nomenclature. 
• 
Synopsis / Name of Active 
Ingredient 
• 
Section 8.4.2.1 
Revised study drug code, chemical 
name and description of molecular 
weight of HM30181.  Standardized 
use of product name of tablets 
(HM30181AK-US) vs study drug code 
(HM30181). 
Standardization of chemical 
nomenclature. 
• 
Section 8.4.2.2 
• 
Throughout document 
Changed address of Sponsor 
responsible for packaging/labeling of 
investigational materials 
Administrative. 
• 
Section 8.4.2.4 
Revised prohibited medications noted 
in Section 8.4.7.2 to be consistent with 
exclusion criteria.  Clarification that 
prohibited P450 (CYP) 3A4 and 
CYP2C8 inducers are strong inducers.  
To be consistent with KX-ORAX-003, 
examples of oral medications with a 
narrow therapeutic index known to be 
a P-gp substrate are provided.  It is 
noted that a list of prohibited 
medications will be provided to the 
sites as part of the Pharmacy Manual.  
Reference 7 is deleted which adjusts 
numbering of other references. 
Typographical correction and 
clarification. 
• 
Synopsis / Exclusion Criteria 
• 
Section 8.3.2 
• 
Section 8.4.7.2 
• 
Section 9 
Removed participant withdrawal as 
sole reason for noncompliance 
Clarification. 
• 
Section 8.4.8 
Additional instructions for PK blood 
sampling are included, specifically, 
about not using a central line; 
information on the placement of an IV 
catheter for this purpose is provided. 
Clarification. 
• 
Section 8.5.1.4.1 


Clinical Study Protocol_Amendment 05 
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Revisions to KX-ORAX-002 Version 1.0 (original protocol) 
Current Version and Date:  v2.0_23 Jan 2016 
Change 
Rationale 
Affected Protocol Sections 
Revised dose calculation to be made 
according to the screening BSA; added 
text to qualify dose adjustment; 
stipulated that BSA will be 
recalculated if there is a ≥10% weight 
change, and that BSA will be 
calculated to 1 decimal place. 
Clarification. 
• 
Synopsis / Investigational product, 
dosage and mode of administration  
• 
Section 8.1 
• 
Section 8.4.1.1 
• 
Section 8.5.1.5.5 
• 
Section 8.5.2.1, Table 10, footnote e 
• 
Section 8.5.2.1, Table 11, footnote e 
Indicated measurement of weight at 
Baseline for Treatment Period 1. 
Typographical correction. 
• 
Section 8.5.2.1, Table 10 
• 
Section 8.5.2.1, Table 11 
Removed axis as part of ECG 
recording. 
This parameter will not be 
reported routinely. 
• 
Section 8.5.1.5.7 
Instructions added on management of 
participants who have clinically 
significant ECG abnormalities 
identified post dosing 
Investigator request for 
clarification of safety 
management. 
• 
Section 8.5.1.5.7 
The status of treatment compliance is 
removed as part of information 
gathered if a participant who 
discontinued and does not return for 
visits. 
All treatments are given at the 
study site. 
• 
Section 8.5.5 
Miscellaneous edits and correction of 
formatting 
Administrative. 
Throughout document 
 




Clinical Study Protocol_Amendment 05 
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Confidential 
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INVESTIGATOR SIGNATURE PAGE 
 
Study Protocol Number: 
KX-ORAX-002 
Study Protocol Title: 
A Randomized Crossover Study to Determine the Bioequivalence of 
Three Consecutive Daily Doses of Oraxol in Cancer Patients Treated 
With Intravenous Paclitaxel 
Investigational Product 
Name: 
Oraxol 
UTN Number: 
U1111-1167-2526 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
 
 
<Name, degree(s)> 
 
 
 
 
Investigator 
 
Signature 
 
Date 
<Name of study site> 
 
 
 
 
Study Site  
 
 
 
 
 
 


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1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
KX-ORAX-002 
Study Protocol Title: 
A Randomized Crossover Study to Determine the Bioequivalence of Three 
Consecutive Daily Doses of Oraxol in Cancer Patients Treated With 
Intravenous Paclitaxel 
Sponsor: 
United States: 
Kinex Pharmaceuticals, Inc. 
20 Commerce Drive 
Cranford, New Jersey 07016, US 
Tel:  +1 908-272-0628 
New Zealand: 
Zenith Technology Corporation, Ltd. 
156 Frederick Street 
Dunedin 9016, New Zealand 
Tel:  +64 3–477 9669 
Investigational 
Product Name: 
Oraxol 
Indication: 
Cancers treated with Intravenous Paclitaxel  
Phase: 
1 
Approval Date:  
v1.0 
v2.0 
v3.0 
v4.0 
v5.0 
v6.0 
28 May 2015 (original protocol) 
23 Jan 2016 (Amendment 01) 
26 Jan 2017 (Amendment 02) 
13 May 2017 (Amendment 03) 
05 Jul 2017 (Amendment 04) 
09 Nov 2017 (Amendment 05) 
UTN Number: 
U1111-1167-2526 
GCP Statement: 
This study is to be performed in full compliance with International Council 
for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information of Kinex 
Pharmaceuticals, Inc. (the Sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly 
prohibited.  Such information may be used solely for the purpose of 
reviewing or performing this study. 


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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound:  Oraxol (oral HM30181AK-US tablet and paclitaxel capsule) 
Name of Active Ingredient 
HM30181 methanesulfonate monohydrate:  
N-(2-(2-(4-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-
dimethoxyphenyl)-4-oxo-4H-chromene-2-carboxamide Methanesulfonate monohydrate 
Paclitaxel: 
 
5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13- ester 
with (2R,3S)-N-benzoyl-3-phenylisoserine 
Study Protocol Title 
A Randomized Crossover Study to Determine the Bioequivalence of Three Consecutive Daily Doses 
of Oraxol in Cancer Patients Treated With Intravenous Paclitaxel 
Lead Principal Investigator 
Christopher Jackson, MBChB, FRACP  
Sites 
Approximately 4-5 centers internationally  
Study Period and Phase of Development 
First participant in to last participant out, approximately 12-18 months 
Phase 1 
Objectives 
Primary Objective: 
• 
To compare the bioequivalence (BE) based on the area under the curve extrapolated to 
infinity (AUC0-∞) of orally administered paclitaxel (Oraxol) at the estimated clinical dose to 
that of intravenous (IV) paclitaxel 
Secondary Objective: 
• 
To determine the safety and tolerability of Oraxol 
Background 
Oraxol is an oral dosage form of the IV chemotherapeutic agent paclitaxel (Taxol® and generics).  It 
is administered orally as a combination of 2 separate drugs, a novel P-glycoprotein (P-gp) inhibitor, 
HM30181 methanesulfonate monohydrate and oral paclitaxel.  Oraxol has been administered to 
approximately 111 patients with cancer at paclitaxel doses ranging from 60 mg/m2 to 420 mg/m2 once 
weekly to up to 270 mg per day given 5 days per week (approximately 150 mg/m2 per day or 750 
mg/m2 per week) for 3 out of 4 weeks.  The overall safety profile of Oraxol was similar to that of IV 
Taxol, with the exception that premedication is not required since the paclitaxel is administered orally 
and the formulation does not contain Cremophor®. 
A variety of dosage regimens are approved for the therapeutic use of Taxol, including 135 mg/m2, 
and 175 mg/m2 administered as both 3-hour and 24-hour infusions once every 3 weeks.  These 
various doses and infusion durations led to a wide range in Cmax values (195 – 3650 ng/mL) while the 
paclitaxel exposure (AUC) for these doses vary to a lesser extent (6300 – 15,007 ng·hr/mL).  An 
alternative dosing regimen of 80 mg/m2 weekly which may be associated with better outcomes is 


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increasingly used, including in New Zealand. 
Results of a study recently completed in New Zealand (ORAX-01-14-NZ) show that the absolute 
bioavailability (BA) of paclitaxel in Oraxol is approximately 14%.  Therefore, an oral paclitaxel dose 
of 205 mg/m2 administered for 3 consecutive days per week (ie, a total weekly dose of 615 mg/m2) is 
likely to produce a paclitaxel exposure (AUC) similar to that of 80 mg/m2 IV paclitaxel per week.   
Study Design 
This is a multicenter, open-label, 2-stage study with a 2-treatment period crossover design.  Eligible 
participants are adults with cancer for whom weekly therapy with IV paclitaxel at a dose of 80 mg/m2 
over 1 hour is indicated. 
Stage 1 will consist of an initial cohort (Cohort 1) up to 6 evaluable participants who will receive a 
dosing regimen of Oraxol consisting of a 15-mg oral HM30181AK-US tablet plus an oral paclitaxel 
dose of 205 mg/m2, both administered once daily for 3 consecutive days.  The stages and cohorts are 
further described in the “Study Design - Stages and Cohorts” table below.  An interim analysis of 
pharmacokinetic (PK) data from Cohort 1 will be conducted to determine if the administered regimen 
would appear likely to achieve BE (AUC0-∞), if tested in a greater number of participants in Stage 2.  
If it appears unlikely that the selected regimen will meet the criteria for BE based on AUC0-∞ data, a 
second cohort (Cohort 2) of up to 6 evaluable participants may be enrolled in Stage 1, and the dose of 
paclitaxel in Oraxol may be adjusted by a maximum of +/- 25%.  If Cohort 2 is enrolled, a second 
interim analysis will be conducted. 
After the interim analysis/analyses (depending on the outcomes), a decision will be made by 
consensus of the DSMB, Kinex, Zenith Technology, and the Principal Investigator as to what dose 
should be administered in Stage 2.  The DSMB will consist of a clinical oncologist, an ethicist, an 
independent statistician, and additional members, as deemed necessary.  A DSMB charter will 
describe the planned evaluations and decision points used to determine the dose for Stage 2.  An 
additional 18 to 42 evaluable participants will be enrolled into Stage 2 based on the Stage 1 results 
(AUC0-∞).  Thus a total of up to 54 evaluable participants could potentially be enrolled in this study 
(6 each from Stage 1, Cohorts 1 and 2, and up to 42 participants in Stage 2).   
Study Design – Stages and Cohorts 
Stage 1:  
Cohort 1 
An initial cohort of up to 6 participants will be treated at an oral paclitaxel dose of 205 mg/m2 once 
daily for 3 consecutive days to confirm that it is an acceptable regimen.  The standard deviation (SD) 
and the 90% 2-sided confidence interval (CI) on AUC0-∞ will be determined.  If it appears likely that 
the selected regimen will meet the criteria for BE based on AUC0-∞, additional participants will be 
enrolled in Stage 2 at this dose. 
Cohort 2 
If it appears unlikely that the selected regimen will meet the criteria for BE based on AUC0-∞ data 
from the first cohort, the dose of paclitaxel in Oraxol may be further adjusted by a maximum of 
+/- 25% in an additional cohort of up to 6 participants in Stage 1. 
Stage 2: 
An additional 18 to 42 participants will be enrolled in Stage 2 at the dosing regimen from Stage 1 that 
is considered most likely to demonstrate bioequivalence.  Including the 6 participants from Stage 1, a 
total of 24 to 48 participants will receive the Stage 1 dose that is considered most likely to 
demonstrate bioequivalence. 
 


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The study includes a Pretreatment and Treatment Phase.  The Pretreatment Phase consists of 
Screening and Baseline Periods.  During the 2-treatment crossover sequence (Sequence A or B) in the 
Treatment Phase, participants will be treated with a single dose of IV paclitaxel 80 mg/m2 infused 
over 1 hour and a dosing regimen of Oraxol expected to achieve BE to the IV paclitaxel dosing 
regimen.  (The actual Oraxol dosing regimen will depend on the cohort, as explained above).  
Treatment may be delayed for unacceptable toxicities (Appendix 2).  A Follow-up Period will occur 
after completion of both treatment periods. 
The treatment sequences will be: 
A. Oraxol (HM30181AK-US tablet + paclitaxel capsules) on Days 1, 2, and 3 of Treatment 
Period 1 followed by IV paclitaxel on Day 1 of Treatment Period 2 
B. IV paclitaxel on Day 1 of Treatment Period 1 followed by Oraxol on Days 1, 2, and 3 of 
Treatment Period 2 
Participants will be randomized to receive either treatment Sequence A or B (see below). 
 
Pretreatment Phase 
Treatment Phase 
 
 
Screening 
Baseline 
Treatment Period 1 
Treatment Period 2 
Final 
Visit 
Sequence A 
(Oraxol, IV 
paclitaxel) 
Day -28 
to Day -2 
Day –1 
Days 1-3 (dosing) 
Days 1-9 (treatment 
period) 
Days 1-9 (PK sampling)a,b 
Day 1 (dosing) 
Days 1-8 (treatment 
period) 
Days 1-5 (PK 
sampling)a 
Within 
2 weeks 
after the 
last PK 
sample 
 
Sequence B 
(IV 
paclitaxel, 
Oraxol) 
Day -28 
to Day -2 
Day –1 
Day 1 (dosing) 
Days 1-8 (treatment 
period)c 
Days 1-5 (PK sampling)a 
Days 1-3 (dosing) 
Days 1-9 (treatment 
period) 
Days 1-9 (PK 
sampling)a,d 
Within 
2 weeks 
after the 
last PK 
sample 
IV = intravenous; PK = pharmacokinetic. 
a:  Pharmacokinetic sampling timepoints may be adjusted based on the Stage 1 results. 
b:  For Sequence A, Treatment Period 1 ends on the morning of Day 9 (144 hrs after the third dose of 
Oraxol).  If Day 9 of Treatment Period 1 is also Day 1 of Treatment Period 2, the last PK sampling timepoint 
in Treatment Period 1 may serve as the predose timepoint for IV paclitaxel in Treatment Period 2. 
c:  For Sequence B, Treatment Period 1 ends on the morning of Day 8 (168 hrs after IV paclitaxel dosing).  
d:  For Sequence B, a predose PK sampling must be taken prior to Oraxol dosing on Day 1 in Treatment 
Period 2, as the PK sampling for IV paclitaxel ends on Day 5 of Treatment Period 1. 
For Sequence A, the second treatment may be administered 6 days after completion of the 3-day 
Oraxol dosing (ie, on Day 9) in Treatment Period 1 and the 144-hour PK sample has been collected.  
For Sequence B, the second treatment may be administered 7 days after completion of the IV 
paclitaxel dosing in Treatment Period 1 (ie, on Day 8). 
The second period of randomized treatment may be delayed for up to 3 weeks, if needed, to allow the 
participant to recover to ≤ Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) or 
baseline toxicity from the prior study treatment or to allow the participants flexibility in scheduling 
inpatient treatment.   
Pharmacokinetic blood samples will be collected according to designated timepoints.  
Pharmacokinetic sampling timepoints may be adjusted based on the Stage 1 results. 
 


Clinical Study Protocol_Amendment 05 
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FINAL (v6.0):  09 Nov 2017  
Confidential 
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Participants who successfully complete this study may be eligible to receive additional treatment with 
Oraxol in a follow-on, safety, clinical response, and PK study.  Participants who experience 
unacceptable toxicity following Oraxol treatment in this study, may enroll in Study KX-ORAX-003, 
with dose reduction as allowed in that protocol, if considered appropriate by the Investigator.   
Inclusion Criteria 
Eligible participants must have/be: 
1. Signed written informed consent 
2. Males and females ≥18 years of age on day of consent 
3. Cancer patients for whom treatment with IV paclitaxel at 80 mg/m2 has been recommended by 
their oncologist, either as monotherapy or in combination with other agents 
4. Adequate hematologic status at Screening/Baseline:  
• 
Absolute neutrophil count (ANC) ≥1.5 x 109/L 
• 
Platelet count ≥100 x 109/L 
• 
Hemoglobin (Hgb) ≥90 g/L 
5. Adequate liver function at Screening/Baseline as demonstrated by:  
• 
Total bilirubin of ≤20 μmol/L or ≤30 μmol/L for participants with liver metastasis 
• 
Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN) or ≤5 x ULN if liver 
metastasis is present 
• 
Alkaline phosphatase (ALP) ≤3 x ULN or ≤5 x ULN if liver or bone metastasis are present 
• 
ALP >5 x ULN if liver or bone metastasis are present and the major fraction of ALP is 
from bone metastasis, at the discretion of the Investigator  
• 
Gamma glutamyl transferase (GGT) <10 x ULN 
6. Adequate renal function at Screening/Baseline as demonstrated by serum creatinine ≤177 μmol/L 
or creatinine clearance >50 mL/min as calculated by the Cockcroft and Gault formula 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
8. Life expectancy of at least 3 months 
9. Willing to fast for 8 hours before and 4 hours after Oraxol administration 
10. Willing to abstain from alcohol consumption for 3 days before the first dose of study drug 
through the completion of protocol-specified PK sampling in Treatment Period 2 
11. Willing to refrain from caffeine consumption for 12 hours before each treatment period through 
the completion of protocol-specified PK sampling for that dose 
12. Women must be postmenopausal (>12 months without menses) or surgically sterile (ie, by 
hysterectomy and/or bilateral oophorectomy) or, if sexually active, must be using effective 
contraception (ie, oral contraceptives, intrauterine device, double barrier method of condom and 
spermicide) and agree to continue use of contraception for the duration of their participation in 
the study. Women of childbearing potential must agree to use contraception for 30 days after their 
last dose of study drug. 
13. Sexually active male participants must use a barrier method of contraception during the study and 
agree to continue the use of male contraception for at least 30 days after the last dose of study 
drug. 
 


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Exclusion Criteria 
Eligible participants must not have/be: 
1. Currently taking a prohibited concomitant medication: 
• 
Strong inhibitors (eg, ketoconazole) or strong inducers (eg, rifampin or St. John's Wort) of 
cytochrome P450 (CYP) 3A4 (within 2 weeks prior to the start of dosing in the study) 
• 
Strong inhibitors (eg, gemfibrozil) or strong inducers (eg, rifampin) of CYP2C8 (within 
2 weeks prior to the start of dosing in the study) 
• 
Known P-glycoprotein (P-gp) inhibitors or inducers.  Participants who are taking such 
medications but who are otherwise eligible may be enrolled if they discontinue the 
medication ≥1 week before dosing and remain off that medication through the end of PK 
sampling after the administration of the second study treatment 
• 
An oral medication with a narrow therapeutic index known to be a P-gp substrate (eg, 
digoxin, dabigatran) within 24 hours prior to start of dosing in the study 
2. Use of warfarin.  Participants receiving warfarin who are otherwise eligible and who may be 
appropriately managed with low molecular weight heparin, in the opinion of the Investigator, 
may be enrolled in the study provided they are switched to low molecular weight heparin at least 
7 days prior to receiving study treatment. 
3. Unresolved toxicity from prior chemotherapy (participants must have recovered all significant 
toxicity to ≤ Grade 1 CTCAE toxicity from previous anticancer treatments or previous 
investigational agents). This does not extend to symptoms or findings that are attributable to the 
underlying disease 
4. Received investigational agents within 14 days or 5 half-lives prior to the first study dosing day, 
whichever is longer 
5. Women of childbearing potential who are pregnant or breast feeding 
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, clinically significant myocardial infarction within the last 
6 months, unstable angina pectoris, clinically significant cardiac arrhythmia, bleeding disorder, 
chronic pulmonary disease requiring oxygen, or psychiatric illness/social situations that would 
limit compliance with study requirements 
7. Major surgery to the upper gastrointestinal (GI) tract, or have a history of GI disease or other 
medical condition that, in the opinion of the Investigator may interfere with oral drug absorption 
8. A known history of allergy to paclitaxel. Participants whose allergy was due to the IV solvent 
(such as Cremophor) and not paclitaxel will be eligible for this study. 
9. Any other condition which the Investigator believes would make a subject’s participation in the 
study not acceptable 
Investigational product, dosage and mode of administration  
Test drug:  Oraxol (oral HM30181 + paclitaxel) 
• 
HM30181 methansulfonate monohydrate – supplied as 15-mg HM30181AK-US tablets 
• 
Paclitaxel – supplied as 30-mg capsules 
Reference Drug:  IV paclitaxel – supplied as Taxol or generic from a single manufacturer 
 


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Dosing will be as follows: 
Oraxol:  
• 
15 mg oral HM30181AK-US tablet daily for 3 consecutive days plus oral paclitaxel capsules 
administered once daily for 3 consecutive days.  The HM30181AK-US tablet will be 
administered 1 hour before the oral paclitaxel capsules; no premedication is allowed before 
the first dose of Oraxol.  Premedication may be given before subsequent doses for 
hypersensitivity reactions and/or nausea or vomiting. 
o Stage 1, Cohort 1:  oral paclitaxel capsules dose - 205 mg/m2 once daily for 
3 consecutive days.   
o or if needed, Stage 1, Cohort 2:  oral paclitaxel capsules adjusted dose of a maximum 
of +/- 25% of the 205 mg/m2 dose once daily for 3 consecutive days  
o Stage 2:  dose determined in Stage 1 as likely to achieve BE based on PK interim 
analysis/analyses  
Paclitaxel: 
• 
80 mg/m2 IV paclitaxel (from a single manufacturer) infused over 1 hour plus premedication 
per standard local practice. 
The dose of oral paclitaxel for Stage 1, Cohort 1 will be calculated as the number of 30-mg capsules 
needed to dose participants with 615 mg/m2 over 3 days based on screening body surface area (BSA).  
The total number of capsules will be rounded up.  If the number of capsules is not divisible by 3, a 
single extra capsule will be taken on Day 1; 2 extra capsules will be taken as 1 capsule each on Days 
1 and 2.  The dose of oral paclitaxel for Stage 1, Cohort 2 and Stage 2 will be calculated similarly 
based on results of the planned interim analyses. 
Duration of Study Participation 
The total duration of participation for each participant will be up to a maximum of 80 days as follows: 
Phase 
Periods 
Days 
Pretreatment Phase 
Screening Period and Baseline Period 
up to 28 days 
Treatment Phase 
Treatment Periods 1 and 2: 
16 to 17 days (plus up to 21 days 
if treatment delay is needed) 
 
Follow-up Period: 
up to 14 days 
 
 
 


Clinical Study Protocol_Amendment 05 
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Assessments 
Activity Assessments: Not applicable  
Pharmacokinetic: PK sampling times for measurement of plasma concentrations of study drug are 
shown below. 
Treatment 
PK Sampling Timepoints 
Oraxol 
(HM30181 + paclitaxel) 
Treatment Period 1 or 2: 
Day 1 dosing:  predose, and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 
and 12 hours after the first dose (Day 1) 
Day 2 dosing:  predose, and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 
and 12 hours after the second dose (Day 2) 
Day 3 dosing:  predose, and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 
12, 24, 48, 72, 96, 120, and 144 hours after the third dose (Days 
3-9) 
IV Paclitaxela 
Treatment Period 1 or 2: 
Predose, during infusion at 2, 5, 8, 12, 20, 40, and 60 minutes, 
after infusion at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 
56, 72, and 96 hours (Days 1-5) 
a. In the event that the IV paclitaxel infusion is slowed or temporarily interrupted due to IV paclitaxel infusion 
reaction, PK blood sampling should continue according to the modified schedule in Appendix 3. 
Pharmacodynamic:  Not applicable 
Pharmacokinetic-Pharmacodynamic:  Not applicable 
Safety:  Safety will be assessed by recording all adverse events (AEs) including serious adverse 
events (SAEs) and concomitant medications, laboratory evaluation of hematology, biochemistry, and 
urinalysis values, measurement of vital signs, evaluation of electrocardiograms (ECGs) and ECOG 
performance status, and the performance of physical examinations. 
Bioanalytical Methods 
Plasma concentrations of study drug will be measured using a validated assay. 
Statistical Methods 
A total of 24 to 48 evaluable participants receiving the selected Stage 1 dose will be evaluated for BE 
between Oraxol and IV paclitaxel based on a 2-sided 90% CI of log-transformed AUC0-∞ between 
80% and 125%. 
Participants evaluable for BE will be those who receive both study treatments and complete 
scheduled post-treatment PK evaluations.  Nonevaluable participants will be replaced until up to 
48 participants have completed the study at the dose determined in Stage 1 as likely to achieve BE 
based on PK interim analysis/analyses. 
Statistical analyses will be reported using summary tables, graphs, and data listings. Continuous 
variables will be summarized using the mean, SD, median, minimum, and maximum.  Summaries of 
PK parameters will also include the geometric mean and the coefficient of variation.  Categorical 
variables will be summarized by counts and by percentage of participants in corresponding 
categories.  All raw data obtained from the electronic case report form (eCRF) as well as any derived 
data will be included in data listings. 
 


Clinical Study Protocol_Amendment 05 
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FINAL (v6.0):  09 Nov 2017  
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Pharmacokinetic Analyses 
Plasma concentrations for paclitaxel only will be analyzed to determine the following PK parameters:  
Cmax, AUC0-t and AUC0-∞ (2-sided 90% CIs); paclitaxel plasma concentrations will be normalized to 
615 mg/m2 or the final agreed dose for Stage 2 for Oraxol and 80 mg/m2 for IV paclitaxel.  
Pharmacokinetic analysis and statistical analysis will be based on normalized plasma concentrations.  
Tmax and other summary PK parameters and individual timepoints will be tabulated and displayed 
graphically and listed for all participants. 
The equivalence of the extent of absorption will be determined by comparing the AUC0-∞ of the 
selected dose of oral paclitaxel (as Oraxol) (administered over 3 consecutive days) to the AUC0-∞ of 
IV paclitaxel. 
The primary PK parameters will be compared between IV paclitaxel (reference) and oral paclitaxel 
(test) formulations.  Analysis of variance (ANOVA) will be performed (α=0.05) on the un-
transformed and log10-transformed PK parameters Cmax, AUC0-t, and AUC0-∞ for paclitaxel. The 
ANOVA model will include sequence, subjects nested within the sequence, period, and formulation 
as factors. The significance of the sequence effect will be tested using the subjects nested within the 
sequence as the error term.  Two-sided 90% CIs for the log-transformed ratio of test/reference of the 
least squares means obtained from the ANOVA for Cmax, AUC0-t, and AUC0-∞ will be estimated. 
Safety Analyses 
All participants who receive at least 1 dose of paclitaxel will be included in the safety analyses.  For 
AEs, verbatim terms on the eCRF will be mapped to preferred terms (PTs) and system organ classes 
(SOCs) using the Medical Dictionary for Regulatory Activities (MedDRA; version 16.1 or later).  
The CTCAE criteria v4.03 (or later) will be used to grade severity of the AEs.  Participant incidence 
of AEs will be displayed by SOC.  The incidence of AEs will be summarized by treatment, treatment 
period, and treatment sequence.  Adverse events will also be summarized by severity and relationship 
to the study drug and treatment sequence.  Participant incidence of SAEs will also be displayed.  
Laboratory parameters will be summarized using descriptive statistics at baseline and at each 
subsequent timepoints.  Changes from baseline will also be summarized. 
Interim Analyses 
There will be an interim analysis of PK data after each dose tested in Stage 1 to determine if the 
administered regimen would appear likely to achieve BE of Oraxol to IV paclitaxel.  After the interim 
analysis/analyses (depending on the outcomes), a decision will be made by consensus of the DSMB, 
Kinex, Zenith Technology, and the Principal Investigator as to what dose should be administered in 
Stage 2.  An additional 18 to 42 participants will be enrolled into Stage 2 based on the Stage 1 results 
(AUC0-∞). 
Sample Size Rationale 
Based on the within-subject variability of at most 30% through a comparison of pharmacokinetics of 
Oraxol to Taxol, a sample size of 24 to 48 patients is needed to achieve BE within the 80% - 125% 
confidence limits with 90% statistical power. 
Based on analysis of data from the first 6 evaluable participants in Stage 1, an additional 34 evaluable 
participants will be enrolled into Stage 2.  A total sample size of 40 evaluable participants is projected 
to provide 90% power for the 90% CI of the GMR for AUC0-∞ to fall in the range of 80% and 125%. 
Final Version and Date 
v6.0_09 Nov 2017 


Clinical Study Protocol_Amendment 05 
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Confidential 
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3 
TABLE OF CONTENTS 
REVISION HISTORY............................................................................................................... I 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................10 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................15 
5 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................17 
6 
INTRODUCTION ...........................................................................................................17 
6.1 
Indication ...............................................................................................................17 
6.1.1 
Oraxol ..........................................................................................................17 
6.1.1.1 
Clinical Experience with Oraxol ..........................................................17 
6.1.1.2 
Common Serious Adverse Events Expected to Occur in the Study 
Population Even in the Absence of Study Drug Exposure ..................19 
6.2 
Study Rationale ......................................................................................................19 
7 
STUDY OBJECTIVES ....................................................................................................20 
7.1 
Primary Objective ..................................................................................................20 
7.2 
Secondary Objective ..............................................................................................20 
8 
INVESTIGATIONAL PLAN ..........................................................................................20 
8.1 
Overall Study Design and Plan ..............................................................................20 
8.1.1 
Pretreatment Phase .......................................................................................23 
8.1.2 
Treatment Phase ...........................................................................................24 
8.1.2.1 
Treatment Periods ................................................................................24 
8.1.2.2 
Follow-up Period .................................................................................26 
8.2 
Discussion of Study Design, Including Choice of Control Groups .......................26 
8.3 
Selection of Study Population ................................................................................27 
8.3.1 
Inclusion Criteria .........................................................................................27 
8.3.2 
Exclusion Criteria ........................................................................................28 
8.3.3 
Removal of Participants from Therapy or Assessment................................29 
8.4 
Treatments..............................................................................................................29 
8.4.1 
Treatments Administered .............................................................................30 
8.4.1.1 
Oraxol ..................................................................................................30 
8.4.1.2 
Intravenous Paclitaxel ..........................................................................31 
8.4.1.3 
Criteria for Temporary Discontinuation of Treatment and 
Resumption of Treatment ....................................................................31 
8.4.2 
Identity of Investigational Product...............................................................31 
8.4.2.1 
Chemical Name, Structural Formula of Paclitaxel ..............................31 


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8.4.2.2 
Chemical Name, Structural Formula of HM30181 
Methanesulfonate Monohydrate ...........................................................32 
8.4.2.3 
Comparator Drug .................................................................................32 
8.4.2.4 
Labeling for Study Drug ......................................................................32 
8.4.2.5 
Storage Conditions ...............................................................................33 
8.4.3 
Method of Assigning Participants to Treatment Groups .............................33 
8.4.4 
Selection of Doses in the Study ...................................................................34 
8.4.5 
Selection and Timing of Dose for Each Participant .....................................34 
8.4.6 
Blinding........................................................................................................34 
8.4.7 
Prior and Concomitant Therapy ...................................................................34 
8.4.7.1 
Drug-Drug Interactions ........................................................................35 
8.4.7.2 
Prohibited Concomitant Therapies and Drugs .....................................35 
8.4.8 
Treatment Compliance .................................................................................36 
8.4.9 
Drug Supplies and Accountability ...............................................................36 
8.5 
Study Assessments .................................................................................................36 
8.5.1 
Assessments .................................................................................................37 
8.5.1.1 
Demography .........................................................................................37 
8.5.1.2 
Baseline Assessments ..........................................................................37 
8.5.1.2.1 
Medical History .............................................................................37 
8.5.1.2.2 
Prior Medications ...........................................................................37 
8.5.1.2.3 
Height .............................................................................................37 
8.5.1.3 
Efficacy Assessments...........................................................................37 
8.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................38 
8.5.1.4.1 
Pharmacokinetic Assessments .......................................................38 
8.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments ...................................................................................42 
8.5.1.5 
Safety Assessments ..............................................................................42 
8.5.1.5.1 
Adverse Events ..............................................................................42 
8.5.1.5.2 
Serious Adverse Events and Other Events of Interest ...................45 
8.5.1.5.3 
Concomitant Medications ..............................................................46 
8.5.1.5.4 
Physical Examinations ...................................................................46 
8.5.1.5.5 
Weight and Body Surface Area .....................................................46 
8.5.1.5.6 
Vital Signs ......................................................................................47 
8.5.1.5.7 
Electrocardiograms ........................................................................47 
8.5.1.5.8 
Laboratory Measurements .............................................................47 
8.5.1.5.9 
Other Safety Assessments ..............................................................48 
8.5.1.5.10 Eastern Cooperative Oncology Group Status ................................48 


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8.5.1.6 
Other Assessments ...............................................................................49 
8.5.2 
Schedule of Procedures/Assessments ..........................................................49 
8.5.2.1 
Schedule of Procedures/Assessments ..................................................49 
8.5.3 
Appropriateness of Measurements ...............................................................54 
8.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest..........................................................................................................54 
8.5.4.1 
Reporting of Serious Adverse Events ..................................................54 
8.5.4.2 
Reporting of Pregnancy .......................................................................54 
8.5.4.3 
Reporting of Other Events of Interest ..................................................55 
8.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose or Medication Error .......................................................55 
8.5.4.3.2 
Reporting of Treatment-Emergent Significant Laboratory 
Abnormality ...................................................................................55 
8.5.4.4 
Expedited Reporting ............................................................................56 
8.5.4.5 
Breaking the Blind ...............................................................................56 
8.5.4.6 
Regulatory Reporting of Adverse Events ............................................56 
8.5.5 
Completion/Discontinuation of Participants ................................................56 
8.5.6 
Abuse or Diversion of Study Drug ..............................................................57 
8.5.7 
Confirmation of Medical Care by another Physician ..................................57 
8.6 
Data Quality Assurance .........................................................................................57 
8.6.1 
Data Collection ............................................................................................57 
8.6.2 
Clinical Data Management ..........................................................................58 
8.7 
Statistical Methods .................................................................................................58 
8.7.1 
Statistical and Analytical Plans ....................................................................58 
8.7.1.1 
Study Endpoints ...................................................................................58 
8.7.1.1.1 
Primary Endpoints .........................................................................58 
8.7.1.1.2 
Secondary Endpoints .....................................................................59 
8.7.1.2 
Definitions of Analysis Sets.................................................................59 
8.7.1.3 
Disposition ...........................................................................................59 
8.7.1.4 
Demographic and Other Baseline Characteristics ...............................59 
8.7.1.5 
Prior and Concomitant Therapy ...........................................................59 
8.7.1.6 
Efficacy Analyses ................................................................................60 
8.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................60 
8.7.1.7.1 
Pharmacokinetic Analyses .............................................................60 
8.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................60 
8.7.1.8 
Safety Analyses ....................................................................................61 


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8.7.1.8.1 
Extent of Exposure .........................................................................61 
8.7.1.8.2 
Adverse Events ..............................................................................61 
8.7.1.8.3 
Laboratory Values ..........................................................................62 
8.7.1.8.4 
Vital Signs ......................................................................................62 
8.7.1.8.5 
Electrocardiograms ........................................................................62 
8.7.1.8.6 
Other Analyses ...............................................................................62 
8.7.2 
Determination of Sample Size .....................................................................62 
8.7.3 
Interim Analysis ...........................................................................................63 
8.7.4 
Other Statistical/Analytical Issues ...............................................................63 
9 
REFERENCE LIST .........................................................................................................64 
10 PROCEDURES AND INSTRUCTIONS ........................................................................65 
10.1 
Institutional Review Boards/Independent Ethics Committees ..............................65 
10.2 
Ethical Conduct of the Study .................................................................................65 
10.3 
Participant Information and Informed Consent .....................................................65 
11 ADMINISTRATIVE PROCEDURES ............................................................................66 
11.1 
Changes to the Protocol .........................................................................................66 
11.2 
Adherence to the Protocol ......................................................................................67 
11.3 
Monitoring Procedures...........................................................................................67 
11.4 
Recording of Data ..................................................................................................68 
11.5 
Identification of Source Data .................................................................................68 
11.6 
Retention of Records..............................................................................................68 
11.7 
Auditing Procedures and Inspection ......................................................................68 
11.8 
Handling of Study Drug .........................................................................................68 
11.9 
Publication of Results ............................................................................................69 
11.10 Disclosure and Confidentiality ..............................................................................69 
11.11 Discontinuation of Study .......................................................................................69 
11.12 Participant Insurance and Indemnity .....................................................................70 
12 APPENDICES .................................................................................................................71 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Study Design, Dosing, and PK Sampling in Study KX-ORAX-002 .........22 
Table 2 
Treatments Administered in KX-ORAX-002 ............................................30 
Table 3 
Blood Collection Volumes for Pharmacokinetic Analyses .......................38 
Table 4 
Pharmacokinetic Sampling for IV Paclitaxel Days 1 and 2 (Treatment 
Periods 1 or 2) ............................................................................................39 
Table 5 
Pharmacokinetic Sampling for IV Paclitaxel Days 3 to 5 (Treatment 
Periods 1 or 2) ............................................................................................39 
Table 6 
Dosing and Pharmacokinetic Sampling for Oraxol Day 1 (Treatment 
Periods 1 or 2) ............................................................................................40 
Table 7 
Dosing and Pharmacokinetic Sampling for Oraxol Day 2 (Treatment 
Periods 1 or 2) ............................................................................................40 
Table 8 
Dosing and Pharmacokinetic Sampling for Oraxol Days 3 to 9 
(Treatment Periods 1 or 2) .........................................................................41 
Table 9 
Clinical Laboratory Tests ...........................................................................48 
Table 10 
Schedule of Procedures/Assessments for Sequence A (Oraxol in 
Treatment Period 1) ...................................................................................50 
Table 11 
Schedule of Procedures/Assessments for Sequence B (IV Paclitaxel in 
Treatment Period 1) ...................................................................................52 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Crossover Study Design for Study KX-ORAX-002 ..................................21 
 
LIST OF APPENDICES 
Appendix 1 
ECOG Performance Status ........................................................................72 
Appendix 2 
Unacceptable Toxicity (Common Terminology Criteria for Adverse 
Events [CTCAE] v4.03).............................................................................73 
Appendix 3 
Instructions for Collection of Pharmacokinetic Blood Samples if 
IV Paclitaxel Infusion is Interrupted ..........................................................74 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANZCTR 
Australian New Zealand Clinical Trials Registry 
BA 
bioavailability 
BE 
bioequivalence 
BSA 
body surface area 
CI 
confidence interval 
CRA 
clinical research associate  
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FDA 
(US) Food and Drug Administration 
GCP 
good clinical practice 
GI 
gastrointestinal 
GGT 
gamma glutamyl transferase 
HA 
Health Authority 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IP 
investigational product 
IV 
intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Medsafe 
New Zealand Medicines and Medical Devices Safety Authority 
MTD 
maximum tolerated dose 


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Abbreviation 
Term 
NOS 
not otherwise specified 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PT 
preferred term 
RBC 
red blood cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SCOTT 
Standing Committee on Therapeutic Trials 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cells 
 
 
 


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5 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified Investigators under the United States sponsorship 
of Kinex Pharmaceuticals, Inc. with the New Zealand contract research organizations 
(CROs) (Zenith Technology Corporation, Ltd.) providing delegated services.  This study will 
be conducted at approximately 4-5 centers  internationally. 
The name, telephone and fax numbers, and email addresses of the medical monitor and other 
contact personnel at the Sponsor and of the CROs will be listed in the Investigator Study File 
provided to each site. 
6 
INTRODUCTION 
6.1 
Indication 
In this study, the pharmacokinetics (PK) of oral paclitaxel as Oraxol will be evaluated in 
adults with cancers for whom weekly therapy with intravenous (IV) paclitaxel at a dose of 
80 mg/m2 infused over 1 hour is indicated.  
6.1.1 
Oraxol 
Oraxol is a combination product of 2 separate drugs; oral paclitaxel and a novel 
P-glycoprotein (P-gp) inhibitor, HM30181 methanesulfonate monohydrate.  Experience to 
date indicates that co-administration of HM30181 methanesulfonate monohydrate allows for 
clinically relevant levels of paclitaxel to be achieved following oral dosing.  Oraxol is 
intended to allow for oral treatment of cancers that would otherwise be treated with IV 
paclitaxel.  Comprehensive data on the preclinical, toxicology, and clinical experience to date 
can be found in the Investigator’s Brochure. 
6.1.1.1 
Clinical Experience with Oraxol 
Previous human experience with HM30181 methanesulfonate monohydrate comes from 
3 PK studies in healthy male subjects.  In these studies, a total of 81 individuals received 
single oral doses of HM30181 methanesulfonate monohydrate ranging from 1 to 900 mg and 
24 individuals received multiple doses ranging from 60 mg to 360 mg per day for 5 days.  In 
addition to evaluating single- and multiple-dose safety and PK, 2 of these studies evaluated 
the effect of HM30181 methanesulfonate monohydrate on the PK of loperamide, a P-gp 
substrate, and 1 study also compared the effects of HM30181 methanesulfonate monohydrate 
to quinidine, a known P-gp inhibitor.  These data indicate that exposure to HM30181 
methanesulfonate monohydrate increases with dose, but not in a dose-proportional manner, 
and that the effect of HM30181 methanesulfonate monohydrate on P-gp may last for up to 
15 days following a single dose of 10 mg or higher but is not as pronounced as that of 
600 mg of quinidine. 
Oraxol has been administered to approximately 111 patients with cancer at paclitaxel doses 
ranging from 60 mg/m2 to 420 mg/m2 once weekly to up to 270 mg per day given 5 days per 


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week (approximately 150 mg/m2 per day or 750 mg/m2 per week) for 3 out of 4 weeks.  The 
overall safety profile of Oraxol was similar to that of IV Taxol®, with the exception that 
premedication is not required since the paclitaxel is administered orally and the formulation 
does not contain Cremophor®.  To date, Oraxol has been evaluated in 4 studies.  A summary 
of these studies is presented below.  For further details, please refer to the Investigator 
Brochure. 
The HM-OXL-101 study attempted to define the maximum tolerated dose (MTD) for Oraxol 
in 24 subjects with advanced solid cancer.  This was a “3+3” design in which cycles were 
28 days and dosing with HM30181A tablets and an oral liquid formulation of paclitaxel was 
given on Days 1, 8, and 15 of each cycle.  Paclitaxel doses evaluated ranged from 60 to 
420 mg/m2.  HM30181A doses were half of paclitaxel doses (30 to 210 mg/m2).  The MTD 
was not reached in this study and dose escalation was stopped because of PK nonlinearity at 
paclitaxel doses above 300 mg/m2.  The most common nonserious adverse events (AEs) were 
gastrointestinal (GI) AEs, hematologic AEs, and alopecia.  Neutropenia was the event that 
led to either temporary (4 cases) or permanent (1 case) discontinuation of Oraxol.  The only 
serious adverse event (SAE) occurred at the paclitaxel dose of 420 mg/m2.  This subject was 
hospitalized with cholangio-hepatitis and recovered after treatment with endoscopic 
retrograde biliary drainage.  The event was considered unrelated to the study medication. 
HM-OXL-201 was a 2-part study including an initial MTD assessment of Oraxol doses 90, 
120, or 150 mg/m2 paclitaxel per day for 2 days per week for 3 weeks out of a 4-week cycle 
(as liquid-filled capsules), with paclitaxel given concomitantly with a 15-mg HM30181A 
tablet on Day 1.  In the second part of this study, the selected dose of Oraxol, 150 mg/m2 per 
day, was given for 2 days per week, for 3 weeks out of a 4-week cycle.  The Investigators 
were also given the flexibility of giving an additional 15-mg tablet of HM30181A on Day 2 
of each dosing week.  A total of 56 subjects enrolled in this study, 10 subjects with advanced 
malignant tumors in Part 1 and 46 subjects with advanced gastric cancer in Part 2.  The most 
common AEs were neutropenia, anorexia, diarrhea, nausea, and abdominal pain.  In the first 
part of this study, 1 subject had SAEs of pyrexia and bacteremia (probably not related to 
study treatment).  In the second part of the study, 26 SAEs occurred in 15 subjects.  Of these, 
3 subjects experienced at least 1 SAE considered at least possibly related to study treatment.  
These included 1 subject with diarrhea and neutropenia, 1 subject with fatigue, and 1 subject 
with nausea and vomiting.  Among 43 subjects in the Intent-to-Treat population in the gastric 
cancer part of this study, 4 subjects (9.3%) had a partial response by Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria. 
Pharmacokinetic results from these 2 studies showed that the paclitaxel maximum 
concentration (Cmax) and area under the curve extrapolated to infinity (AUC0-∞) increased 
with dose up to 300 mg/m2 following administration of Oraxol.  At doses above 300 mg/m2, 
both Cmax and AUCinf plateaued.  Half-life (t1/2) ranged from 19.9 to 32.1 hours, consistent 
with published values for paclitaxel.  Metabolic ratios of 3’p-hydroxy paclitaxel and 6α-
hydroxy paclitaxel metabolites were approximately 0.1 to 0.25 and 0.04 to 0.13, respectively.  
Following 2 consecutive daily doses of Oraxol at doses of 60, 90, or 150 mg/m2, minimal to 
no accumulation occurred in paclitaxel Cmax and AUC.  The Cmax ranged from 202 to 
280 ng/mL (Day 1) and 159 to 315 ng/mL (Day 2), with minimal increase in Cmax across the 


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dose levels.  The AUC0-24 ranged from 611 to 894 ng·hr/mL (Day 1) and 735 to 
1081 ng·hr/mL (Day 2).  Overall exposure on Day 2 was about 20% to 30% higher.  These 
data indicate that Oraxol may represent a clinically useful alternative to IV paclitaxel. 
Study ORAX-01-13-US is an ongoing “3+3” MTD study of Oraxol at a fixed dose of 270 mg 
(approximately 150 mg/m2 per day) orally given 2 to 5 consecutive days per week for 3 out of 
4 weeks.  Preliminary data indicate that the most common AEs are gastrointestinal.  Ten 
SAEs have been reported to date in 7 subjects; 1 case each of neoplasm posterior fossa mass, 
syncope, right upper quadrant pain, urosepsis, liver dysfunction, nausea, vomiting, abdominal 
pain, febrile neutropenia, and pain (NOS).  Of these, febrile neutropenia, occurring in the 
5-day cohort in Cycle 1 was the only SAE considered related to study treatment and is the 
only dose-limiting toxicity (DLT) reported to date. 
A Phase 1 crossover study (Study ORAX-01-14-NZ) to determine the absolute 
bioavailability (BA) of Oraxol was conducted in New Zealand and is clinically complete.  
Oraxol doses were 270 mg paclitaxel orally daily (approximately 150 mg/m2) on 
2 consecutive days (n=6), 274 mg/m2 administered daily on 2 consecutive days (n=2), and 
313 mg/m2 daily on 2 consecutive days (n=2).  The reference treatment was paclitaxel 
80 mg/m2 IV, administered over 1 hour as a one-time infusion.  Results show that the 
absolute BA of paclitaxel in Oraxol is approximately 14% but the total drug exposure (AUC) 
of oral paclitaxel plateaus at a dose of approximately 300 mg/m2.  Therefore, an oral 
paclitaxel dose of 205 mg/m2 administered daily for 3 consecutive days per week (ie, a total 
weekly dose of 615 mg/m2) is likely to produce a paclitaxel exposure similar to that of 
80 mg/m2 IV paclitaxel per week.  The only SAE reported was urosepsis, which occurred 
prior to receiving study treatment. 
6.1.1.2 
Common Serious Adverse Events Expected to Occur in the Study Population 
Even in the Absence of Study Drug Exposure 
Serious AEs commonly occur in patients with cancer.  Manifestations typically reflect 
progression of disease, with the clinical presentation varying depending on the affected organ 
system. 
6.2 
Study Rationale 
The regimen selected for initial evaluation in this study (15 mg oral HM30181AK-US tablet 
plus 205 mg/m2 oral paclitaxel capsules both administered once daily for 3 consecutive days 
per week [ie, a total weekly dose oral paclitaxel of 615 mg/m2]) is expected to produce 
paclitaxel exposure similar to that of 80 mg/m2 IV paclitaxel administered over 1 hour given 
weekly.  A variety of dosage regimens are approved for the therapeutic use of Taxol, 
including 135 mg/m2, and 175 mg/m2 administered as both 3-hour and 24-hour infusions 
once every 3 weeks.  These various doses and infusion durations led to a wide range in Cmax 
values (195 – 3650 ng/mL) while the paclitaxel exposure (AUC) for these doses vary to a 
lesser extent (6300 – 15,007 ng·hr/mL).  An alternative dosing regimen of 80 mg/m2 weekly, 
which may be associated with better outcomes, is increasingly used.  This regimen is 
currently used in New Zealand.  A recent meta-analysis suggests that weekly paclitaxel may 


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be superior to the approved regimen (175 mg/m2 IV over 3 hours every 3 weeks) for 
advanced breast cancer.2  A similar result has been reported in adjuvant use for breast 
cancer,3 and weekly paclitaxel 80 mg/m2 IV administered over 1 hour is increasingly accepted 
as a dosing regimen in treatment guidelines.4,5 
7 
STUDY OBJECTIVES 
7.1 
Primary Objective 
The primary objective of the study is to compare the bioequivalence (BE) based on the 
AUC0-∞ of orally administered paclitaxel (Oraxol) at the estimated clinical dose to that of IV 
paclitaxel. 
7.2 
Secondary Objective 
The secondary objective of the study is to determine the safety and tolerability of Oraxol. 
8 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan 
This is a multicenter, open-label, 2-stage study with a 2-treatment period crossover design.  
Eligible participants are adults with cancer for whom weekly therapy with IV paclitaxel at a 
dose of 80 mg/m2 infused over 1 hour is indicated. 
Stage 1 will consist of an initial cohort (Cohort 1) of up to 6 evaluable participants who will 
receive a dosing regimen of Oraxol consisting of a 15-mg oral HM30181 plus an oral 
paclitaxel dose of 205 mg/m2, both administered once daily for 3 consecutive days.  The 
stages and cohorts are further described below.  An interim analysis of PK data from Cohort 
1 will be conducted to determine if the administered regimen would appear likely to achieve 
BE (using AUC0-∞), if tested in a greater number of participants in Stage 2.  If it appears 
unlikely that the selected regimen will meet the criteria for BE based on AUC0-∞ data, a 
second cohort of up to 6 evaluable participants may be enrolled in Stage 1 and the dose of 
paclitaxel in Oraxol may be adjusted by a maximum of +/- 25%.  If this cohort is enrolled, a 
second interim analysis will be conducted. 
After the interim analysis/analyses (depending on the outcomes), a decision will be made by 
consensus of the DSMB, Kinex, Zenith Technology, and the Principal Investigator as to what 
dose should be administered in Stage 2.  The DSMB will consist of a clinical oncologist, an 
ethicist, an independent statistician, and additional members, as deemed necessary.  A DSMB 
charter will describe the planned evaluations and decision points used to determine the dose 
for Stage 2.  An additional 18 to 42 participants will be enrolled into Stage 2 based on the 
Stage 1 results (AUC0-∞).  Thus a total of up to 54 evaluable participants could potentially be 
enrolled in this study (6 each from Stage 1, Cohorts 1 and 2), and up to 42 participants in 
Stage 2. 


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Study Stages:  The study will be carried out in 2 stages as follows: 
Stage 1: 
Cohort 1 
An initial cohort of up to 6 participants will be treated at an oral paclitaxel dose of 
205 mg/m2 once daily for 3 consecutive days to confirm that it is an acceptable regimen.  The 
standard deviation (SD) and the 90% 2-sided confidence interval (CI) on AUC0-∞ will be 
determined.  If it appears likely that the selected regimen will meet the criteria for BE based 
on AUC0-∞, additional participants will be enrolled in Stage 2 at this dose. 
Cohort 2 
If it appears unlikely that the selected regimen will meet the criteria for BE based on AUC0-∞ 
data from the first cohort of participants, the dose of paclitaxel in Oraxol may be further 
adjusted by a maximum of +/- 25% in an additional cohort of up to 6 participants in Stage 1. 
Stage 2: 
An additional 18 to 42 participants will be enrolled in Stage 2 at the dosing regimen from 
Stage 1 that is considered most likely to achieve bioequivalence.  Consequently, there will be 
a total of 24 to 48 participants receiving the Stage 1 dose that is considered most likely to 
demonstrate bioequivalence. 
Study Design: 
The 2-treatment period crossover design is shown in Figure 1. 
 
Figure 1 
Crossover Study Design for Study KX-ORAX-002 
The study includes a Pretreatment and Treatment Phase (see Table 1).  The Pretreatment 
Phase consists of Screening and Baseline Periods.  During the 2-treatment crossover 
sequence (Sequence A or B) in the Treatment Phase, participants will be treated with a single 
dose of IV paclitaxel 80 mg/m2 infused over 1 hour and a dosing regimen of oral Oraxol 
expected to achieve BE to the IV paclitaxel dosing regimen (Table 1).  (The actual Oraxol 
dosing regimen will depend on the cohort, as explained above).  Treatment may be delayed 


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for unacceptable toxicities (see Section 8.1.2.1 and Appendix 2).  A Follow-up Period will 
occur after completion of both treatment periods. 
The treatment sequences will be: 
A 
Oraxol (paclitaxel + HM30181) on Days 1, 2, and 3 of Treatment Period 1 
followed by IV paclitaxel on Day 1 of Treatment Period 2 
B 
IV paclitaxel on Day 1 of Treatment Period 1 followed by Oraxol on Days 1, 2, 
and 3 of Treatment Period 2 
Participants will be randomized to receive either treatment Sequence A or B.  Table 1 
summarizes the study design and the dosing and PK sampling timing for each sequence. 
Table 1 
Study Design, Dosing, and PK Sampling in Study KX-ORAX-002 
 
Pretreatment Phase 
Treatment Phase 
 
Screening 
Baseline 
Treatment Period 1 
Treatment Period 2 
Final Visit 
Sequence A 
(Oraxol, IV 
paclitaxel) 
Day -28 to 
Day -2 
Day –1 
Days 1-3 (dosing) 
Days 1-9 (treatment 
period) 
Days 1-9 (PK 
sampling)a,b 
Day 1 (dosing) 
Days 1-8 (treatment 
period) 
Days 1-5 (PK 
sampling)a 
Within 
2 weeks 
after last 
PK sample 
 
Sequence B 
(IV paclitaxel, 
Oraxol) 
Day -28 to 
Day -2 
Day –1 
Day 1 (dosing) 
Days 1-8 (treatment 
period)c 
Days 1-5 (PK 
sampling)a 
Days 1-3 (dosing) 
Days 1-9 (treatment 
period) 
Days 1-9 (PK 
sampling)a,d 
Within 
2 weeks 
after last 
PK sample 
IV = intravenous; PK = pharmacokinetic. 
a:  Pharmacokinetic sampling timepoints may be adjusted based on the Stage 1 results. 
b:  For Sequence A, Treatment Period 1 ends on the morning of Day 9 (144 hrs after the third dose of 
Oraxol).  If Day 9 of Treatment Period 1 is also Day 1 of Treatment Period 2, the last PK sampling timepoint 
in Treatment Period 1 may serve as the predose timepoint for IV paclitaxel in Treatment Period 2. 
c:  For Sequence B, Treatment Period 1 ends on the morning of Day 8 (168 hrs after IV paclitaxel dosing).  
d:  For Sequence B, a predose PK sampling must be taken prior to Oraxol dosing on Day 1 in Treatment 
Period 2, as the PK sampling for IV paclitaxel ends on Day 5 of Treatment Period 1. 
For Sequence A, the second treatment may be administered 6 days after completion of the 
3-day Oraxol dosing (ie, on Day 9) in Treatment Period 1 and the 144-hour PK sample has 
been collected.  For Sequence B, the second treatment may be administered 7 days after 
completion of the IV paclitaxel dosing in Treatment Period 1 (ie, on Day 8). 
The second period of randomized treatment may be delayed for up to 3 weeks if needed, to 
allow the participant to recover to ≤ Grade 1 Common Terminology Criteria for Adverse 
Events (CTCAE)1 or baseline toxicity from the prior study treatment or to allow the 
participants flexibility in scheduling inpatient treatment. 


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Subjects whose Oraxol dosing is temporarily suspended may be re-enrolled at a later date. 
Dosing: 
Oraxol: 
• 15 mg oral HM30181AK-US tablet daily for 3 consecutive days plus oral paclitaxel 
capsules administered once daily for 3 consecutive days.  The HM30181AK-US 
tablet will be administered 1 hour before the oral paclitaxel capsules; no 
premedication is allowed before the first dose of Oraxol.  Premedication may be 
given before subsequent doses for hypersensitivity reactions and/or nausea or 
vomiting. 
o Stage 1, Cohort 1:  oral paclitaxel capsules dose - 205 mg/m2 once daily for 
3 consecutive days. 
o or if needed, based on PK interim analysis/analyses for BE, Stage 1, Cohort 2:  
oral paclitaxel capsules adjusted dose of a maximum of +/- 25% of the 
205 mg/m2 dose once daily for 3 consecutive days  
o Stage 2:  dose determined in Stage 1 as likely to achieve BE based on PK 
interim analysis/analyses 
IV paclitaxel:  
• 80 mg/m2 IV paclitaxel (from a single manufacturer) infused over 1 hour plus 
premedication per standard local practice. 
The dose of oral paclitaxel for Stage 1, Cohort 1 will be calculated as the number of 30-mg 
capsules needed to dose participants with 615 mg/m2 over 3 days based on screening body 
surface area (BSA).  The total number of capsules will be rounded up.  If the number of 
capsules is not divisible by 3, a single extra capsule will be taken on Day 1; 2 extra capsules 
will be taken as 1 capsule each on Days 1 and 2.  The dose of oral paclitaxel for Stage 1, 
Cohort 2 and Stage 2 will be calculated similarly based on results of the planned interim 
analyses. 
Blood samples for PK assessments will be collected according to designated timepoints (see 
Section 8.5.1.4.1).  Sampling timepoints may be adjusted based on the Stage 1 results. 
Participants who successfully complete this study may be eligible to receive additional 
treatment with Oraxol at their assigned weekly dose in a follow-on safety, clinical response, 
and PK study (KX-ORAX-003).  Participants who experience unacceptable toxicity 
following Oraxol treatment in this study, may enroll in Study KX-ORAX-003, with dose 
reduction as allowed in that protocol, if considered appropriate by the Investigator.   
8.1.1 
Pretreatment Phase 
The Pretreatment Phase will consist of a Screening Period and a Baseline Period for 
Treatment Period 1. 


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Participants will be screened within 28 days prior to the first dose of study drug.  After the 
participant provides informed consent, all screening evaluations, as detailed in Table 10 and 
Table 11, will be performed to determine whether eligibility criteria are met. 
Before Treatment Period 1, participants must have abstained from alcohol for 3 days and 
refrained from caffeine consumption for 12 hours.  On Day -1, before each treatment period, 
participants will undergo baseline assessments as detailed in Table 10 and Table 11. 
Participants in treatment Sequence A are required to fast for 8 hours prior to receiving 
treatment in Treatment Period 1.  Fasting prior to Treatment Period 1 is not required for 
participants in treatment Sequence B. 
8.1.2 
Treatment Phase 
The Treatment Phase will include Treatment Period 1, a Baseline Period for Treatment 
Period 2, Treatment Period 2, and a Follow-Up Period. 
8.1.2.1 
Treatment Periods 
Participants may be admitted to the clinical site the night before dosing of both Oraxol and 
IV paclitaxel.  Participants will be instructed to fast for at least 8 hours before and 4 hours 
after Oraxol administration; no fasting is required before the IV paclitaxel dosing.  For 
participants who are admitted to the clinical site on the day of Oraxol dosing, fasting will be 
verified and participants who have not fasted for the required 8 hours may have their Oraxol 
dosing delayed or rescheduled, at the discretion of the Investigator. 
Participants should remain at the study site for at least the first 24 hours after dosing of IV 
paclitaxel for PK blood sample collection (see Section 8.5.1.4.1).  Participants should remain 
at the study site, or at a nearby designated facility, for the first 72 hours after Day 1 dosing of 
Oraxol for PK blood sample collection (see Section 8.5.1.4.1).  Participants will return to the 
study site for the remaining PK blood collections.  If more convenient, at the discretion of the 
Investigator, the participants may be discharged to a local accommodation or remain housed 
at the study site for the entirety of the PK blood collection periods for both IV paclitaxel and 
Oraxol. 
Participants must abstain from alcohol consumption for 3 days prior to Treatment Period 1 
until the completion of protocol-specified PK sampling at the end of Treatment Period 2.  In 
addition, they must refrain from caffeine consumption for 12 hours before each treatment 
period through the completion of protocol specified PK sampling for that treatment.  
Participants must not have water or other liquids for 1 hour after taking their last paclitaxel 
capsule.  After the required 1 hour withholding of all liquids, water and decaffeinated coffee 
and tea will be provided. 
The Treatment Phase will begin with the first dose of study drug administration in Treatment 
Period 1.  Study treatments will be administered consecutively on Day 1 (IV paclitaxel) or 
Days 1, 2, and 3 (Oraxol) of Treatment Period 1 and Treatment Period 2.  Oraxol may be 
administered in a general inpatient clinical research unit, while IV paclitaxel will be 


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administered in a qualified oncology unit.  Transportation of participants between the general 
inpatient clinical research unit and the oncology unit will be provided. 
For Sequence A, the second treatment may be administered 6 days after completion of the 
3-day Oraxol dosing (ie, on Day 9) in Treatment Period 1 and the 144-hour PK sample has 
been collected.  For Sequence B, the second treatment may be administered 7 days after 
completion of the IV paclitaxel dosing in Treatment Period 1 (ie, on Day 8). 
Treatment may be delayed for unacceptable toxicities (see Unacceptable Toxicity section 
below).  The second randomized treatment may be delayed for up to 3 weeks, if needed, to 
allow the participant to recover to ≤ Grade 1 CTCAE or baseline toxicity from the prior study 
treatment or to allow the participants flexibility in scheduling inpatient treatment.  A Follow-
up Period will occur after completion of both treatment periods. 
The dose of IV paclitaxel used in this study (80 mg/m2 infused over 1 hour weekly) is the 
dose commonly in clinical use in New Zealand and elsewhere.  The oral paclitaxel dose in 
Oraxol (205 mg/m2 daily for 3 consecutive days per week) is expected to result in similar 
paclitaxel exposure as the IV dose as observed in prior studies. 
Unacceptable Toxicity  
Unacceptable toxicities for which treatment may be delayed are listed in Appendix 2.  A 
participant who has a treatment delay may resume treatment once the toxicity has resolved to 
CTCAE Grade 1 or less. 
Participants who experience unacceptable toxicity following Oraxol treatment in this study 
(KX-ORAX-002), may enroll in Study KX-ORAX-003, with dose reduction as allowed in 
that protocol, if considered appropriate by the Investigator.   
Safety Management 
The Investigators at each clinical site are oncologists who are experienced in managing 
toxicities associated with paclitaxel chemotherapy.  Treatments will be administered 
following successful completion of pre-dosing evaluations.  Intravenous paclitaxel will be 
administered in an oncology unit using standard premedication.  Oraxol will be administered 
in a clinical research unit, since premedication is not required for this treatment.  
Emergencies will be managed by unit staff in accordance with established procedures. 
An Investigator and/or delegated oncology nurse will be on site on each Oraxol dosing day 
through 4 hours postdose.  Serious AEs will be reviewed by the DSMB as well as the PK 
data. 
Management of Infusion Reactions 
If anaphylaxis and severe hypersensitivity reaction occur after IV paclitaxel infusion, IV 
paclitaxel infusion should be stopped and antihistamines, corticosteroids, etc, should be 
administered according to the instructions from the prescription information of the paclitaxel 


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manufacturer.  Minor infusion reactions to IV paclitaxel will be managed according to each 
site’s standard practice.  This may include slowing, temporarily interrupting, or discontinuing 
the infusion, as clinically indicated, and administration of other medications as clinically 
indicated.  In the event that the infusion is slowed or temporarily interrupted due to IV 
paclitaxel infusion reaction, PK blood sampling should continue according to the modified 
schedule in Appendix 3.  Participants who do not receive the full dose of IV paclitaxel are 
considered inevaluable for PK. 
Participants experiencing hypersensitivity-type reactions related to infusion of IV paclitaxel 
may continue to receive Oraxol treatment at their assigned dose either in this study or in KX-
ORAX-003, if considered appropriate to the Investigator.   
Participants who experience unacceptable toxicity following Oraxol treatment in this study 
(KX-ORAX-002), may enroll in Study KX-ORAX-003, with dose reduction as allowed in 
that protocol, if considered appropriate by the Investigator.   
Management of Nausea or Vomiting 
Premedication is not required for Oraxol and is not allowed before the first dose.  Nausea or 
vomiting following the first dose of Oraxol may be managed with anti-emetic medications 
(eg, metoclopramide, IV or sublingual ondansetron, or other 5-HT 3 or NK-1 antagonists), 
including premedication for subsequent doses, as appropriate.  On PK sampling days, in the 
event vomiting occurs within 4 hours postdose of oral paclitaxel, the Investigator should 
contact Zenith Technology immediately. 
8.1.2.2 
Follow-up Period 
During the Follow-up Period, for participants who do not elect to enter the follow-on study 
for Oraxol, a Final Visit will occur within 2 weeks after the last PK sampling, preferably 
before the participant receives additional chemotherapy.  For participants who elect to 
continue weekly Oraxol treatment in the follow-on study KX-ORAX-003, the Final Visit 
may serve as screening/baseline for the follow-on study. 
8.2 
Discussion of Study Design, Including Choice of Control Groups 
This is an open-label, randomized, crossover, safety, and tolerability study to determine the 
absolute BA and extent of absorption of Oraxol.  The crossover design is well established for 
BE studies, and allows each participant to act as his/her own control. 
Randomization will be used in this study to avoid bias in the assignment of participants to 
treatment sequence, to increase the likelihood that known and unknown participant attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups. 


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8.3 
Selection of Study Population 
Eligible participants are adults with cancer for whom weekly therapy with IV paclitaxel at a 
dose of 80 mg/m2 infused over 1 hour is indicated. 
Up to approximately 54 evaluable participants will be randomized at approximately 4-5 
centers internationally.  Participants who do not meet all of the inclusion criteria or who meet 
any of the exclusion criteria will not be eligible to receive study drug. 
8.3.1 
Inclusion Criteria 
Eligible participants must have/be: 
1. Signed written informed consent 
2. Males and females ≥18 years of age on day of consent 
3. Cancer patients for whom treatment with IV paclitaxel at 80 mg/m2 has been 
recommended by their oncologist, either as monotherapy or in combination with other 
agents 
4. Adequate hematologic status at Screening/Baseline:  
• Absolute neutrophil count (ANC) ≥1.5 x 109/L 
• Platelet count ≥100 x 109/L 
• Hemoglobin (Hgb) ≥90 g/L 
5. Adequate liver function at Screening/Baseline as demonstrated by:  
• Total bilirubin of ≤20 μmol/L or ≤30 μmol/L for participants with liver metastasis 
• Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN) or ≤5 x ULN 
if liver metastasis is present 
• Alkaline phosphatase (ALP) ≤3 x ULN or ≤5 x ULN if liver or bone metastasis 
are present  
• ALP >5 x ULN if liver or bone metastasis are present and the major fraction of 
ALP is from bone metastasis, at the discretion of the Investigator  
• Gamma glutamyl transferase (GGT) <10 x ULN 
6. Adequate renal function at Screening/Baseline as demonstrated by serum creatinine 
≤177 μmol/L or creatinine clearance >50 mL/min as calculated by the Cockcroft and 
Gault formula 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 16 
8. Life expectancy of at least 3 months 
9. Willing to fast for 8 hours before and 4 hours after Oraxol administration 


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10. Willing to abstain from alcohol consumption for 3 days before the first dose of study 
drug through the completion of protocol-specified PK sampling in Treatment Period 2 
11. Willing to refrain from caffeine consumption for 12 hours before each treatment 
period through the completion of protocol-specified PK sampling for that dose 
12. Women must be postmenopausal (>12 months without menses) or surgically sterile 
(ie, by hysterectomy and/or bilateral oophorectomy) or, if sexually active, must be 
using effective contraception (ie, oral contraceptives, intrauterine device, double 
barrier method of condom and spermicide) and agree to continue use of contraception 
for the duration of their participation in the study.  Women of childbearing potential 
must agree to use contraception for 30 days after their last dose of study drug. 
13. Sexually active male participants must use a barrier method of contraception during 
the study and agree to continue the use of male contraception for at least 30 days after 
the last dose of study drug. 
8.3.2 
Exclusion Criteria 
Eligible participants must not have/be: 
1. Currently taking a prohibited concomitant medication: 
• Strong inhibitors (eg, ketoconazole) or strong inducers (eg, rifampin or St. John's 
Wort) of cytochrome P450 (CYP) 3A4 (within 2 weeks prior to the start of dosing 
in the study) 
• Strong inhibitors (eg, gemfibrozil) or strong inducers (eg, rifampin) of CYP2C8 
(within 2 weeks prior to the start of dosing in the study) 
• Known P-glycoprotein (P-gp) inhibitors or inducers.  Participants who are taking 
such medications but who are otherwise eligible may be enrolled if they 
discontinue the medication ≥1 week before dosing and remain off that medication 
through the end of PK sampling after the administration of the second study 
treatment. 
• An oral medication with a narrow therapeutic index known to be a P-gp substrate 
(eg, digoxin, dabigatran) within 24 hours prior to start of dosing in the study 
2. Use of warfarin.  Participants receiving warfarin who are otherwise eligible and who 
may be appropriately managed with low molecular weight heparin, in the opinion of the 
Investigator, may be enrolled in the study provided they are switched to low molecular 
weight heparin at least 7 days prior to receiving study treatment. 
3. Unresolved toxicity from prior chemotherapy (participants must have recovered all 
significant toxicity to ≤ Grade 1 CTCAE toxicity1 from previous anticancer treatments 
or previous investigational agents). This does not extend to symptoms or findings that 
are attributable to the underlying disease 
4. Received investigational agents within 14 days or 5 half-lives prior to the first study 
dosing day, whichever is longer 
5. Women of childbearing potential who are pregnant or breastfeeding 


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6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, clinically significant myocardial 
infarction within the last 6 months, unstable angina pectoris, clinically significant 
cardiac arrhythmia, bleeding disorder, chronic pulmonary disease requiring oxygen, or 
psychiatric illness/social situations that would limit compliance with study 
requirements 
7. Major surgery to the upper GI tract, or have a history of GI disease or other medical 
condition that, in the opinion of the Investigator may interfere with oral drug absorption 
8. A known history of allergy to paclitaxel.  Participants whose allergy was due to the IV 
solvent (such as Cremophor®) and not paclitaxel will be eligible for this study. 
9. Any other condition which the Investigator believes would make a subject’s 
participation in the study not acceptable 
8.3.3 
Removal of Participants from Therapy or Assessment 
The Investigator may discontinue treating a participant with study treatment or withdraw the 
participant from the study at any time for safety or administrative reasons.  The participant 
may decide to discontinue study treatment or withdraw from the study at any time for any 
reason.   
Participants may be discontinued early from the study treatment due to: 
• Death 
• Progression of disease 
○ radiologic progression of disease not associated with AE(s) 
○ radiologic progression of disease associated with AE(s) 
○ other clinical findings indicating disease progression, eg, pain with bone 
metastases or seizure with brain metastases 
• AEs not associated with progression of disease 
• Withdrawal of consent (participant will be asked but not required, to provide a 
reason) 
• Termination of the study by the Sponsor 
• Other (specify) 
If the study is terminated by the Sponsor, the Investigator will promptly explain to the 
participant involved that the study will be discontinued and provide appropriate medical 
treatment and other necessary measures for the participant. 
8.4 
Treatments 
Detailed information regarding study drugs will be in the Pharmacy Manual provided to the 
sites. 


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8.4.1 
Treatments Administered 
The investigational product (IP) in the study is Oraxol. 
Oraxol is a combination product of 2 separate drugs:  oral paclitaxel capsules and 
HM30181AK-US tablets. 
The comparator drug in the study is IV paclitaxel, supplied as Taxol or generic from a single 
manufacturer. 
Information regarding study treatments is provided in Table 2. 
Table 2 
Treatments Administered in KX-ORAX-002 
 
Strength 
Oral Dose 
Form 
Number Dispensed and 
Frequency 
Study Days 
Administered 
Investigational Product 
HM30181AK-US 
15 mg 
Tablet 
1 × 15-mg tablet, on designated 
treatment mornings, 1 hour before 
oral paclitaxel 
Days 1, 2, and 3 of 
each treatment 
period 
Oral paclitaxel 
30 mg 
Capsule 
Number dispensed based on 
calculated doses (see 
Section 8.4.1.1) once on 
designated treatment mornings 
Days 1, 2, and 3 of 
each treatment 
period 
Reference Treatment 
IV paclitaxel 
N/A 
N/A 
80 mg/m2 infused over 1 hour on 
designated treatment morning 
Day 1 of each 
treatment period 
IV = intravenous, N/A = not applicable. 
8.4.1.1 
Oraxol 
Participants will be instructed to have fasted for at least 8 hours before and 4 hours after 
Oraxol dosing.  The amount of water consumed with HM30181 and oral paclitaxel dosing 
must be documented. 
Oraxol dosing will consist of 15 mg oral HM30181AK-US tablet daily for 3 consecutive 
days (Days 1, 2, and 3 of either treatment period) plus oral paclitaxel administered over the 
3 dosing days.  The HM30181AK-US tablet will be administered 1 hour before the oral 
paclitaxel capsules; no premedication is allowed before the first dose of Oraxol.  
Premedication may be given before subsequent doses for hypersensitivity reactions and/or 
nausea or vomiting (see Section 8.4.7.2). 
The dose of oral paclitaxel in the study will be determined as described in Section 8.1; the 
doses are expected to produce exposure similar to IV paclitaxel 80 mg/m2 infused over 
1 hour. 


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The dose of oral paclitaxel for Stage 1, Cohort 1 will be calculated as the number of 30-mg 
capsules needed to dose participants with 615 mg/m2 over 3 days based on screening BSA.  
The total number of capsules will be rounded up.  If the number of capsules is not divisible 
by 3, a single extra capsule will be taken on Day 1; 2 extra capsules will be taken as 
1 capsule each on Days 1 and 2.  The dose of oral paclitaxel for Stage 1, Cohort 2 and 
Stage 2 will be calculated similarly based on results of the planned interim analyses. 
8.4.1.2 
Intravenous Paclitaxel 
No fasting is required before IV paclitaxel dosing. 
Intravenous paclitaxel 80 mg/m2 will be administered in a qualified oncology unit as a one-
time infusion over 1 hour on Day 1 of either treatment period.  Premedication will be 
administered according to standard local practice. 
8.4.1.3 
Criteria for Temporary Discontinuation of Treatment and Resumption of 
Treatment 
The second period of randomized treatment may be delayed for up to 3 weeks, if needed, to 
allow the participant to recover to ≤ Grade 1 CTCAE or baseline toxicity from the prior study 
treatment or to allow the participants flexibility in scheduling inpatient treatment. 
8.4.2 
Identity of Investigational Product 
Oraxol is a combination product of 2 separate drugs:  oral paclitaxel capsules and 
HM30181AK-US tablets. 
8.4.2.1 
Chemical Name, Structural Formula of Paclitaxel  
• Study drug code: 
Paclitaxel 
• Chemical name:  
5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 
4,10-diacetate 2-benzoate 13- ester with (2R,3S)-N-benzoyl-3-phenylisoserine 
• Molecular formula: C47H51NO14 
• Molecular weight: 
853.91 
• Structural formula:  
 


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8.4.2.2 
Chemical Name, Structural Formula of HM30181 Methanesulfonate 
Monohydrate 
• Study drug code: 
HM30181 
• Chemical name:  
N-(2-(2-(4-(2-(6,7-Dimethoxy-3,4-
dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-
dimethoxyphenyl)-4-oxo-4H-chromene-2-carboxamide Methanesulfonate 
monohydrate 
• Molecular formula: C38H36N6O7·CH3SO3H·H2O   
• Molecular weight: 
802.85 (methanesulfonate monohydrate salt) / 688.72 (free 
base) 
• Structural formula: 
NH
H3CO
H3CO
O
O
O
N
N
N
N
N
OCH3
OCH3
S
O
O
OH
H3C
H2O
 
8.4.2.3 
Comparator Drug 
Commercially available IV paclitaxel in Cremophor EL (Taxol or generic from a single 
manufacturer) 
8.4.2.4 
Labeling for Study Drug 
Study drugs will be obtained and/or packaged and labeled in a manner consistent with the 
study design, by: 
Oral Paclitaxel Capsules 
HM30181AK-US Tablets 
IV Paclitaxel 
Kinex Pharmaceuticals, Inc. 
1001 Main Street 
Suite 600 
Buffalo, NY 14203 
United States 
Kinex Pharmaceuticals, Inc. 
1001 Main Street 
Suite 600 
Buffalo, NY 14203 
United States 
Commercially available IV 
paclitaxel in Cremophor EL 
(Taxol or generic from a single 
manufacturer) that is approved for 
medical use  
 
Labels for investigational product (Oraxol [oral paclitaxel and HM30181AK-US]) will be in 
accordance with national/local regulations of the participating country and will contain the 
following information: 
 
 


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• Protocol number 
• Name of study drug 
• Strength of study drug 
• Formulation 
• Lot number 
• Date of manufacture 
• Expiry date 
• Storage conditions, including temperature 
• Warning statement 
• Statement saying “Limited to Investigational Use Only” 
• Name of Sponsor 
• Participant number (to be added by site) 
• Participant initials (to be added by site) 
8.4.2.5 
Storage Conditions 
Study drug will be stored in a secure location with access limited to the Investigators and 
designees.  Study drug will be stored in accordance with labelled storage conditions.  
Temperature monitoring is required at the storage location to ensure that the study drug is 
maintained within an established temperature range.  The Investigator is responsible for 
ensuring that the temperature is monitored throughout the total duration of the trial and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system or a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. 
Paclitaxel capsules and HM30181AK-US tablets that are dispensed to participants should be 
kept at room temperature (15°C to 30°C) until used.  Paclitaxel for infusion should be stored 
under the conditions noted on the commercial packaging. 
8.4.3 
Method of Assigning Participants to Treatment Groups 
Participants will be randomized to receive either treatment Sequence A or B (see Table 1). 
Assignment to treatment sequence will be based on a computer-generated central 
randomization scheme that will be reviewed and approved by an independent statistician.  
The randomization code will be stored in a secure location with access limited to the 
Investigators and designees.  The randomization scheme and identification for each 
participant will be included in the final clinical study report for this study. 


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In Stage 1, no center can enter more than 4 of the first 6 participants at any dose level without 
authorization from Kinex. 
In Stage 2, no center can enter more than half of the number of participants estimated to 
achieve bioequivalence.  For example, if BE is estimated to involve 36 participants, 6 of 
whom come from Stage 1, a center cannot enter more than 15 participants in Stage 2 without 
authorization from Kinex. 
Replacement participants will be assigned to the same treatment sequence as the participant 
they replace. 
8.4.4 
Selection of Doses in the Study 
The dose of oral paclitaxel in the study will be determined as described for each stage of the 
study (see Section 8.4.1.1); the doses are expected to produce exposure similar to IV 
paclitaxel 80 mg/m2 infused over 1 hour. 
The dose of IV paclitaxel used in this study (80 mg/m2 over 1 hour weekly) is the dose 
commonly in clinical use in New Zealand and elsewhere. 
8.4.5 
Selection and Timing of Dose for Each Participant 
See Section 8.1 for a discussion of Oraxol and IV paclitaxel dosing. 
The dose of HM30181 of 15 mg daily is being used in current studies of Oraxol based on PK 
data from healthy volunteer studies that examined the inhibitory effect of HM30181 on gut 
P-gp (see the Investigator's Brochure).  The HM30181AK-US tablet will be administered 
1 hour before the oral paclitaxel capsules. 
8.4.6 
Blinding 
The study will not be blinded. 
8.4.7 
Prior and Concomitant Therapy 
All medications (prescription and nonprescription including vitamins and dietary 
supplements), treatments, and therapies including radiotherapy taken 28 days before the 
initiation of the study through the final study visit must be recorded in the electronic case 
report form (eCRF).  A complete oncologic treatment history will be recorded on the 
Oncologic Treatment History eCRF. 
Any medication (including nonprescription medications) or therapy administered to the 
participant during the course of the study (starting at the date of informed consent) will be 
recorded on the Concomitant Medication eCRF.  The Investigator will record any AE on the 
Adverse Events eCRF for which the concomitant medication/therapy was administered. 


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8.4.7.1 
Drug-Drug Interactions 
Possible drug interactions with Oraxol include those known to occur with paclitaxel 
treatment.  Treatment with HM30181 may also lead to possible drug interactions attributable 
to inhibition of P-gp in the gut.  Thus increased exposure from co-administration of Oraxol 
with oral medications that are P-gp substrates is possible.  This may be clinically significant 
when the medications involved have a narrow therapeutic index (eg, digoxin or dabigatran).  
Also, a possible increased or decreased exposure to paclitaxel may occur when Oraxol is 
taken together with P-gp inhibitors or inducers, respectively. 
8.4.7.2 
Prohibited Concomitant Therapies and Drugs 
Participants are excluded from participation in this study are those who are currently taking:  
• a medication known to be a strong inhibitor (eg, ketoconazole) or strong inducer (eg, 
rifampin or St. John's Wort) of cytochrome P450 (CYP) 3A4 within 2 weeks prior to 
the start of dosing in the study 
• a medication known to be a strong inhibitor (eg, gemfibrozil) or strong inducer (eg, 
rifampin) of CYP2C8 within 2 weeks prior to the start of dosing in the study 
• a medication known to be a P-gp inhibitor or inducer within 1 week before dosing in 
the study.  Participants must remain off that medication through the end of PK 
sampling after the administration of the second study treatment. 
• an oral medication with a narrow therapeutic index known to be a P-gp substrate (eg, 
digoxin, dabigatran) within 24 hours prior to the start of dosing in the study 
A list of drugs prohibited due to potential drug-drug interactions will be provided to the sites 
as part of the Pharmacy Manual. 
Participants should not start such medications while enrolled in this protocol.   
Use of warfarin is not permitted.  Participants receiving warfarin who are otherwise eligible 
and who may be appropriately managed with low molecular weight heparin, in the opinion of 
the Investigator, may be enrolled in the study provided they are switched to low molecular 
weight heparin at least 7 days prior to receiving study treatment. 
For participants treated with Oraxol, no premedication is allowed before the first dose.  
Premedication in these participants may be given before subsequent doses if clinically 
indicated in the judgment of the Investigator.  Steroids or H-1 receptor antagonists should be 
given only for prophylaxis or treatment of hypersensitivity reactions; 5-HT 3 or NK-1 
antagonists should be used for prophylaxis or initial treatment of nausea or vomiting. 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration. 


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8.4.8 
Treatment Compliance 
Records of treatment compliance for each participant will be kept during the study.  
Designated study personnel will review treatment compliance during investigational site 
visits and at the completion of the study.  Because all study drugs are administered at the 
study site/s, participants should be 100% compliant, unless doses are not administered. 
8.4.9 
Drug Supplies and Accountability 
The Investigator and study staff will be responsible for the accountability of all clinical 
supplies (dispensing, inventory, and record keeping) following the Sponsor’s instructions.  In 
this matter, the Investigator and study staff must adhere to GCP guidelines, as well as 
national requirements. 
Under no circumstances will the Investigator allow the study drugs to be used other than as 
directed by this protocol.  Clinical supplies will be dispensed only by an appropriately 
qualified person and will not be dispensed to any individual who is not enrolled in the study.  
An accurate and timely record of the receipt of all clinical supplies and dispensing of study 
drug to the participant must be maintained.  This includes, but is not limited to: 
• documentation of receipt of clinical supplies 
• study drugs dispensing 
• study drugs accountability log 
• all shipping service receipts 
All forms will be provided by the Sponsor (or its designee).  Any comparable forms that the 
investigational site wishes to use must be approved by the Sponsor.  A copy of the drug 
accountability record must be provided to the Sponsor at the end of the study. 
Retention samples from each site will need to be maintained per Food and Drug 
Administration (FDA) guidance.7  Details regarding handling of retention samples of study 
drug will be provided in the Pharmacy Manual.   
The clinical research associate (CRA) will review drug accountability during monitoring site 
visits and at the completion of the study. 
8.5 
Study Assessments 
All assessments and timing of the assessments should be performed according to the 
Schedule of Procedures and Assessments (Table 10 and Table 11). 


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8.5.1 
Assessments 
8.5.1.1 
Demography 
Participant demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity. 
8.5.1.2 
Baseline Assessments 
8.5.1.2.1 MEDICAL HISTORY 
Medical and surgical history and current medical conditions will be recorded at Screening.  
All pertinent medical history must be noted in the eCRF.  A complete oncologic medical 
history will also be recorded. 
Medical history will include:  
• A complete medical and surgical history; childhood diseases are not required and 
common colds are not required unless it is ongoing at Screening 
• A complete oncology history (all malignancies including the malignancy currently 
being treated, regardless of diagnosis date or status, eg, skin cancer >5 years).  The 
Tumor, Node, Metastases (TNM) status at time of diagnosis and Screening will be 
recorded for the malignancy currently being treated. 
• A complete oncology treatment history including all commercial and investigational 
products, radiation therapy, and other prescribed and nonprescription therapies dating 
back to the initial diagnosis of the malignancy currently being treated 
8.5.1.2.2 PRIOR MEDICATIONS 
Prior medications taken within 28 days before Day 1, including nonprescription remedies, 
vitamins, etc, will be recorded at Screening. 
8.5.1.2.3 HEIGHT 
Height will be recorded only at Screening and will be used to calculate BSA. 
8.5.1.3 
Efficacy Assessments 
Not applicable 


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8.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
8.5.1.4.1 PHARMACOKINETIC ASSESSMENTS 
As designated on the Schedule of Procedures/Assessments (Table 10 and Table 11), blood 
samples (approximately 6 mL per testing timepoint) will be collected for analysis of plasma 
concentrations of both formulations (oral and IV) of paclitaxel.   
The actual time of PK sampling will be recorded. 
Central lines should not be used for blood sample collection.  Blood samples for PK 
sampling should be obtained through an IV catheter placed contralateral to a central line or 
the IV catheter used for the administration of IV paclitaxel.  However, it is acceptable to 
place a pre-emptive peripherally inserted central catheter (PICC) line for patients with 
difficult venous access at the discretion of the clinical Investigator, for taking a limited 
number of blood PK samples if problems arise when taking blood from the peripheral IV 
catheter during PK sampling.  Special procedures for taking blood from a central line will be 
provided by the Sponsor as a Protocol Clarification Letter. 
Table 3 presents the amounts of blood (mL) that will be collected over the course of the 
study for PK analysis.  
Table 3 
Blood Collection Volumes for Pharmacokinetic Analyses 
 
IV Paclitaxel 
Oraxol 
(HM30181 and paclitaxel) 
Volume per timepoint (mL) 
6 
6 
Number of timepoints 
25 
42 
Total (mL) 
150 
252 
Overall Total (mL) 
402 
IV = intravenous. 
A breakdown of PK sampling for IV dosing is presented in Table 4 (Days 1 and 2) and 
Table 5 (Days 3-5); PK sampling for oral paclitaxel dosing is presented in Table 6 (Day 1), 
Table 7 (Day 2), and Table 8 (Days 3-9). 
Samples will be analyzed for paclitaxel levels using a validated assay. 
A description of collection, handling, and shipping procedures for PK samples will be 
provided to the sites. 
 


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Table 4 
Pharmacokinetic Sampling for IV Paclitaxel Days 1 and 2 (Treatment Periods 1 or 2) 
Day of  
Treatment Period 
Day 1  
Day 2 
Time 
0 
(Predose) 
2 
m 
5 
m 
8 
m 
12 
m 
20 
m 
40 
m 
60 
m 
0.25 
h 
0.5 
h 
0.75 
h 
1 
h 
2 
h 
3 
h 
4 
h 
6 
h 
8 
h 
12 
h 
18 
h 
24 
h 
32 
h 
 
 
During IV infusiona,b 
After end of IV infusion 
PK sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h = hours; IV = intravenous; m = minutes; PK = pharmacokinetic. 
a:  IV paclitaxel dosing will begin at approximately 0830 at the oncology unit. 
b:  In the event that the IV paclitaxel infusion is slowed or temporarily interrupted due to IV paclitaxel infusion reaction, PK blood sampling should continue according to the 
modified schedule in Appendix 3.  
 
 
 
 
Table 5 
Pharmacokinetic Sampling for IV Paclitaxel Days 3 to 5 (Treatment Periods 1 or 2) 
Day of 
Treatment Period 
Day 3 
Day 4 
Day 5 
Time (hours) 
48 
56 
72 
96 
 
After end of IV infusion 
PK sample 
X 
X 
X 
X 
PK = pharmacokinetic. 
 
 
 
 
 


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Table 6 
Dosing and Pharmacokinetic Sampling for Oraxol Day 1 (Treatment Periods 1 or 2) 
Day of Treatment Period 
Day 1 
Time (hours) 
-1 
0 
(Predose) 
0 
0.5 
0.75 
1 
1.25 
1.5 
2 
3 
4 
6 
8 
12 
Dosinga 
 
 
 
After completion of Day 1 dosing 
 
HM30181 
X 
 
 
 
Oral paclitaxelb 
 
 
X 
PK samplec 
 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK = pharmacokinetic. 
a:  Oraxol (HM30181 + oral paclitaxel) dosing at the clinical site.  HM30181AK-US tablets will be administered at approximately 0700 on Days 1, 2, and 3. Oral paclitaxel 
capsules will be administered 1 hour later at approximately 0800 on Days 1, 2, and 3. 
b:  In the event vomiting occurs within 4 hours postdose of oral paclitaxel, the Investigator should contact Zenith Technology immediately. 
c:  Approximately 6 mL per PK sample. 
 
 
Table 7 
Dosing and Pharmacokinetic Sampling for Oraxol Day 2 (Treatment Periods 1 or 2) 
Day of Treatment Period 
Day 2 
Time (hours) 
-1 
0 
(Predose) 
0 
0.5 
0.75 
1 
1.25 
1.5 
2 
3 
4 
6 
8 
12 
Dosinga 
 
 
 
After completion of Day 2 dosing 
 
HM30181 
X 
 
 
 
Oral paclitaxelb 
 
 
X 
PK samplec 
 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK = pharmacokinetic. 
a:  Oraxol (HM30181 + oral paclitaxel) dosing at the clinical site.  HM30181AK-US tablets will be administered at approximately 0700 on Days 1, 2, and 3. Oral paclitaxel 
capsules will be administered 1 hour later at approximately 0800 on Days 1, 2, and 3. 
b:  In the event vomiting occurs within 4 hours postdose of oral paclitaxel, the Investigator should contact Zenith Technology immediately. 
c:  Approximately 6 mL per PK sample. 
 
 


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Table 8 
Dosing and Pharmacokinetic Sampling for Oraxol Days 3 to 9 (Treatment Periods 1 or 2) 
Day of Treatment 
Period 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Time (hours) 
-1 
0 
(Predose) 
0 
0.5 
0.75 
1 
1.25 
1.5 
2 
3 
4 
6 
8 
12 
24 
48 
72 
96 
120 
144 
Dosinga 
 
 
 
After completion of Day 3 dosing 
 
HM30181 
X 
 
 
 
Oral paclitaxelb 
 
 
X 
PK samplec 
 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK = pharmacokinetic. 
a:  Oraxol (HM30181 + oral paclitaxel) dosing at the clinical site.  HM30181AK-US tablets will be administered at approximately 0700 on Days 1, 2, and 3.  Oral paclitaxel 
capsules will be administered 1 hour later at approximately 0800 on Days 1, 2, and 3. 
b:  On PK sampling days, in the event vomiting occurs within 4 hours postdose of oral paclitaxel, the Investigator should contact Zenith Technology immediately. 
c:  Approximately 6 mL per PK sample.  


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8.5.1.4.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS 
Not applicable 
8.5.1.5 
Safety Assessments 
Safety assessments will consist of determining and recording all AEs including CTCAE 
grades v4.031 (or later) (for both increasing and decreasing severity) and SAEs. 
Safety assessments also include recording of concomitant medications; performance of 
physical examinations, measurements of weight and vital signs, and evaluation of 
electrocardiograms (ECGs) and ECOG performance status; and laboratory evaluation of 
hematology, biochemistry, and urinalyses, as detailed in the sections below and in the 
Schedule of Procedures and Assessments (Table 10 and Table 11). 
8.5.1.5.1 ADVERSE EVENTS  
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug(s) are Oraxol 
(HM30181 and oral paclitaxel) and IV paclitaxel. 
The criteria for identifying AEs are: 
• any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational 
product, whether or not considered related to the investigational product 
• any new disease or exacerbation of an existing disease (Note, however, that in 
instances of progression of disease, the clinical manifestations would be reported as 
an AE and the progression of disease itself, as a reason for discontinuation of 
treatment) 
• any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (eg, ECG or x-ray) that results in symptoms, a change in 
treatment, or discontinuation from study drug 
• recurrence of an intermittent medical condition (eg, headache) not present at 
Baseline 
All AEs, regardless of relationship to study drug or procedure, should be collected 
beginning from the time the participant signs the study ICF through the last participant 
contact.  Participants who fail screening primarily due to AE(s) must have the AE(s) 
leading to screen failure reported on the Screening Disposition eCRF. 
Participants with onset of an AE or deterioration of a pre-existing condition will be 
followed until resolution, resolved with sequelae, or under medical care.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization. 


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Adverse events associated with progression of disease should be recorded on the AE eCRF.   
Laboratory Adverse Events 
An abnormal laboratory result should be considered by the Investigator to be an AE if it: 
• results in the withdrawal of study drug 
• results in withholding of study drug pending some investigational outcome 
• results in the initiation of an intervention, based on medical evaluation (eg, 
potassium supplement for hypokalemia) 
• results in any out of range laboratory value that in the Investigator’s judgment 
fulfills the definitions of an AE with regard to the participant’s medical profile 
All AEs observed during the study will be reported on the eCRF. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
Investigator to review all laboratory findings in all participants and determine if they 
constitute an AE.  Medical and scientific judgment should be exercised in deciding whether 
an isolated laboratory abnormality should be classified as an AE.  Any laboratory 
abnormality considered to constitute an AE should be reported on the Adverse Event eCRF.  
Any laboratory abnormality considered to constitute an SAE should be reported using the 
SAE procedures described in Section 8.5.4.1. 
ECG changes and associated clinical symptoms determined to be clinically significant by the 
Investigator will be reported as AEs.  An ECG abnormality in a participant with symptoms 
may meet the criteria for an AE as described in this protocol.  In these instances, the AE 
corresponding to the symptomatic ECG abnormality will be recorded on the Adverse Events 
eCRF. 
For symptomatic ECG abnormalities meeting criteria as SAEs, the study site must submit an 
SAE report, including the ECG report to the Sponsor, or designee, using the SAE reporting 
procedures (Section 8.5.4.1). 
The Investigator must categorize each AE according to its severity and its relationship 
to study treatment. 


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Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to CTCAE v4.031 (or later) as 
follows: 
Grade 1 = 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2 = 
Moderate: minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
Grade 3 = 
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 
Grade 4 = 
Life-threatening consequences: urgent intervention indicated 
Grade 5 = 
Death related to AE 
Investigators will collect all CTCAE grades for AEs (for both increasing and decreasing 
severity).  All AEs reported using CTCAE classification and graded as 4 or 5 are to be 
considered serious.  The criteria for assessing severity are different from those used for 
seriousness (see Section 8.5.1.5.2, Serious Adverse Events and Other Events of Interest for 
the definition of an SAE). 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• temporal relationship of the onset of the event to the initiation of the study treatment 
• the course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• whether the event is known to be associated with the study treatment or with other 
similar treatments 
• the presence of risk factors in the study participant known to increase the occurrence 
of the event 
• the presence of nonstudy treatment-related factors that are known to be associated 
with the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the eCRF using the 
following criteria: 


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Definitely Related:  A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be explained by 
concurrent or underlying disease or other drugs or conditions 
Probably Related:  A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent or 
underlying disease or other drugs or conditions  
Possibly Related:  A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be explained by concurrent 
or underlying disease or other drugs or conditions 
Unlikely Related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship improbable, and in 
which other drugs, conditions or concurrent or underlying disease provide plausible 
explanations 
8.5.1.5.2 SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
An SAE is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening (ie, the participant was at immediate risk of death from the AE as 
it occurred; this does not include an event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death) 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect (in the child of a participant who was exposed 
to the study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the participant or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest, which include pregnancy and overdose (see 
Section 8.5.1.5.1), are to be captured and reported on a pregnancy or overdose form as 
appropriate as soon as possible, but no later than 1 business day from the date the 
Investigator becomes aware of the event.  These events of interest are to be considered as 
SAEs only if they meet one of the above criteria.  Treatment-emergent significant laboratory 
abnormalities should be reported as AEs and must be evaluated to see if they represent SAEs. 
If the treatment-emergent significant laboratory abnormality is considered to be an SAE, it 


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should be reported using SAE reporting procedures (Section 8.5.4.1) and is considered an 
event of interest. 
The following hospitalizations are not considered to be SAEs because there is no “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization: 
• hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
• hospitalization for administration of study drug or insertion of access for 
administration of study drug, provided that the hospitalization is not prolonged due 
to complication 
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
8.5.1.5.3 CONCOMITANT MEDICATIONS 
Concomitant medications will be assessed at Screening, at Baseline of each treatment period, 
on every day of each treatment period, and at the Final Visit (Table 10 and Table 11).  Any 
medication (including nonprescription medications) or therapy administered to the 
participant during the course of the study (starting at the date of informed consent) will be 
recorded on the Concomitant Medication eCRF.  The Investigator will record any AE on the 
Adverse Events eCRF for which the concomitant medication/therapy was administered. 
8.5.1.5.4 PHYSICAL EXAMINATIONS 
A complete physical examination will be performed at Screening and at Baseline of each 
treatment period, and at the Final Visit (Table 10 and Table 11). 
A complete physical examination will include an assessment of general appearance, head, 
eyes, ears, nose, and throat (HEENT), thorax (including cardiovascular and respiratory), 
abdomen, skin, musculoskeletal, extremities, and neurological examination. 
Additional examinations will be performed as clinically indicated to assess AEs.  
Documentation of the physical examination will be included in the source documentation at 
the site.  Only changes from screening physical examination findings that meet the definition 
of an AE will be recorded on the Adverse Events eCRF. 
8.5.1.5.5 WEIGHT AND BODY SURFACE AREA 
Weight will be recorded at Screening, at Baseline of each treatment period, and at the 
Final Visit (Table 10 and Table 11).  Height (recorded at Screening) and weight (with indoor 
clothing) will be measured to calculate BSA.  BSA will be calculated to 1 decimal place.  
Sites may use any of the established formulae for BSA, but must use the same formula for all 
participants at their site, and the method of BSA calculation must be recorded on the eCRF 
for each participant.  Dosing of Oraxol and IV paclitaxel will be calculated according to the 
screening BSA.  If weight changes by ≥10%, BSA will be recalculated and dose may be 


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adjusted by the Investigator if clinically indicated, providing there are no concerns regarding 
increased toxicity from dose adjustment.   
8.5.1.5.6 VITAL SIGNS 
Vital sign (pulse rate, systolic and diastolic blood pressure, respiratory rate, and body 
temperature) measurements will be taken after the participant has been seated for at least 
5 minutes at the visits designated on the Schedule of Procedures and Assessments (Table 10 
and Table 11).  All blood pressure measurements should be performed on the same arm, 
preferably by the same person at the designated visits.  Serial vital signs may be obtained to 
confirm accurate readings. 
8.5.1.5.7 ELECTROCARDIOGRAMS 
A 12-lead ECG is to be completed 5 times: at Screening, Baseline for Treatment Period 2, 
on-treatment 1 hour postdosing on Day 1 of each treatment period, and at the Final Visit 
(Table 10 and Table 11).  The Screening and Final Visit ECGs may be performed at a 
convenient time during the visit.  Participants must be in the recumbent position for a period 
of 5 minutes prior to the ECG.  The ECG data recorded on the eCRF must include rate, 
rhythm, intervals, and QTcF. 
Participants with a clinically significant ECG abnormality following IV paclitaxel or Oraxol 
treatment may continue to receive treatment with Oraxol as clinically indicated.  Alternatives 
to medications known to be associated with ECG abnormalities (eg, ondansetron and QTc 
prolongation) should be considered in participants with QTc prolongation.  Participants with 
QTc prolongation following Oraxol treatment may continue to receive Oraxol treatment in 
study KX-ORAX-003, with dose reductions as allowed in that protocol as clinically 
indicated. 
8.5.1.5.8 LABORATORY MEASUREMENTS 
Blood and urine will be collected for clinical laboratory tests.  Collection of both blood and 
urine may be conducted at a local laboratory or at the clinic site.  Approximately 20 mL of 
blood will be collected for clinical laboratory testing, including the pregnancy test when 
required, at Screening, at Screening/Baseline for Treatment Period 1, Baseline for Treatment 
Period 2, and the Final Visit (Table 10 and Table 11).  Participants must be fasted for the 
Screening and Final Visit laboratory assessments.  Fasting is recommended, but not required 
at other laboratory assessment times.  Fasting status must be documented for all laboratory 
samples. 
Microscopic urinalysis will be conducted only when clinically indicated based on dipstick 
results (laboratory protocol), or as determined by the Investigator.  When conducted, 
microscopic urinalysis results will be recorded on the eCRF. 
Clinical laboratory sampling and testing may be conducted anytime within 72 hours prior to 
the scheduled assessment time.  Laboratory test results, including pregnancy test, must be 
reviewed and acceptable to the Investigator before dosing. 


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A Laboratory Manual will be provided to detail handling, processing, and shipping 
procedures.  Local laboratories will be used to measure laboratory parameters. 
The clinical laboratory tests to be measured during the study are provided in Table 9. 
Table 9 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Red blood cells (RBC), hemoglobin, hematocrit, platelets, and white 
blood cells (WBC) with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), RBC distribution width (RDW) 
Chemistry 
 
 Electrolytes 
Chloride, potassium, sodium, bicarbonate (HCO3) 
 Liver function tests 
Alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), gamma glutamyl transpeptidase (GGT), direct 
bilirubin, total bilirubin 
 Renal function tests 
Blood urea/blood urea nitrogen, creatinine 
 Other 
Albumin, calcium, cholesterol, glucose, lactate dehydrogenase (LDH), 
phosphorus, total protein, triglycerides, uric acid 
Urinalysis 
hydrogen ion concentration (pH), specific gravity, protein, glucose, 
ketones, leukocyte esterase, nitrite, bilirubin, urobilinogen, blood 
 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 8.5.1.5.1).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event eCRF. 
For laboratory abnormalities meeting the criteria of SAEs (see Section 8.5.1.5.2), the site 
must electronically transmit the SAE report including the laboratory report to the Sponsor 
using the SAE form (see Section 8.5.4.1). 
8.5.1.5.9 
OTHER SAFETY ASSESSMENTS 
Pregnancy Testing 
Serum or urine pregnancy tests will be obtained in females of childbearing potential (ie, 
premenopausal women and postmenopausal women who have been amenorrheic for less than 
12 months) at Screening and within 72 hours before Day 1 dosing of each treatment period, 
and at the Final Visit (Table 10 and Table 11).  Test results must be reviewed before dosing. 
8.5.1.5.10 EASTERN COOPERATIVE ONCOLOGY GROUP STATUS  
The participant’s performance status should be assessed according to ECOG criteria 
(Appendix 1).  ECOG performance status will be assessed at Screening, Baseline for 
Treatment Period 2, and at the Final Visit. 


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8.5.1.6 
Other Assessments 
Participants will be asked a treatment preference question at the Final Visit. 
8.5.2 
Schedule of Procedures/Assessments 
8.5.2.1 
Schedule of Procedures/Assessments 
Table 10 and Table 11 present the schedule of procedures/assessments for Treatment 
Sequence A and B, respectively. 
 


 
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Table 10 
Schedule of Procedures/Assessments for Sequence A (Oraxol in Treatment Period 1) 
Phase 
Pretreatment 
Treatment 
Period 
Screening 
Treatment 
Period 1 
Baselinea 
Treatment Period 1b  
Treatment 
Period 2 
Baselinea 
Treatment Period 2b 
Follow-
up  
Day/Visit 
Day -28 to 
Day -2 
Day –1 
Day 1 
Day 2 
Day 3 
Days 4-9 
Day -1 
Day 1 
Day 2  
Days 3-5 
Days 6-8 
Final 
Visitc 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology History 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and/or Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical Examinationd 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Weight and BSAe 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECOG Performance Status 
X 
 
 
 
 
 
X 
 
 
 
 
X 
12-lead ECG 
X 
 
Xg 
 
 
 
X 
Xg 
 
 
 
X 
Pregnancy testh 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Hematology/Biochemistryi 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Administer study medicationj 
 
 
X 
X 
X 
 
 
X 
 
 
 
 
PK blood samplesk 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Adverse eventsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Treatment preference question 
 
 
 
 
 
 
 
 
 
 
 
X 
BSA = body surface area; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; IV = 
intravenous; PK = pharmacokinetic.  
a. 
All baseline data should be collected and assessed within 72 hours prior to dosing on Day 1 of each treatment period. 
b. 
Treatment Periods:  Oraxol = Days 1 to 9; IV paclitaxel = Days 1 to 8.  The second period of randomized treatment may be delayed for up to 3 weeks, if needed, to allow the 
participant to recover to ≤ Grade 1 CTCAE or baseline toxicity from the prior study treatment or to allow the participants flexibility in scheduling inpatient treatment.   
c. 
The Final Visit may occur as early as the last day of PK sampling in Treatment Period 2, up to 2 weeks after the end of PK sampling, and preferably before the participant 


 
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Table 10 
Schedule of Procedures/Assessments for Sequence A (Oraxol in Treatment Period 1) 
receives any additional chemotherapy.  For participants who elect to continue weekly Oraxol treatment, the Final Visit may serve as screening/baseline for the follow-on study; for 
these participants, the Final Visit should occur within 72 hours prior to receiving the Week 1 dose of Oraxol in the follow-on study.  If the participant withdraws informed consent, 
Final Visit assessments should be completed as much as possible during the final visit on study.  If the participant is taken off for other reasons (eg, toxicities), the Final Visit 
should be completed within 2 weeks after the withdrawal from study and preferably before the participant receives any additional chemotherapy. 
d. 
Complete physical examinations will be performed at Screening and the Final Visit.  All other physical examinations do not require complete examinations but will be 
targeted to the signs and symptoms related to Adverse Event Reporting.  Physical examinations performed on Day -2 do not need to be repeated on Day -1.   
e. 
BSA will be calculated to 1 decimal place based on screening body weight and height.  Weight will be recorded pretreatment for each treatment period.  If weight changes by 
≥10%, BSA will be recalculated.  Study drug doses may be adjusted using the new BSA by the clinical Investigator, if clinically indicated, providing there are no concerns 
regarding increase toxicity from dose adjustment. 
f. 
Vital signs to include pulse rate, systolic/diastolic blood pressure, respiration, and temperature.  Vital sign measurement should be taken before dosing and once daily on 
nondosing days.  Vital signs should be taken in the morning on inpatient days, or when participants are first seen at the clinical site on outpatient days. 
g. 
ECGs will be performed 1 hour postdosing on Day 1 of each treatment period. 
h. 
Serum or urine pregnancy test to be obtained in females of childbearing potential at Screening and within 72 hours prior to Day 1 dosing in either treatment period.  Baseline 
pregnancy testing in Treatment Period 1 does not need to be obtained if the screening test was obtained within 72 hours of Day 1 dosing. 
i. 
Participants must be fasted for the Screening and Final Visit laboratory assessments.  Fasting is recommended but not required at other laboratory assessment times.  It must 
be noted if participants were in a fasted or fed state at the time of blood collection.  Clinical laboratory sampling and testing should be conducted anytime within 72 hours prior to 
the scheduled assessment time. 
j. 
Oraxol will be administered at the inpatient clinical site.  IV paclitaxel will be administered at the oncology unit.  For Sequence A, participants will receive Oraxol on Days 
1, 2, and 3 of Treatment Period 1 and IV paclitaxel on Day 1 of Treatment Period 2. 
k. 
PK blood samples (approximately 6 mL at each testing timepoint) will be collected at the sites.  Please refer to Section 8.5.1.4.1 for all PK sampling timepoints. 
l. 
Collection of all adverse event information will begin immediately after the signing of the informed consent and will continue through the Final Visit. 


 
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Table 11 
Schedule of Procedures/Assessments for Sequence B (IV Paclitaxel in Treatment Period 1) 
Phase 
Pretreatment 
Treatment 
Period 
Screening 
Treatment 
Period 1 
Baselinea 
Treatment Period 1b 
Treatment 
Period 2 
Baselinea 
Treatment Period 2b 
Follow-
up 
Day 
Day -28 to 
Day -2 
Day –1 
Day 1 
Day 2 
Days 3-5 
Days 6-8 
Day –1 
Day 1 
Day 2  
Day 3 
Days 4-9 
Final 
Visitc  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology History 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and/or Concomitant 
Medications 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical Examinationd 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Weight and BSAe 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsf 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
 
 
 
 
 
X 
 
 
 
 
X 
12-lead ECGg 
X 
 
Xg 
 
 
 
X 
Xg 
 
 
 
X 
Pregnancy testh 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Hematology/Biochemistryi 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Administer study medicationj 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
PK blood samplesk 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
Adverse eventsl 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Treatment preference question 
 
 
 
 
 
 
 
 
 
 
 
X 
BSA = body surface area; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; IV = 
intravenous; PK = pharmacokinetic. 
a. 
All baseline data should be collected and assessed within 72 hours prior to dosing on Day 1 of each treatment period. 
b. 
Treatment Periods:  Oraxol = Days 1 to 9; IV paclitaxel = Days 1 to 8.  The second period of randomized treatment may be delayed for up to 3 weeks, if needed, to allow the 
participant to recover to ≤ Grade 1 CTCAE or baseline toxicity from the prior study treatment or to allow the participants flexibility in scheduling inpatient treatment.   


 
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Table 11 
Schedule of Procedures/Assessments for Sequence B (IV Paclitaxel in Treatment Period 1) 
c. 
The Final Visit may occur as early as the last day of PK sampling in Treatment Period 2, up to 2 weeks after the end of PK sampling, and preferably before the participant 
receives any additional chemotherapy.  For participants who elect to continue weekly Oraxol treatment, the Final Visit may serve as screening/baseline for the follow-on 
study; for these participants, the Final Visit should occur within 72 hours prior to receiving the Week 1 dose of Oraxol in the follow-on study.  If the participant withdraws 
informed consent, Final Visit assessments should be completed as much as possible during the final visit on study.  If the participant is taken off for other reasons (eg, 
toxicities), the Final Visit should be completed within 2 weeks after the withdrawal from study and preferably before the participant receives any additional chemotherapy. 
d. 
Complete physical examinations will be performed at Screening and the Final Visit.  All other physical examinations do not require complete examinations but will be 
targeted to the signs and symptoms related to Adverse Event Reporting.  Physical examinations performed on Day -2 do not need to be repeated on Day -1. 
e. 
BSA will be calculated to 1 decimal place based on screening body weight and height.  Weight will be recorded pretreatment for each treatment period.  If weight changes by 
≥10%, BSA will be recalculated.  Study drug doses may be adjusted using the new BSA by the clinical Investigator, if clinically indicated, providing there are no concerns 
regarding increase toxicity from dose adjustment. 
f. 
Vital signs to include pulse rate, systolic/diastolic blood pressure, respiration, and temperature.  Vital sign measurement should be taken before dosing and once daily on 
nondosing days. Vital signs should be taken in the morning on inpatient days, or when participants are first seen at the clinical site on outpatient days. 
g. 
ECGs will be performed 1 hour postdosing on Day 1 of each treatment period. 
h. 
Serum or urine pregnancy test to be obtained in females of childbearing potential at Screening and within 72 hours prior to Day 1 dosing in either treatment period.  Baseline 
pregnancy testing in Treatment Period 1 does not need to be obtained if the screening test was obtained within 72 hours of Day 1 dosing. 
i. 
Participants must be fasted for the Screening and Final Visit laboratory assessments.  Fasting is recommended but not required at other laboratory assessment times.  It must 
be noted if participants were in a fasted or fed state at the time of blood collection.  Clinical laboratory sampling and testing should be conducted anytime within 72 hours 
prior to the scheduled assessment time. 
j. 
Oraxol will be administered at the inpatient clinical site.  IV paclitaxel will be administered at the oncology unit.  For Sequence B, participants will receive IV paclitaxel on 
Day 1 of Treatment Period 1 and Oraxol on Days 1, 2, and 3 of Treatment Period 2. 
k. 
PK blood samples (approximately 6 mL at each testing timepoint) will be collected at the sites.  Please refer to Section 8.5.1.4.1 for all PK sampling timepoints. 
l. 
Collection of all adverse event information will begin immediately after the signing of the informed consent and will continue through the Final Visit. 
 


 
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8.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in oncology studies as 
well as in the routine clinical care of patients with cancer. 
8.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest 
8.5.4.1 
Reporting of Serious Adverse Events 
All SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by electronic transmission as soon as possible but no later than 
1 business day from the date the Investigator becomes aware of the event.  Instructions 
for SAE reporting will be provided in the Investigator File. 
All SAEs, regardless of causality assessment, must be collected through the last participant 
contact and followed to resolution or, if resolution is unlikely, to stabilization.  SAEs 
reported to the site from the time of the last participant contact up to 30 days after the last 
contact, will be collected.  These SAEs will be discussed in the clinical study report.  Any 
SAE event judged by the Investigator to be related to the study treatment should be reported 
to the Sponsor regardless of the length of time that has passed since study completion.  For 
participants who continue Oraxol treatment in the follow-on study (KX-ORAX-003), any 
new SAEs reported after the Final Visit will be captured in the database for study 
KX-ORAX-003. 
Deaths and life-threatening events should be reported immediately by telephone.  The 
immediate report should be followed up within 1 business day by electronically 
transmitting the completed SAE form. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the Investigator’s assessment of causality.  All 
supporting documents should be sent de-identified and should contain the assigned 
participant number.  Send only supporting documents directly related to the event. 
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the Investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the Sponsor. 
8.5.4.2 
Reporting of Pregnancy 
Any pregnancy whether occurring in a subject or in the female partner of a male subject for 
which the estimated date of conception was either before the last visit or within 30 days of 
last study treatment must be reported. 


 
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If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 8.5.4.1). 
Pregnancies must be reported by electronic transmission as soon as possible but no later than 
1 business day from the date the Investigator becomes aware of the pregnancy.  The contact 
information for the reporting of pregnancies is provided in the Investigator File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the Investigator becomes aware of the outcome. 
A participant who becomes pregnant must be withdrawn from study treatment.  If the female 
partner of a male participant becomes pregnant, that male participant may continue in the 
study, but should be requested to provide outcome information on the pregnancy. 
8.5.4.3 
Reporting of Other Events of Interest  
8.5.4.3.1 REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE OR 
MEDICATION ERROR 
Study drug overdose is defined as the accidental or intentional use of the drug in an amount 
higher than the dose being studied. 
Any study drug overdose during the study should be noted on the Study Medication eCRF. 
All AEs associated with overdose or medication error should be captured on the Adverse 
Event eCRF.  The overdose must be reported by electronic transmission as soon as possible, 
but no later than 1 business day from the date the Investigator becomes aware of the event.  
Contact information for reporting of overdose will be provided in the Investigator File.  The 
overdose form should be used for reporting.  If the overdose is associated with an SAE, an 
SAE report form should be completed and sent along with an overdose form. 
8.5.4.3.2 REPORTING OF TREATMENT-EMERGENT SIGNIFICANT LABORATORY ABNORMALITY 
Any treatment-emergent significant laboratory abnormality observed during the clinical 
study should be evaluated by the Investigator to determine if the abnormality meets the 
criteria as an SAE.  If the treatment-emergent significant laboratory abnormality meets the 
criteria for an SAE as specified in Section 8.5.1.5.2, it should be reported as directed in 
Section 8.5.4.1.  If the treatment-emergent significant laboratory abnormality does not meet 
the seriousness criteria, it must still be reported on an Adverse Event eCRF. 


 
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A laboratory result should be considered a treatment-emergent significant abnormality if the 
result: 
• is within normal limits at Baseline and has increased in severity to meet CTCAE 
v4.031 (or later) grading criteria for laboratory values of Grade 3 or above 
• is outside normal limits at Baseline and increases in severity to CTCAE v4.03 (or 
later) grading criteria for laboratory values of Grade 4 or above 
• is otherwise considered by the Investigator to meet serious criteria as defined in 
Section 8.5.1.5.2 
8.5.4.4 
Expedited Reporting 
The Sponsor (or its designee) must inform Investigators and regulatory authorities of 
reportable events, in compliance with applicable regulatory requirements, on an expedited 
basis (ie, within specific timeframes).  For this reason, it is imperative that sites provide 
complete SAE information in the manner described above. 
In determining what SAEs meet criteria for expedited reporting, the following reference 
safety information will be used: 
For Oraxol: 
 
 
The current version of the Oraxol Investigator’s Brochure 
For IV paclitaxel:  
The approved national labeling in each country 
8.5.4.5 
Breaking the Blind 
Not applicable 
8.5.4.6 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the Sponsor or a third party acting on behalf of the 
Sponsor to regulatory authorities in compliance with local law and established guidance.  The 
format of these reports will be dictated by the local and regional requirements. 
8.5.5 
Completion/Discontinuation of Participants 
A participant may elect to discontinue from the study at any time for safety, medical, or 
personal reasons.  See Section 8.3.3 for reasons why participants may be discontinued early 
from study treatment.  In addition to the primary reason, the participant may have indicated 
one or more secondary reasons for discontinuation.  Investigators must document the actual 
reason(s) why they decided to discontinue participants, or why participants withdrew 
consent, as applicable.  Study disposition information will be collected on the Disposition 
eCRF. 
Participants who withdraw from study treatment (with the exception of death or withdrawal 
of consent) will be encouraged to complete the Final Visit assessments at the time of 
withdrawal as indicated in the Schedule of Procedures/Assessments (Table 10 and Table 11). 


 
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A participant who has ceased to return for visits will be followed up by mail, phone, or other 
means to gather information such as the reason for failure to return, the presence or absence 
of AEs, and clinical courses of signs and symptoms.  This information will be recorded in the 
eCRF. 
A participant removed from the study for any reason may be replaced.  Participants may be 
replaced until up to 48 have completed the study at the dose determined in Stage 1 as likely 
to achieve BE based on PK interim analysis/analyses. 
8.5.6 
Abuse or Diversion of Study Drug 
Not applicable 
8.5.7 
Confirmation of Medical Care by another Physician 
The Investigator will instruct participants to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the Investigator will ask the 
participant whether he/she has received medical care by another physician since the last visit 
or is planning to do so in the future.  When the participant is going to receive medical care by 
another physician, the Investigator, with the consent of the participant, will inform the other 
physician that the participant is participating in the clinical study. 
8.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
may be made periodically by the Sponsor’s or the CRO’s qualified compliance auditing 
team, which is an independent function from the study team responsible for conduct of the 
study. 
8.6.1 
Data Collection 
Data required by the protocol will be documented in the participant source documentation 
and entered into a validated electronic data capture (EDC) system. 
Responsible site personnel will enter the information required by the protocol onto the 
eCRFs in accordance with the eCRF Completion Guidelines that are provided.  A CRA will 
visit each site as documented in the monitoring plan to verify the data on eCRFs for 
completeness and accuracy against the source documents.  
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the eCRF. 
Data that are provided by an external vendor will be transferred and validated according to 
the procedures specified in the Data Management Plan. 


 
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All data derived from the study will be the property of the Sponsor and should not be made 
available in any form to third parties without written permission from the Sponsor, except for 
authorized representatives of the Sponsor or appropriate regulatory authorities. 
8.6.2 
Clinical Data Management 
There will be a Data Management Plan to detail all relevant data management activities, from 
eCRF design to database lock. 
Quality control for all relevant data management activities and data validation procedures 
will be applied to ensure the validity and accuracy of the clinical data.  
8.7 
Statistical Methods 
All statistical analyses will be performed by the Sponsor or designee after the study is 
completed and the database is locked and released.  Statistical analyses will be performed 
using SAS software or other validated statistical software as required. 
A total of 24 to 48 evaluable participants receiving the selected Stage 1 dose will be 
evaluated for bioequivalence between Oraxol and IV paclitaxel based on a 2-sided 90% CI of 
log-transformed AUC0-∞ between 80% and 125%. 
Participants evaluable for BE will be those who receive both study treatments and complete 
scheduled post treatment PK evaluations.  Nonevaluable participants will be replaced until up 
to 48 participants have completed the study at the dose determined in Stage 1 as likely to 
achieve BE based on PK interim analysis/analyses. 
Statistical analyses will be reported using summary tables, graphs, and data listings. 
Continuous variables will be summarized using the mean, SD, median, minimum, and 
maximum.  Summaries of PK parameters will also include the geometric mean and the 
coefficient of variation.  Categorical variables will be summarized by counts and by 
percentage of participants in corresponding categories.  All raw data obtained from the 
eCRF, as well as any derived data will be included in data listings. 
8.7.1 
Statistical and Analytical Plans 
The statistical analyses of study data are described in this section. 
8.7.1.1 
Study Endpoints 
8.7.1.1.1 PRIMARY ENDPOINTS 
The primary endpoint is area under the concentration–time curve zero time extrapolated to 
infinite time (AUC0-∞) derived for each participant by noncompartmental analysis using 
plasma concentration-time data for oral and IV paclitaxel. 


 
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8.7.1.1.2 SECONDARY ENDPOINTS 
Secondary endpoints include, but are not limited to the following PK parameters which will 
be derived for each participant by noncompartmental analysis using plasma concentration-
time data for oral and IV paclitaxel: 
• 
Maximum observed concentration (Cmax) 
• 
Area under the concentration–time curve zero time to time of last quantifiable 
concentration (AUC0-t) 
• 
Time at which the highest drug concentration occurs (Tmax) 
• 
Terminal elimination phase half-life (t½) 
In addition, the safety and tolerability of Oraxol compared with IV are secondary endpoints 
in the study.  These will be assessed primarily by evaluation of AEs and laboratory findings.  
The results of other safety assessments (concomitant medications, vital signs, physical 
examinations, ECGs, and ECOG performance status) will also be evaluated. 
8.7.1.2 
Definitions of Analysis Sets 
The Pharmacokinetic Analysis Set is the group of participants who receive both study 
treatments, complete scheduled post-treatment PK evaluations, and are protocol-compliant.   
Participants who vomit within twice the median Tmax will be excluded from the primary 
analysis. 
The Safety Analysis Set is the group of participants who receive at least 1 dose of paclitaxel 
(as Oraxol or IV) and have at least 1 postdose safety assessment. 
8.7.1.3 
Disposition 
All participants who are randomized will be tabulated by treatment group as to study 
discontinuation and the reasons for discontinuation as described in Section 8.3.3 and 
Section 8.5.5. 
8.7.1.4 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized.  For continuous demographic 
variables, results will be summarized and presented as N, mean, SD, median, and minimum 
and maximum values.  For categorical (nominal or ordinal) variables, the number and 
percentage of participants will be used.  No statistical testing will be performed. 
8.7.1.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary drug codes. 


 
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Prior medications will be defined as medications that stopped before the first dose of study 
drug. 
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug.  Concomitant medications will be further 
coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification.  A listing of concomitant medications by drug and drug class will 
be included in the clinical study report for this protocol. 
All medications will be presented in participant data listings. 
8.7.1.6 
Efficacy Analyses 
Not applicable 
8.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
8.7.1.7.1 PHARMACOKINETIC ANALYSES 
The PK analysis will be performed on the Pharmacokinetic Analysis Set using plasma 
concentrations of oral paclitaxel (in Oraxol) and IV paclitaxel.  Paclitaxel plasma 
concentrations will be normalized to 615 mg/m2 or the final agreed dose for Stage 2 for 
Oraxol and 80 mg/m2 for IV paclitaxel.  Pharmacokinetic analysis and statistical analysis will 
be based on normalized plasma concentrations. 
The primary PK parameters will be compared between IV paclitaxel (reference) and oral 
paclitaxel (test) formulations.  Analysis of variance (ANOVA) will be performed (α=0.05) 
on the un-transformed and log10-transformed PK parameters Cmax, AUC0-t, and AUC0-∞ for 
paclitaxel. The ANOVA model will include sequence, subjects nested within the sequence, 
period, and formulation as factors. The significance of the sequence effect will be tested 
using the subjects nested within the sequence as the error term.  Two-sided 90% CIs8 for the 
log-transformed ratio of test/reference of the least squares means obtained from the ANOVA 
for Cmax, AUC0-t, and AUC0-∞ will be estimated.  The equivalence of the extent of absorption 
will be determined by comparing the log-transformed AUC0-∞ of the selected dose of oral 
paclitaxel (as Oraxol administered over 3 consecutive days) to the log-transformed AUC0-∞ 
of IV paclitaxel.  If the 90% CIs for AUC0-∞ fall within 80% to 125%, it will be concluded 
that the oral paclitaxel (in Oraxol) is bioequivalent to IV paclitaxel. 
Tmax and other summary PK parameters and individual timepoints will be tabulated and 
displayed graphically and listed for all participants. 
8.7.1.7.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Not applicable 


 
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8.7.1.8 
Safety Analyses 
All participants in the Safety Analysis Set, ie, who receive at least 1 dose of paclitaxel (as 
Oraxol or IV) and have at least 1 postdose safety assessment will be included in the safety 
analyses. 
Safety data, presented by treatment group (Oraxol or IV paclitaxel), will be summarized 
using descriptive statistics (eg, n, mean, SD, median, minimum, maximum for continuous 
variables; n [%] for categorical variables).  Safety variables include AEs, clinical laboratory 
parameters, vital signs, 12-lead ECG results, physical examination findings, and ECOG 
performance status.  For all safety analyses, study Day 1 will be defined as the date of the 
first dose of study drug. 
8.7.1.8.1 EXTENT OF EXPOSURE 
The actual number of doses will be summarized by treatment period. 
8.7.1.8.2 ADVERSE EVENTS 
Treatment-emergent AEs (TEAEs) are defined as: 
• those AEs with an onset after the start of dosing in each treatment period and  
• those pre-existing AEs that worsen after the start of dosing in each treatment period 
For AEs, verbatim terms on the eCRFs will be mapped to preferred terms (PTs) and system 
organ classes (SOCs) using the Medical Dictionary for Regulatory Activities (MedDRA; 
version 16.1 or later).  The CTCAE criteria v4.031 (or later) will be used to grade the severity 
of the AEs.  Participant incidence of AEs will be displayed by SOC and PT.  Adverse events 
will also be summarized by severity and relationship to the study drug and treatment 
sequence.  
Participant incidence of SAEs will also be displayed. 
The incidence of AEs will be summarized by treatment, treatment period, and treatment 
sequence, and will be presented in participant data listings as well. 
The number (percentage) of participants with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment, treatment period, and treatment sequence.  A 
participant data listing of all AEs leading to death will be provided. 
The number (percentage) of participants with TEAEs leading to discontinuation from study 
drug will be summarized by MedDRA SOC and PT for each treatment, treatment period, and 
treatment sequence.  A participant data listing of all AEs leading to discontinuation from 
study drug will be provided. 


 
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8.7.1.8.3 LABORATORY VALUES 
Laboratory parameters will be summarized using descriptive statistics at baseline and at 
subsequent timepoints.  Changes from baseline will also be summarized. 
In addition, shift tables (ie, low-normal-high at Baseline versus low-normal-high at follow-up 
in a 3-by-3 contingency table) will be provided to assess changes in laboratory values from 
Baseline to follow-up. 
Clinical laboratory results after baseline will be evaluated for markedly abnormal values 
based on the CTCAE v4.031 (or later) criteria for the Investigations SOC.  For the incidence 
of markedly abnormal laboratory values, each participant may be counted once in the 
laboratory parameter value high and in the laboratory parameter low categories as applicable.   
8.7.1.8.4 VITAL SIGNS 
Vital sign values will be evaluated on an individual basis by participant.  Abnormal vital sign 
values will be identified as those outside (above or below) the reference range. 
8.7.1.8.5 ELECTROCARDIOGRAMS 
ECG data will be summarized for each individual participant. 
8.7.1.8.6 OTHER ANALYSES 
Pregnancy Tests 
Results of pregnancy tests will be listed for all participants, as applicable. 
Physical Examinations 
Physical examination findings will be listed for each participant. 
Eastern Cooperative Oncology Group 
ECOG performance status responses will be tabulated by treatment, treatment period, and 
treatment sequence. 
8.7.2 
Determination of Sample Size 
Based on the within-subject variability of at most 30% through a comparison of the PK of 
Oraxol to Taxol, a sample size of 24 to 48 patients is needed to achieve BE within the 
80% - 125% confidence limits with 90% statistical power. 
Based on analysis of data from the first 6 evaluable participants in Stage 1, an additional 
34 evaluable participants will be enrolled into Stage 2.  A total sample size of 40 evaluable 
participants is projected to provide 90% power for the 90% CI of the GMR for AUC0-∞ to fall 
in the range of 80% and 125%. 


 
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8.7.3 
Interim Analysis 
There will be an interim analysis of PK data after each dose tested in Stage 1 to determine if 
the administered regimen would appear likely to achieve BE of Oraxol to IV paclitaxel.  
After the interim analysis/analyses (depending on the outcomes), a decision will be made by 
consensus of the DSMB, Kinex, Zenith Technology, and the Principal Investigator as to what 
dose should be administered in Stage 2.  An additional 18 to 42 participants will be enrolled 
into Stage 2 based on the Stage 1 results (AUC0-∞). 
8.7.4 
Other Statistical/Analytical Issues 
Not applicable 
 


 
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9 
REFERENCE LIST 
1. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
1 4_QuickReference_8.5x11.pdf. 
2. Mauri D, Kamposioras K, Tsali L, Bristianou M, Valachis A, Karathanasi I, et al.  
Overall survival benefit for weekly vs. three-weekly taxanes regimens in advanced breast 
cancer: 
A 
meta-analysis. 
Cancer 
Treat 
Rev. 
2010 
Feb;36(1):69-74. 
doi: 
10.1016/j.ctrv.2009.10.006. Epub 2009 Nov 27. Review. 
3. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, et al.  Weekly 
paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 
17;358(16):1663-71. doi:10.1056/NEJMoa0707056. 
4. NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, Version 3. 2014. 
5. Cardoso F, Harbeck N, Fallowfield L, Kyriakides S, and Senkus E, on behalf of the 
ESMO Guidelines Working Group.  Locally recurrent or metastatic breast cancer: ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 
23 (Supplement 7): vii11–vii19, 2012. 
6. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity 
and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982.  Courtesy of Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. http://www.ecog.org/general/perf_stat.html.  Accessed April 2015. 
7. Guidance for Industry:  Handling and Retention of BA and BE Testing Samples. U.S. 
Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). May 2001. 
8. Guidance for Industry:  Statistical Approaches to Establishing Bioequivalence. U.S. 
Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). January 2001. 
9. ICH Harmonised Tripartite Guideline for Good Clinical Practice E6 (R1): June1996. 


 
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10 PROCEDURES AND INSTRUCTIONS  
10.1 Institutional Review Boards/Independent Ethics Committees 
The protocol, any protocol amendments, and the informed consent form (ICF) will be 
reviewed and approved by a Health Authority (HA) and Ethics Committee (EC) and in New 
Zealand, by New Zealand Medicines and Medical Devices 
Safety 
Authority 
(Medsafe)/Standing Committee on Therapeutic Trials (SCOTT) before participants are 
screened for entry.  Any protocol amendment and/or revision to the ICF will receive 
appropriate approval prior to implementation.  Verification of unconditional approval of the 
protocol will be transmitted to the Sponsor prior to the shipment of drug supplies to the 
investigational site.  The Investigators or the Sponsor will submit, depending on local 
regulations, periodic reports and inform the HA/EC and Medsafe (New Zealand) of any 
reportable AEs per International Council for Harmonisation (ICH) guidelines and local 
HA/EC standards of practice. 
10.2 Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
Sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
This study will be conducted in accordance with the requirements and principles of ICH GCP 
guidelines [ICH - E6 (R1) Guideline for GCP Harmonised Tripartite Guideline9], the World 
Medical Association Declaration of Helsinki 2013, Guideline on the Regulation of 
Therapeutic Products in New Zealand. Part 11:  Clinical Trials – Regulatory Approval and 
Good Clinical Practice Requirements, and other applicable national or local regulations. 
This study will meet requirements for FDA acceptance of foreign studies not conducted 
under an IND (21 CFR 312.120). 
This protocol will be listed on the Australian New Zealand Clinical Trials Registry 
(ANZCTR) website. 
10.3 Participant Information and Informed Consent 
As part of administering the informed consent document, the Investigator must explain to 
each participant the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the participant, and the extent 
of maintaining confidentiality of the participant’s records.  Each participant must be 
informed that participation in the study is voluntary, that he/she may withdraw from the 
study at any time, and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician. 


 
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The informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The participant should understand the statement before signing and 
dating it and will be given a copy of the signed document.  At the Screening Visit, after the 
ICF and any other written information to be provided is read and explained, the participant 
will be asked to sign the ICF before any study-specific procedures are performed.  No 
participant can enter the study before his/her informed consent has been obtained. 
An unsigned copy of an approved ICF must be prepared in accordance with ICH E69, 
Section 4, and all applicable regulations.  Each participant must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The 
original, signed ICF for each participant will be verified by the Sponsor and kept on file at 
the study site and a copy will be provided to the study participant according to local 
procedures at the site. 
The participant should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the study.  
The communication of this information should be documented. 
11 ADMINISTRATIVE PROCEDURES 
11.1 Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.  The 
protocol will be followed as written. 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the Sponsor before implementation.  Amendments specifically 
affecting the safety of participants, the scope of the investigation, or the scientific quality of 
the study require submission to health or regulatory authorities as well as additional approval 
by the applicable Ethics Committees.  These requirements should in no way prevent any 
immediate action from being taken by the Investigator, or by the Sponsor, in the interest of 
preserving the safety of all participants included in the study.  If an immediate change to the 
protocol is felt by the Investigator to be necessary for safety reasons, the Sponsor’s medical 
monitor and the EC for the site must be notified immediately.  The Sponsor must notify the 
health or regulatory authority as required per local regulations.  A protocol change intended 
to eliminate an immediate hazard may be implemented immediately, provided the health or 
regulatory authority and ECs are immediately notified and appropriate documentation of the 
urgent protocol change are submitted per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the EC, but the health or regulatory authority 
and EC should be kept informed of such changes as required by local regulations. 


 
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11.2 Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E69, Section 4.5). 
11.3 Monitoring Procedures 
The Sponsor’s/CRO’s CRA will maintain contact with the Investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The Investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The eCRFs and participant’s 
corresponding original medical records (source documents) are to be fully available for 
review by the Sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and EC review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following: 
• 
Clinic, office, or hospital charts 
• 
Copies or transcribed health care provider notes which have been certified for accuracy 
after production 
• 
Recorded data from automated instruments such as x-rays, and other imaging reports, 
(eg, sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, 
rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless of how 
these images are stored, including microfiche and photographic negatives 
• 
Medical history or other questionnaires completed by participants 
• 
Records of telephone contacts 
• 
Diaries or evaluation checklists 
• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• 
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks) 
• 
Correspondence regarding a study participant’s treatment between physicians or 
memoranda sent to the Ethics Committees 
• 
eCRF components (eg, questionnaires) that are completed directly by participants and 
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11.4 Recording of Data 
An eCRF must be completed for each participant by qualified and authorized personnel.  All 
data on the eCRF must reflect the corresponding source document.  Any correction to entries 
made on the eCRF must have a respective audit trail where the correction is dated, the 
individual making the correction is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 
11.5 Identification of Source Data 
Data to be recorded on the eCRF must reflect the corresponding source documents. 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
Investigator is responsible for retaining all study documents, including but not limited to the 
protocol, randomization list, copies of eCRFs, the Investigator's Brochure, and any regulatory 
agency registration documents, ICFs, and EC correspondence.  The site should plan to retain 
study documents, as directed by the Sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  Records must also be 
retained for the minimum period specified by New Zealand requirements (ie, retain for at 
least 10 years). 
It is requested that at the completion of the required retention period, or should the 
Investigator retire or relocate, the Investigator contact the Sponsor, allowing the Sponsor the 
option of permanently retaining the study records. 
11.7 Auditing Procedures and Inspection 
In addition to the routine monitoring procedures, qualified personnel designated by the 
Sponsor may conduct audits of clinical research activities in accordance with the Sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the Investigator must inform the Sponsor immediately. 
11.8 Handling of Study Drug 
All study drugs will be supplied to the Investigator (or a designated pharmacist) by the 
Sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and 
stored according to the conditions specified on the drug labels.  The Investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the Sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 


 
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each participant must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose.  The 
Investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply prior to approval to do so by the Sponsor.  At the conclusion of the study and as 
appropriate during the study, the Investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the Sponsor/designee or, when approval is given by the Sponsor, will destroy supplies and 
containers at the site.  See Section 8.4.9 for specific drug handling information. 
11.9 Publication of Results 
The Investigators shall have the right to publish the results from this study in accordance 
with the New Zealand Association of Clinical Research (NZACR) Clinical Trial Research 
Agreement. 
11.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the Investigator, the Investigator’s staff, Medsafe (New 
Zealand), and the HA/EC, and will not be disclosed in whole or in part to others, or used for 
any purpose other than reviewing or performing the study, without the written consent of the 
Sponsor.  No data collected as part of this study will be used in any written work, including 
publications, without the written consent of the Sponsor.  These obligations of confidentiality 
and nonuse shall in no way diminish such obligations as set forth in any Confidentiality 
Agreement or Clinical Trial Agreement executed between the Sponsor/CRO and the 
institution/Investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and nonuse set forth in any Confidentiality Agreement or Clinical Trial 
Agreement executed between the Investigator and the Sponsor/CRO. 
11.11 Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the Sponsor will 
promptly inform the Investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The EC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
Sponsor or by the Investigator/institution, as specified by the applicable regulatory 
requirement(s). 
The Investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the Investigator terminates or suspends a study without prior agreement of the 


 
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Sponsor, the Investigator should inform the institution where applicable, and the 
Investigator/institution should promptly inform the Sponsor and the EC and provide them 
with a detailed written explanation of the termination or suspension.  Study records must be 
retained as noted above. 
11.12 Participant Insurance and Indemnity 
The Sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations. 


 
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12 APPENDICES 


 
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Appendix 1 
ECOG Performance Status 
Grade 
Status 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light house work, office work). 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair. 
5 
Dead. 
ECOG = Eastern Cooperative Oncology Group. 
Adapted from Oken MM et al. Am J Clin Oncol. 1982;5:649-5. 
 
 
 


 
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Appendix 2 
Unacceptable Toxicity (Common Terminology Criteria for 
Adverse Events [CTCAE] v4.03) 
Unacceptable toxicity occurs when any of the events listed below are considered at least 
possibly related to the investigational product (IP): 
• 
Grade 4 absolute neutrophil count (ANC) (<0.5 x 109/L) 
• 
Grade 3 or 4 ANC plus fever (defined as temperature 38.5°C or greater; febrile 
neutropenia) or Grade 3 or 4 ANC with bacteremia or sepsis  
• 
Grade 3 thrombocytopenia (<50 x 109/L platelets) for more than 7 days, or 
accompanied by clinically significant bleeding 
• 
Grade 4 thrombocytopenia (<25 x 109/L platelets) regardless of duration or clinical 
manifestations 
• 
Grade ≥3 nausea, vomiting, or diarrhea persisting for more than 48 hours despite 
optimal medical management 
• 
Grade ≥3 nonhematologic abnormalities not listed above.  This does not include:  
○ laboratory abnormalities not considered to be serious adverse events (SAEs) and 
which resolve back to Grade 1 or baseline within 7 days  
○ alopecia 
○ anorexia or asthenia which resolve within 7 days 
• 
Nonhematologic toxicities and hematologic toxicities not mentioned above which 
cause a dose delay of >14 days 
 
 


 
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Appendix 3 
Instructions for Collection of Pharmacokinetic Blood Samples if 
IV Paclitaxel Infusion is Interrupted 
If the infusion is stopped and re-started, then the following changes should be made to the 
scheduled time of collection of the remaining PK samples: 
• 
Collect the next sample at the time the infusion is stopped. 
• 
Treat the patient as required. 
• 
Restart the infusion at a slower rate (or as per hospital protocol). 
• 
Take the next sample at the time the IV is restarted. 
• 
All remaining samples scheduled during the infusion should be collected at even 
intervals. 
• 
The 60-minute sample should be collected at the time the infusion ends. 
• 
All post infusion samples will be calculated as usual from the infusion end time. 
Examples of adjusting the infusion PK samples times are as follows: 
A. If the IV infusion is stopped 10 minutes after sampling, sample numbers 1-4 would 
already have been collected (Sample #4 is scheduled at 8-minutes). The PK sample 
collections should be: 
• 
Collect sample #5 at the time the IV is stopped. 
• 
Collect sample #6 at the time the IV is restarted. 
• 
Collect sample #7 at a time mid-way between when the IV is restarted and when the IV is 
scheduled to finish. 
• 
Collect sample #8 at the time the IV finishes. 
• 
Remaining sampling times shall be calculated from the IV finish time. 
B. If the IV infusion is stopped 15 minutes after sampling, sample number 1-5 would 
already have been collected (Sample #5 is scheduled at 12-minutes). The PK sample 
collections should be: 
• 
Collect sample #6 at the time the IV is stopped. 
• 
Collect sample #7 at the time the IV is restarted. 
• 
Collect sample #8 at the time the IV finishes. 
• 
Remaining sampling times shall be calculated from the IV finish time. 
Note: If the infusion is stopped and not re-started, then the PK samples do not need to be 
collected after the timepoint collected when the infusion was stopped. 
If an IV is stopped after collection of sample # 6 (scheduled at 20-minutes) then that 
participant is considered inevaluable for PK. 

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STATISTICAL ANALYSIS PLAN 
CONFIDENTIAL 
Oraxol 
KX-ORAX-002 
PHASE:  I 
A Randomized Crossover Study to Determine the Bioequivalence of Three 
Consecutive Daily Doses of Oraxol in Cancer Patients Treated With 
Intravenous Paclitaxel 
Date: 17 Sep 2019 
Version: Final 1.0 
Sponsor: 
United States: 
Kinex Pharmaceuticals, Inc. 
20 Commerce Drive 
Cranford, New Jersey 07016, US 
Tel:  +1 908-340-6996 
New Zealand: 
Zenith Technology Corporation, Ltd. 
156 Frederick Street 
Dunedin 9016, New Zealand 
Tel:  64 3–477 9669








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TABLE OF CONTENTS
APPROVAL SIGNATURE(S) ..........................................................................................2
TABLE OF CONTENTS ..................................................................................................3
1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .........................5
2
INTRODUCTION ......................................................................................................6
3
OBJECTIVES AND ENDPOINTS ...........................................................................6
3.1
Study Objectives.....................................................................................................6
3.1.1
Primary Objective ............................................................................................6
3.1.2
Secondary objective(S) ....................................................................................6
3.2
Study Endpoints .....................................................................................................6
3.2.1
Primary Endpoint ............................................................................................6
3.2.2
Secondary Endpoints .......................................................................................6
4
STUDY DESIGN ........................................................................................................7
5
DETERMINATION OF SAMPLE SIZE .................................................................9
5.1
Original Sample Size Assumptions.......................................................................9
5.2
Final Sample Size Assumptions ............................................................................9
6
PATIENT DISPOSITION .........................................................................................9
7
PROTOCOL DEVIATIONS .....................................................................................9
8
ANALYSIS POPULATION ......................................................................................9
8.1
Safety Analysis Set .................................................................................................9
8.2
Pharmacokinetic Analysis Set .............................................................................10
8.3
Randomized Set ....................................................................................................10
9
STUDY POPULATION ...........................................................................................10
9.1
Baseline and Demographic Characteristics .......................................................10
9.2
Medical History and Prior Medication ..............................................................10
10
EXPOSURE AND COMPLIANCE ........................................................................11
10.1
Extent of Exposure ...............................................................................................11
10.2
Treatment Compliance ........................................................................................11
11
STATISTICAL ANALYSIS ....................................................................................12
11.1
Working Platform ................................................................................................12
11.2
Time-Points for Analysis .....................................................................................12
11.3
Methods for Handling Missing, Dropout, Outlier Data ...................................12
11.4
General Consideration.........................................................................................12
12
PHARMACOKINETIC ANALYSIS ......................................................................12
13
SAFETY.....................................................................................................................14
13.1
Adverse Events .....................................................................................................14
13.2
Laboratory Evaluations.......................................................................................15
13.3
Concomitant Medications ...................................................................................15
13.4
Vital Signs .............................................................................................................16
13.5
12-Lead Electrocardiograms (ECG) ..................................................................16
13.6
Physical Examination and Other Safety Parameters .......................................16
13.6.1
Physical Examination ....................................................................................16
13.6.2
ECOG ..............................................................................................................17
13.6.3
Pregnancy Tests .............................................................................................17


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14
INTERIM ANALYSES ............................................................................................17
15
DEVIATIONS FROM PROTOCOL ANALYSIS .................................................17
16
REFERENCE LIST..................................................................................................17


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1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation
Definition
AE
Adverse event
AUC
Area under the curve
BE
Bioequivalence
BLQ
Below limit of quantification
BSA
Body surface area
CI
Confidence interval
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
ECG
Electrocardiograms
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
GMR
Geometric mean ratio
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic
PT
Preferred term
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SD
Standard deviation
SOC
System organ class
TEAE
Treatment-emergent adverse event
TNM 
The Tumor, Node, Metastases status
WHO-DD
World Health Organization Drug dictionary


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2
INTRODUCTION 
This statistical analysis plan (SAP) has been developed after reviewing of the clinical study 
protocol (protocol v6.0, dated 09Nov2017). 
This SAP describes the planned analysis of the safety and tolerability data from this study. 
The planned TFLs to be presented in the clinical study report (CSR) will be originally 
copied or modified from the SAP accompanying TFL shells document. 
The intent of this document is to provide guidance for the statistical analyses of 
investigating the pharmacokinetic (PK) data of orally administered paclitaxel and IV 
paclitaxel. In general, the analyses are based on information from the protocol, unless 
otherwise specified. A limited amount of information concerning this study (e.g., 
objectives, study design) is given to help the reader’s interpretation. This SAP must be 
finalized prior to the lock of the clinical database for this study. When the SAP and TFL 
shells are agreed upon and finalized, they will serve as the template for this study’s CSR. 
This SAP supersedes the 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 in the CSR. 
3
OBJECTIVES AND ENDPOINTS 
3.1
Study Objectives 
3.1.1
Primary Objective 
The Primary objective of the study is to compare the bioequivalence (BE) based on the 
area under the curve extrapolated to infinity (AUC0-∞) of orally administered paclitaxel 
(Oraxol) at the estimated clinical dose to that of intravenous (IV) paclitaxel. 
3.1.2
Secondary objective(S) 
The secondary objectives are to determine the safety and tolerability of Oraxol. 
3.2
Study Endpoints 
3.2.1
Primary Endpoint
The primary endpoint is area under the concentration-time curve zero time extrapolated 
to infinite time (AUC0-∞) derived for each participant by noncompartmental analysis 
using plasma concentration-time data for oral and IV paclitaxel.  
3.2.2
Secondary Endpoints
Secondary endpoints include, but are not limited to the following PK parameters which 
will be derived for each participant by noncompartmental analysis using plasma 
concentration time data for oral and IV paclitaxel:  


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-
Maximum observed concentration (Cmax) 
-
Area under the concentration–time curve zero time to time of last quantifiable 
concentration (AUC0-t) 
-
Time at which the highest drug concentration occurs (Tmax) 
-
Terminal elimination phase half-life (t½) 
In addition, the safety and tolerability of Oraxol compared with IV are secondary 
endpoints in the study. These will be assessed primarily by evaluation of AEs and 
laboratory findings. The results of other safety assessments (concomitant medications, 
vital signs, physical examinations, ECGs, and ECOG performance status) will also be 
evaluated.  
The relationship of AEs with PK exposure parameters (Cmax and AUC0-t) will be explored 
via descriptive statistics in Tables as well as Figures (e.g. side-by-side Boxplots). 
4
STUDY DESIGN 
This is a randomized, multicenter, open-label, 2-stage study with a 2-treatment period 
crossover study to determine the bioequivalence of three consecutive daily doses of Oraxol 
in cancer patients treated with intravenous paclitaxel. The 2-treatment period crossover 
design is shown in Figure 1.
The study will be carried out in 2 stages. Stage 1 will consist of an initial cohort (Cohort 
1) of up to 6 evaluable participants who will receive a dosing regimen of Oraxol 
consisting of a 15-mg oral HM30181 plus and oral paclitaxel dose of 205mg/m2 once 
daily for 3 consecutive days. An interim analysis of PK data from Cohort 1 will be 
conducted to determine if the administered regimen would appear likely to achieve BE of 
Oraxol to IV paclitaxel. If it appears unlikely that the selected regimen will meet the 
criteria for BE based on AUC0-∞ data from Cohort 1 data, the dose of paclitaxel in Oraxol 
may be further adjusted by a maximum of +/- 25% in an additional cohort (Cohort 2) of 
up to 6 participants in Stage 1. After the interim analysis, a decision will be made by 
consensus of the DSMB, Sponsors and the Principal Investigator as to what dose should 
be administered in Stage 2.  An additional 18 to 42 participants will be enrolled into 
Stage 2 based on the Stage 1 results (AUC0-∞). 


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Figure 1 
Crossover Study Design for Study KX-ORAX-002 
Participants in both stages will be randomized to receive either treatment sequence A or 
B. Randomization will be conducted using a computer-generated central randomization 
scheme that will be reviewed and approved by an independent statistician. An overview 
of the 2-treatment period crossover study design and the dosing and PK sampling timing 
for each sequence are presented in Table 1.
Table 1. Study Design, Dosing and PK Sampling in Study KX-ORAX-002 
Pretreatment Phase 
Treatment Phase 
Screening 
Baseline 
Treatment 
Period 1 
Treatment 
Period 2 
Final 
Visit 
Sequence A 
(Oraxol,   
IV paclitaxel) 
Day -28 to 
Day -2 
Day -1 
Days 1-3 (dosing) 
Days 1-9 (treatment 
period)  
Days 1-9 (PK 
sampling)a,b
Day 1 (dosing) 
Days 1-8 (treatment 
period)  
Days 1-5 (PK 
sampling)a
Within 2 
weeks 
after last 
PK 
sample
Sequence B 
(IV paclitaxel, 
Oraxol) 
Day -28 to 
Day -2 
Day -1 
Day 1 (dosing) 
Days 1-8 (treatment 
period)c
Days 1-5  
(PK sampling)a
Days 1-3 (dosing) 
Days 1-9 (treatment 
period)  
Days 1-9  
(PK sampling)a,d
Within 2 
weeks 
after last 
PK 
sample
a: Pharmacokinetic sampling timepoints may be adjusted based on the Stage 1 results. 
b: For Sequence A, Treatment Period 1 ends on the morning of Day 9 (144 hrs after the third dose of 
Oraxol). If Day 9 of Treatment Period 1 is also Day 1 of Treatment Period 2, the last PK sampling 
timepoint in Treatment Period 1 may serve as the predose timepoint for IV paclitaxel in Treatment Period 
2. 
c: For Sequence B, Treatment Period 1 ends on the morning of Day 8 (168 hrs after IV paclitaxel dosing). 
d: For Sequence B, a predose PK sampling must be taken prior to Oraxol dosing on Day 1 in Treatment 
Period 2, as the PK sampling for IV paclitaxel ends on Day 5 of Treatment Period 1. 


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5
DETERMINATION OF SAMPLE SIZE 
5.1
Original Sample Size Assumptions 
Based on the within-subject variability of at most 30% through a comparison of 
pharmacokinetics of Oraxol to Taxol, a sample size of 24 to 48 patients is needed to 
achieve BE within the 80% - 125% confidence limits with 90% statistical power.  
5.2
Final Sample Size Assumptions 
The final sample size is re-considered after interim analysis of the PK data from the 6 
participants in Stage 1. Analysis of variance (ANOVA) was performed (=0.05) on the 
log10-transformed AUC0- for paclitaxel. The analysis of variance model included 
sequence, subjects nested within the sequence, period, and formulation as factors. The 
90% confidence interval (CI) for AUC0-∞ was (74.61%, 101.66%), geometric mean ratio 
(GMR) for AUC0-∞ was 87.09% and intra-subject coefficient of variation (CV) for AUC0-
∞ was 12.62.  
Based on the first 6 evaluable participants from Stage 1, an additional 34 evaluable 
participants were enrolled into Stage 2. A total sample size of 40 evaluable participants 
was projected to provide 90% power for the 90% CI of the GMR for AUC0-∞ to fall in the 
range of 80% and 125%. 
6
PATIENT DISPOSITION 
The number of participants who are screened, screen failed, randomized, dosed and 
completed the study will be summarized. For those who discontinued the study early, the 
reason leading to study discontinuation will also be summarized by treatment group.  
In addition, total number of participants will be summarized by treatment for each 
analysis set (Pharmacokinetic Analysis Set and Safety Analysis Set). 
A listing of patient disposition status, including the patient status (screen failure/ 
completed/ discontinuation), date of informed consent, date of first/last medication, date 
of completion/ discontinued, reason for discontinued from the study. 
7
PROTOCOL DEVIATIONS 
Information regarding subject identification, reason for protocol deviations/protocol 
violation will be presented in data listing.   
8
ANALYSIS POPULATION 
8.1
Safety Analysis Set 
The safety analysis set is the group of participants who receive at least 1 dose of 


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paclitaxel (as Oraxol or IV) and have at least 1 post-dose safety assessment. 
8.2
Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set is the group of participants who receive both study 
treatments, complete scheduled post-treatment PK evaluations, and are protocol-
compliant. Participants who vomit within twice the median Tmax will be excluded from 
the primary analysis. 
8.3
Randomized Set 
The Randomized Set is the group of participants who have been assigned to 
randomization sequence. 
9
STUDY POPULATION 
9.1
Baseline and Demographic Characteristics 
Demographic and baseline characteristics will be summarized by all participants in 
Safety Analysis Set.  
Demographic data, including age (in years), age category (<65, ≥65), gender and race 
will be summarized by treatment sequence.  
Baseline characteristics, including height, baseline weight, baseline BSA, ECOG at 
screening, tumor status at screening and metastatic sites will also be summarized in the 
same way as demographic data. 
For continuous demographic variables, results will be summarized and presented as N, 
mean, SD, median, and minimum and maximum values.  For categorical (nominal or 
ordinal) variables, the number and percentage of participants will be used.  No statistical 
testing will be performed. 
9.2
Medical History and Prior Medication 
Medical and surgical history and current medical conditions will be recorded at Screening.  
All pertinent medical history must be noted in the eCRF.  A complete oncologic medical 
history will also be recorded. 
Medical history including oncology history (other cancer related diagnosis) and non-
oncology medical history will be summarized by MedDRA system organ class (SOC) 
and preferred term (PT) for all patients in Safety Analysis Set. Oncology treatment 
history for surgery/radiation, non-oncology surgical history and non-oncology prior 
therapy will also be coded by MedDRA and summarized by SOC and PT.  
All medications (prescription and nonprescription including vitamins and dietary 
supplements), treatments, and therapies including radiotherapy taken 28 days before the 
initiation of the study through the final study visit must be recorded in the electronic case 


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report form (eCRF).  A complete oncologic treatment history will be recorded on the 
Oncologic Treatment History eCRF. 
Prior medication is defined as medications that stopped before the first dose of study 
drug. Prior medication including oncology treatment history for chemotherapy and non-
oncology prior medication will be summarized by drug and drug class (coded by the 
World Health Organization Drug (WHODrug) dictionary). 
All medical history and prior medication will also be listed. 
10 EXPOSURE AND COMPLIANCE 
10.1
Extent of Exposure 
Oraxol dosing will consist of 15 mg oral HM30181AK-US tablet daily for 3 consecutive 
days plus oral paclitaxel administered over the 3 dosing days. The dose of oral paclitaxel 
as the number of 30-mg capsules needed to dose participants with 615 mg/m2 over 3 days 
based on screening BSA. The total number of capsules will be rounded up.  If the number 
of capsules is not divisible by 3, a single extra capsule will be taken on Day 1; 2 extra 
capsules will be taken as 1 capsule each on Days 1 and 2.   
Intravenous paclitaxel 80 mg/m2 will be administered on Day 1 of either treatment 
period.  
The calculated oral paclitaxel dose for each patient will be rounded up the closest number 
of 30-mg paclitaxel capsules. The total actual doses of oral paclitaxel, HM30181AK-US 
and IV paclitaxel will be summarized by treatment sequence.  
Dosing information will also be listed in the data listing with corresponding fasting 
record. 
10.2
Treatment Compliance 
Overall compliance of study treatment will be performed on the safety analysis set. 
Oraxol compliance will be calculated based on the following formula for HM30181AK-
US tablet and Oral Paclitaxel capsule respectively:  
Compliance(%)
= ܣܿݐݑ݈ܽ݊ݑܾ݉݁ݎ݋݂ݐܾ݈ܽ݁ݏ/ ܿܽ݌ݏݑ݈݁ݏݐܽ݇݁݊݀ݎݑ݅݊݃ݐℎ݁݌݁ݎ݅݋݀
݈ܲܽ݊݊݁݀݊ݑܾ݉݁ݎ݋݂ݐܾ݈ܽ݁ݏ/ܿܽ݌ݏݑ݈݁ݏ݀ݑݎ݅݊݃ݐℎ݁݌݁ݎ݅݋݀
× 100
The planned number of HM30181AK-US tablets is 3. The planned number of 
administered Oral Paclitaxel capsules for patient will be calculated based on the dose of 
oral paclitaxel as the number of 30-mg capsules needed to dose participants with 615 
mg/m2 over 3 days based on screening BSA. The total number of capsules will be 
rounded up.  


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The actual number of tables/capsules taken during treatment period is calculated as the 
number of tablets dispensed-number of tablets returned.  
IV Paclitaxel compliance will be calculated based on the following formula: 
Compliance(%) = ܣܿݐݑ݈ܽܦ݋ݏ݁ܣ݀݉݅݊݅ݏݐ݁ݎ݁݀
݈ܲܽ݊݊݁݀ܦ݋ݏ݁
 × 100
A summary table of compliance will be presented in 2 ways: descriptive statistics for 
compliance expressed as a continuous variable will be presented by treatment sequence. 
In addition, the number and percentage for compliance expressed as a categorical 
variable (<85%, 85-125% and >125%) will be presented by treatment sequence.
11 STATISTICAL ANALYSIS 
11.1
Working Platform 
Statistical analysis programs will be generated with SAS software.   
11.2
Time-Points for Analysis 
A final analysis will be conducted when study completion and database look are reached. 
11.3
Methods for Handling Missing, Dropout, Outlier Data 
Drug concentrations below limit of quantification (BLQ) will be flagged and used for 
descriptive statistics but not for PK parameter estimation. BLQ value will be set to zero 
for this study. 
Except for the concentration data, there will be no imputation for missing data. Missing 
values will be regarded as missing. 
11.4
General Consideration 
Statistical analyses will be reported using summary tables, figures and data listings. 
Continuous data will be summarized with number of participant (N), mean, standard 
deviation (SD), median, minimum and maximum value. Summaries of PK parameters 
will also include the geometric mean and the coefficient of variation.  Categorical data 
will be summarized with the number and percentage of participant. All raw data obtained 
from electronic case report form (eCRF) as well as any derived data will be included in 
data listings. Median and SD will be presented to one more decimal place than the 
standard digits.  
12 PHARMACOKINETIC ANALYSIS 
PK analysis will be performed by Zenith Technology Corporation, Ltd. 
The PK analysis will be performed on the Pharmacokinetic Analysis Set using plasma 
concentrations of oral paclitaxel (in Oraxol) and IV paclitaxel. Paclitaxel plasma 


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concentrations will be normalized to 615 mg/m2 or the final agreed dose for Stage 2 for 
Oraxol and 80 mg/m2 for IV paclitaxel. Pharmacokinetic analysis and statistical analysis 
will be based on normalized plasma concentrations.  
Plasma concentrations for paclitaxel only will be analyzed to determine the following PK 
parameters: Cmax, AUC0-t and AUC0-∞.  
The equivalence of the extent of absorption will be determined by comparing the AUC0-∞ of the 
selected dose of oral paclitaxel (as Oraxol) (administered over 3 consecutive days) to the AUC0-∞
of IV paclitaxel.  
The individual plasma concentration time profiles for paclitaxel will be presented. 
Descriptive statistics (arithmetic mean, standard deviation and CV) will be performed on 
the plasma concentrations for paclitaxel at each sampling time under each treatment 
group. The mean plasma concentration-time data for paclitaxel for each sampling time 
will be listed and shown graphically. 
Descriptive statistics such as arithmetic mean, standard deviation, geometric mean, min, 
median, max and CV for each pharmacokinetic parameter (Cmax, AUC0-t, AUC0-∞, Tmax 
and t1/2) on the original scale will be calculated by treatment group. Geometric mean will 
also be calculated.  
The primary PK parameters will be compared between IV paclitaxel (reference) and oral 
paclitaxel (test) formulations. Analysis of variance (ANOVA) will be performed (α=0.05) 
on the un-transformed and log10-transformed PK parameters Cmax, AUC0-t and AUC0-∞
for paclitaxel. The ANOVA model will include sequence, subjects nested within the 
sequence, period, and formulation as factors. The significance of the sequence effect will 
be tested using the subjects nested within the sequence as the error term.  
Two-sided 90% CIs for the log-transformed ratio of test/reference of the least squares 
means obtained from the ANOVA for Cmax, AUC0-t and AUC0-∞ will be estimated.  
The equivalence of the extent of absorption will be determined by comparing the log-
transformed AUC0-∞ of the oral paclitaxel to the log-transformed AUC0-∞ of IV 
paclitaxel. If the 90% CIs for AUC0-∞ fall within 80% to 125%, it will be concluded that 
the oral paclitaxel (in Oraxol) is bioequivalent to IV paclitaxel. 
Tmax and other summary PK parameters and individual timepoints will be tabulated and displayed 
graphically and listed for all participants. 


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13
SAFETY 
13.1
Adverse Events 
All adverse events (AEs) will be coded with MedDRA (version 16.1 or later) and 
summarized by system organ class (SOC) and preferred term (PT). The CTCAE criteria 
v4.03 (or later) will be used to grade the severity of the AEs. Only treatment-emergent 
AEs (TEAEs) will be summarized. TEAEs will be defined as:  

those AEs with an onset after the start of dosing in each treatment period and  

those pre-existing AEs that worsen after the start of dosing in each treatment period  
If an AE could not be determined by the definition shown above for partial dates or 
missing dates, it would be considered as TEAE unless it stopped before the first dose 
date/time of study treatment. 
An AE will be assigned to the study formulation received in the first dose period if the 
AE occurred after drug administration in the first dose period and prior to taking the 
study formulation in the second period. An AE will be assigned to the study formulation 
received in the second dose period if the AE occurred after drug administration in the 
second period. 
The overall AE information including incidence of AE, TEAEs, TEAEs related to study 
treatment, grade 3 or grade 4 TEAEs, serious TEAE, serious TEAE related to study 
treatment, TEAE leading to study drug discontinuation and AE leading to Deaths will be 
summarized by treatment group, treatment period, and treatment sequence. 
In addition, the incidence of TEAEs and treatment related TEAEs will be summarized by 
PT nested within SOC. TEAEs and treatment related TEAEs will also be summarized by 
PT nested within SOC for worst severity. Similarly, the incidence of serious TEAEs, 
treatment related serious TEAEs, TEAEs leading to study drug discontinuation and 
TEAEs leading to Death will be summarized by PT nested within SOC for each treatment 
group, treatment period, and treatment sequence. 
All AEs, AEs leading to death and AEs leading to study drug discontinuation will be 
provided in data listing separately.  
Participant incidence of SAEs will also be displayed.
The relationship of selected AEs with PK exposure parameters (Cmax, AUC0-t) will be 
explored descriptively (summary statistics in Tables) as well as graphically (side-by-side 
boxplots). For summary tables, PK parameters will be summarized for patients by groups 
either with or without selected AEs (Nausea, vomiting, neutropenia, diarrhea, etc.). 
Oraxol treatment will be summarized separately, in comparison with IV treatment. For 
side-by-side boxplots, y-axis will be the values of PK parameters (Cmax, AUC0-t), and x-
axis will be 4 categories: with or without AEs for Oraxol and IV treatments, respectively. 


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Selected AEs will be presented in a separate plot.   
13.2
Laboratory Evaluations 
Safety analysis set will be used for the summary of laboratory assessments includes 
hematology, blood chemistry and urinalysis (mainly dipstick while microscopic test is 
possible).  Laboratory values base on various units collected from eCRF will be 
normalized with SI units.  
Actual values and change from baseline of following continuous laboratory variables will 
be summarized using descriptive statistics at each scheduled visit by treatment.  

Hematology: all parameters 

Blood Chemistry: all parameters 

Urinalysis: hydrogen ion concentration (PH) and specific gravity. 
Categorical laboratory variables will also be summarized by number and percentage of 
subjects at each scheduled visit by treatment.   
Examination value at Day -1 will be the baseline value for each period. The examination 
at Day -1 of period 2 will be the posttreatment of period 1. The examination at final visit 
will be the posttreatment of period 2. 
Parameters will be assigned an LNH classification according to whether the value is 
lower than (L), within (N) or higher than (H) the corresponding normal range. Results 
will be summarized using shift tables for selected items to evaluate categorical changes 
from baseline to end of study with respect to reference normal range values (lower than, 
within, higher than). 
Laboratory values after baseline will be evaluated for markedly abnormal value based on 
the CTCAE v4.03 (or later) criteria. The number and percentage of patients reporting 
markedly abnormal value with high and low categories will be summarized for each 
parameter by treatment group. For the incidence of markedly abnormal laboratory values, 
each participant may be counted once in the laboratory parameter value high and in the 
laboratory parameter low categories as applicable.   
All laboratory values, with corresponding fasting records, will be provided in the data 
listings.
13.3
Concomitant Medications 
Any medication (including nonprescription medications) or therapy administered to the 
participant during the course of the study (starting at the date of informed consent) will 
be recorded on the Concomitant Medication eCRF.   
Concomitant medications/therapies will be defined as medications/therapies that (1) 
started before the first dose of study drug and were continuing at the time of the first dose 
of study drug, or (2) started on or after the date of the first dose of study medication. 


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Summary table of concomitant medications will be summarized by Anatomical-
Therapeutic-Chemical (ATC) Level 1 and standardized drug name coded by the World 
Health Organization Drug (WHODrug) dictionary and treatment for Safety Analysis Set. 
Summary table of concomitant therapies will be summarized by SOC and PT coded by 
the MedDRA dictionary and treatment for Safety Analysis Set.A concomitant 
medication/therapy is considered to be associated with Oraxol if (1) its start date is within 
the time interval from the first dosing date of Oraxol (inclusively) to the first dosing date 
of IV Paclitaxel (exclusively) in treatment sequence A or (2) its start date is within the 
time interval from the first dosing date of Oraxol (inclusively) to the final visit 
(inclusively) in treatment sequence B.  
Similarly, a concomitant medication/therapy is considered to be associated with IV 
Paclitaxel if (1) its start date is within the time interval from the first dosing date of IV 
Paclitaxel (inclusively) to the first dosing date of Oraxol (exclusively) in treatment 
sequence B or (2) its start date is within the time interval from the first dosing date of IV 
Paclitaxel (inclusively) to the final visit (inclusively) in treatment sequence A. 
Concomitant medications by Anatomical-Therapeutic-Chemical (ATC) Level 1 and 
standardized drug name using WHODrug dictionary will be listed. 
A by-patient listing of concomitant medications will be also provided ATC1 and 
standardized drug name.
13.4
Vital Signs 
Assessments of vital signs include body temperature, respiratory rate, pulse rate, systolic 
and diastolic blood pressure.  
A by-patient listing of vital signs will be also provided at each visit. 
13.5
12-Lead Electrocardiograms (ECG) 
Safety Analysis Set will be used for the analysis of 12-lead ECG. Quantitative ECG 
measurements include heart rate, PR interval, QRS duration, QT interval and QTcF 
interval with their actual values and change from baseline values will be summarized by 
treatment.  
Results of rhythm status and ECG result will be summarized by visit and treatment.  
All 12-lead ECG data, including details of abnormal findings from investigators, will be 
provided in a data listing.
13.6
Physical Examination and Other Safety Parameters 
13.6.1
Physical Examination 
Evaluation of physical examinations will be listed for all participants in Safety Analysis 
Set. Abnormality detected during the study will be also recorded and listed.  


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13.6.2
ECOG 
Eastern Cooperative Oncology Group (ECOG) performance status responses (grade from 
0 to 5) will be summarized by treatment, treatment period, and treatment sequence, and 
visit. A by-patient listing of ECOG performance status responses will be also provided. 
13.6.3
Pregnancy Tests 
Results of pregnancy tests will be listed for all participants as applicable. 
14 INTERIM ANALYSES 
Interim safety and PK data for DSMB Meeting was summarized in 22 Aug 2016 with 
data cutoff date 12 Aug 20162. The DSMB meeting was held on 19 Sep 2016. An interim 
report for bioavailability analysis and sample size for this study was finalized with v1.0, 
dated 21 Oct 20161. 
Bioavailability testing was used to compare PK data acquired in a crossover study from 
an initial cohort (6 participants) treated with 205 mg/m2 Oraxol and 80 mg/m2 IV Taxol. 
Individual AUC0-∞parameter estimates derived from noncompartmental analysis that 
were used for bioavailability testing and variability estimation are presented1. It1 shows 
the estimated AUC0-∞GMR (90% CI) derived from bioequivalence testing for the initial 
6 subject cohort, which was 87.09% (74.61 – 101.66%)2. AUC0-∞intra- subject 
variability (CV%) were estimated to be 12.62% for the initial 6 subject cohort 1. 
15
DEVIATIONS FROM PROTOCOL ANALYSIS 
Additional analysis on the relationship of AEs with PK exposure parameters (Cmax, 
AUC0-t) will be explored descriptively (summary statistics in Tables) as well as 
graphically (side-by-side boxplots). 
16
REFERENCE LIST 
1. Interim Bioavailability Analysis and Clinical Trial Simulations to Predict Sample 
Size for Study KX-ORAX-002 
2. Study KX-ORAX-002 Interim Safety and PK Data for DSMB Meeting 22 August 
2016