Clinical trial NCT03471078
Conditions: Chemotherapy-induced Thrombocytopenia
Keywords: CIT Thrombocytopenia
Sponsor: Sobi, Inc.
Start date: 2018-10-12; Completion date: 2023-01-31
Enrollment: 122 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of avatrombopag in subjects with chemotherapy-induced thrombocytopenia receiving chemotherapy for the treatment of ovarian, lung (small cell and non-small cell) and bladder cancer.

Detailed description:
Subjects will receive placebo controlled test treatment for one cycle of chemotherapy followed by an observational cycle. Subjects will have the option to continue into an open label extension period for all remaining chemotherapy cycles within the current regimen. After the follow-up visit, all subjects will continue to a long-term safety follow-up period.

Arms: arm 1: Study is 2:1 randomization ratio (avatrombopag to placebo). Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment. arm 2: Study is 2:1 randomization ratio (avatrombopag to placebo). Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment.
Interventions: intervention 1: Avatrombopag intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Oral avatrombopag tablet intervention 2: Placebo comparator tablet

Protocol documents:
SAP_002.pdf: 


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Table of Contents 
 
1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 5 
2. 
INTRODUCTION ........................................................................................... 6 
3. 
STUDY DESIGN AND OBJECTIVES ................................................................ 6 
3.1 
Study Objectives...................................................................................... 6 
3.1.1 
Primary Objective .............................................................................. 6 
3.1.2 
Secondary Objectives ........................................................................ 6 
3.2 
Study Design ........................................................................................... 6 
3.2.1 
Double-Blind Treatment Period ........................................................... 7 
3.2.2 
Observational Period .......................................................................... 8 
3.2.3 
Optional Open-Label Extension Period .................................................. 8 
3.2.4 
Long-Term Follow-Up Period ............................................................... 9 
3.2.5 
End of Study..................................................................................... 9 
3.3 
Sample Size Justification ........................................................................... 9 
4. 
GENERAL ANALYSIS DEFINITIONS ............................................................ 10 
4.1 
Study Period and Visit Window Definitions ................................................. 10 
4.1.1 
Study Periods ................................................................................. 10 
4.1.2 
Visit Windows ................................................................................. 10 
4.2 
Definition of Populations ......................................................................... 10 
4.2.1 
Full Analysis Set (FAS) ..................................................................... 10 
4.2.2 
Per-Protocol Analysis Set (PPS) ......................................................... 10 
4.2.3 
Safety Analysis Set (SAF) ................................................................. 11 
4.3 
Data Handling Conventions ..................................................................... 11 
4.3.1 
General Conventions........................................................................ 11 
4.3.2 
Platelet Counts ............................................................................... 11 
4.3.3 
Definition of Study Day .................................................................... 11 
4.3.4 
Definition of Baseline ....................................................................... 11 
4.3.5 
Handling Missing Data...................................................................... 12 
4.3.6 
Partial Dates ................................................................................... 12 
4.3.7 
Clinical Laboratory Values ................................................................ 12 
4.4 
Treatment Groups .................................................................................. 13 
5. 
STUDY PATIENTS ....................................................................................... 13 
5.1 
Disposition of Patients ............................................................................ 13 
5.2 
Protocol Deviations ................................................................................ 13 
5.3 
Inclusion and Exclusion Criteria Not Met ................................................... 13 
5.4 
Randomization....................................................................................... 13 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................ 14 
6.1 
Demographics and Baseline Characteristics ............................................... 14 
6.2 
Medical and Surgical History .................................................................... 14 
6.3 
Oncology History ................................................................................... 14 
7. 
PRIOR AND CONCOMITANT TREATMENT .................................................... 15 
8. 
EFFICACY EVALUATION ............................................................................. 16 
8.1 
Primary Efficacy Analysis ........................................................................ 16 
8.2 
Secondary Efficacy Analysis .................................................................... 16 
8.2.1 
Secondary Efficacy Endpoints............................................................ 16 
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8.2.2 
Hierarchical Testing Strategy for Secondary Efficacy Endpoints ............. 18 
8.3 
Other Efficacy Analysis ........................................................................... 18 
8.4 
Sensitivity Analysis of Primary Efficacy Endpoint ........................................ 19 
8.5 
OLE Period Efficacy Analysis .................................................................... 19 
8.6 
Subgroup Analyses ................................................................................ 19 
8.7 
Interim Analysis .................................................................................... 20 
9. 
SAFETY EVALUATION ................................................................................. 20 
9.1 
Exposure and Treatment Compliance ........................................................ 20 
9.2 
Adverse Events ...................................................................................... 20 
9.3 
Clinical Laboratory Determination ............................................................ 22 
9.4 
Other Safety Measures ........................................................................... 22 
9.4.1 
Vital Signs ...................................................................................... 22 
9.4.2 
ISTH Bleeding Information ............................................................... 22 
9.4.3 
Blood Transfusions .......................................................................... 22 
9.4.4 
ECOG Performance Status ................................................................ 23 
9.4.5 
Long Term Follow-Up (LTFU) Period ................................................... 23 
9.4.6 
COVID-19 Impact ............................................................................ 23 
9.5 
Pharmacokinetics ................................................................................... 23 
10. 
REFERENCES .......................................................................................... 23 
11. 
LIST OF TABLES, LISTINGS, AND FIGURES ............................................. 23 
APPENDIX A: TIME AND EVENTS SCHEDULE ..................................................... 24 
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2.
Introduction 
This Statistical Analysis Plan (SAP) describes the statistical methodology and data 
handling for the clinical trial for Dova Pharmaceuticals with Protocol Number: AVA-
CIT-330 (A Randomized, Double-Blind, Placebo-Controlled Study with an Open-
Label Extension to Evaluate the Efficacy and Safety of Avatrombopag for the 
Treatment of Chemotherapy-Induced Thrombocytopenia in Subjects with Active 
Non-Hematological Cancers). 
The ICH guideline E3 “Structure and Content of Clinical Study Reports” was used as 
a guide to the writing of the plan. 
This SAP is based on the following study document(s): 
x
Clinical Study Protocol V2.0 (Amendment 1), 04 April 2019 
x
Electronic Case Report Form, dated 28 April 2020 
3.
Study Design and Objectives 
3.1
Study Objectives 
3.1.1
Primary Objective 
The primary objective of this study is to evaluate the efficacy of avatrombopag in 
increasing platelet counts and therefore preventing the need for a platelet 
transfusion or chemotherapy dose reduction or delay in subjects with 
Chemotherapy-Induced Thrombocytopenia (CIT). 
3.1.2
Secondary Objectives 
The secondary objectives of this study are the following: 
x
To evaluate the safety of avatrombopag in subjects with CIT, and 
x
To investigate the effect of avatrombopag on bleeding in subjects with 
CIT. 
3.2
Study Design 
This is a Phase 3 randomized, double-blind, placebo-controlled study of the efficacy 
and safety of oral avatrombopag in subjects with CIT with active non-hematological 
cancers. The study consists of 4 periods: a Double-Blind Treatment Period, an 
Observational Period, an optional Open-Label Extension (OLE) Period, and a Long-
Term Follow-Up Period, as described in Figure 1. 
 
 
 
 
 
 
 
 
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Figure 2. Treatment Schedule for Double-Blind Treatment Period 
 
 
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3.2.2
Observational Period 
Cycle X + 2 will be an Observational Period. The Observational Period is designed 
to enable assessment of whether the subjects meet the chemotherapy dose 
modifications or dose delay components of the composite primary endpoint while 
reducing decision-making bias for chemotherapy dose modifications or delays. 
Subjects in the Observational Period will not receive any IP pre- or post-
Chemotherapy Day in Cycle X + 2. 
For subjects not continuing into the optional OLE Period, a Follow-Up Visit will occur 
prior to (within 3 days) Chemotherapy Day in Cycle X + 3. For these subjects, their 
participation in the Observational Period will conclude after they complete the 
Follow-Up Visit and at that point they will enter the Long-Term Follow-Up Period 
(LTFU). 
If Cycle X + 2 is the subject’s last chemotherapy cycle, a Follow-Up Visit will occur 
at 30 days (±3 days) after Chemotherapy Day in Cycle X + 2. 
3.2.3
Optional Open-Label Extension Period 
Subjects who complete the Double-Blind Treatment Period and the Observational 
Period will be eligible to enter an optional OLE Period at 5 days prior to Cycle X + 
3, if they fulfill the inclusion criteria and do not meet any exclusion criteria for the 
optional OLE Period. Subjects must continue to fulfill the inclusion criteria and to 
not meet any exclusion criteria prior to pre-chemotherapy IP treatment in each 
enrolled open-label cycle to continue in the OLE Period. 
All subjects will receive avatrombopag once daily for 5 days prior to Chemotherapy 
Day in Cycle X + 3. Subjects will also receive avatrombopag once daily for 5 days 
immediately following Chemotherapy Day. Avatrombopag will not be administered 
concurrently with chemotherapy on Chemotherapy Day. 
During the study, if the subject has a platelet count >400 x 109/L, IP dosing will be 
stopped temporarily. Dosing may be restarted following discussion with the Medical 
Monitor. 
Subjects may repeat this treatment sequence and continue in the optional OLE 
Period until the end of their current chemotherapy regimen. 
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Subjects will have a Follow-Up Visit at 30 days (±3 days) after the last dose of IP 
treatment of the subject’s last chemotherapy cycle. 
 
Figure 3. Treatment Schedule for Optional Open-Label Extension Period 
 
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3.2.4
Long-Term Follow-Up Period 
After the Follow-Up Visit, all subjects will be contacted approximately every 6 
months for up to 5 years by telephone during the LTFU Period for documentation of 
vital status (if death occurred, record of date of death) and occurrence of 
secondary malignancies. 
3.2.5
End of Study 
The end of study (“study completion”) is defined as the date of the last protocol-
specified visit/assessment (including telephone contact) for the last subject in the 
LTFU Period. 
The study data will be cleaned and locked after the last subject finishes the 
Optional OLE Period. The study will then be unblinded and final analysis will be 
conducted. The data for LTFU Period will be reported once available. 
3.3
Sample Size Justification 
Assuming there is a 40% response rate in the active group and 10% in the placebo 
group, and using a 2:1 randomization, a 10% premature termination rate, and 
90% power with 2-sided alpha = 0.05, the sample size is 120 subjects (80 active 
subjects and 40 placebo subjects). 
The assumptions for the response rates for the null and alternative hypotheses 
were based upon results from a study in CIT completed with oprelvekin (Neumega, 
Pfizer). The study design for oprelvekin was similar in that subjects were 
randomized to active or placebo following occurrence of severe thrombocytopenia 
(platelet count ≤20 × 109/L in a previous cycle [Cycle X]). The primary endpoint of 
the study assessed the ability of oprelvekin to eliminate the need for platelet 
transfusions. In the placebo group (n=30), 93% of subjects required a platelet 
transfusion (7% responder rate) and 72% of active subjects (n=29) required a 
platelet transfusion (28% responder rate). The responder rates assumed for the 
null and alternative hypotheses in the AVA-CIT-330 study were based upon the 
responder rates in this similarly designed study with an assumption for a slightly 
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higher response rate due to the inclusion of subjects with a platelet count in Cycle 
X of <50 × 109/L, rather than ≤20 × 109/L. 
4.
General Analysis Definitions 
4.1
Study Period and Visit Window Definitions 
4.1.1
Study Periods 
The study periods are defined as follows: 
Screening Period: Starting the day of signature of informed consent up to and 
including the day before randomization. For subjects who are not randomized, the 
screening period will end on the day the subject is determined to be a screen 
failure. 
Double-Blind Period: Starting the day of randomization up to and including the 
day before the start of chemotherapy in Cycle X + 2.  
Observational Period: Starting the first day of chemotherapy in Cycle X + 2 up 
to and including the day before the pre-chemotherapy IP administration of Cycle X 
+ 3 (if entering the OLE period) or the day of the Follow-Up visit (if not entering 
the OLE period). 
OLE Period: Starting the first day of the pre-chemotherapy IP administration of 
Cycle X + 3 up to and including the day of the Follow-Up visit in the OLE Period.  
Long-Term Follow-Up Period (LTFU): Starting the day after the Follow-Up visit, 
up to and including a period of 5 years or death, whichever occurs first.  
4.1.2
Visit Windows 
No formal visit windowing will be conducted. For by-visit/by-cycle tabular summaries, 
the scheduled visits or actual chemotherapy cycles will be used in the analyses. The 
exception to this is for nadir platelet counts; both scheduled and unscheduled platelet 
counts will be considered for designation of the nadir value within a cycle.   
For analyses considering the worst post-baseline grade (laboratory shift tables) or 
post-baseline liver tests, all post-baseline values will be considered.  
4.2
Definition of Populations 
The analysis and reporting of the data from this study will be performed using the 
following analysis populations: 
4.2.1
Full Analysis Set (FAS)  
The FAS will include all randomized subjects. 
4.2.2
Per-Protocol Analysis Set (PPS) 
The PPS will include the subset of subjects from the FAS who do not meet the 
criteria that would potentially impact the evaluation of the efficacy endpoints. A full 
list of the criteria will be finalized prior to database lock and unblinding. Examples 
of these criteria may include: 
x
Use of certain prohibited concomitant medications 
x
Selected Inclusion/Exclusion criteria not met for the Double-Blind period 
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x
Lack of compliance with study medication during the Double-Blind period 
x
Study Discontinuation resulting in an inability to assess the primary efficacy 
endpoint 
x
Assigned to incorrect treatment (mis-randomization) or receiving incorrect 
study medication 
4.2.3
Safety Analysis Set (SAF) 
The SAF will include all subjects who receive at least one dose of IP.  
4.3
Data Handling Conventions 
4.3.1
General Conventions 
Data will be analyzed using SAS (Version 9.4 or later). Descriptive analyses will be 
performed on baseline, safety, and efficacy data. 
Descriptive statistics will be tabulated as follows: 
x
Categorical data will be summarized in contingency tables presenting 
frequencies and percentages, and  
x
Continuous data will be summarized using number of non-missing values 
(n), mean, standard deviation, median, minimum, and maximum values.  
4.3.2
Platelet Counts 
Platelet counts are collected at local laboratories for eligibility and efficacy 
assessments. Platelet count is also included in the hematology panel sent to the 
central laboratory as a safety evaluation. For the efficacy analyses, only platelet 
counts assessed by the local laboratories will be included in the calculations and 
summaries. For the safety analyses, only platelet counts assessed by the central 
laboratory will be included in the summaries.  
4.3.3
Definition of Study Day 
The first day of study treatment with avatrombopag or placebo will be Study Day 1. 
There is no Study Day 0. The day before the first day of study treatment will be 
Study Day -1. If an event occurs on or after the first day of study treatment, Study 
Day will be calculated as (Date of Event - Date of first study treatment + 1).  If the 
event occurs prior to the first day of study treatment, Study Day will be calculated 
as (Date of Event - Date of first study treatment). 
4.3.4
Definition of Baseline 
For data displays for the Double-Blind/Observational Period, a baseline value will 
be the last non-missing value taken prior to the start of study treatment in the 
Double-Blind Period, unless otherwise indicated. For the efficacy analyses of 
platelet count, baseline will be defined as the lowest platelet count collected during 
the qualifying period in Cycle X and prior to the first dose of study drug. 
For data displays for the OLE Period, a baseline value is the last non-missing value 
taken prior to the start of the pre-chemotherapy IP of Cycle X+3, unless otherwise 
indicated. For the efficacy analyses of platelet count, baseline will be defined as the 
lowest platelet count collected during Cycle X+2 and prior to the pre-chemotherapy 
IP of Cycle X+3. 
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For data displays for the entire study (avatrombopag group only), a baseline value 
will be the last non-missing value taken prior to the start of study treatment in the 
Double-Blind Period, unless otherwise indicated. For the efficacy analyses of 
platelet count, baseline will be defined as the lowest platelet count collected during 
the qualifying period in Cycle X and prior to the first dose of study drug. 
4.3.5
Handling Missing Data 
Every effort should be made during the conduct of the study to limit the extent of 
missing data with subjects who prematurely discontinue IP but remain in the study 
for collection of data, unless the subject withdraws consent. 
For efficacy summaries where the proportion of responders meeting certain criteria 
is calculated, data will be presented in Yes, No, and Missing categories. In the 
statistical testing (e.g., CMH test), subjects in the Missing category will be treated 
as non-responders.  
4.3.6
Partial Dates 
For the purpose of inclusion of appropriate data records in the analysis, some 
partially missing dates will have date imputation performed. However, these 
imputations will be limited to table summaries; listings will retain the date as 
entered in the database. The following imputations will be performed: 
Time since Primary Cancer Diagnosis: Prior to calculating this variable, missing 
month and day will be set to June 15th. If only day is missing, the day will be set to 
the 15th of the month. If a date is completely missing, no imputation will be 
performed. 
Medications:  
x
If a start date is missing the day 
o
Set to the 1st of the month  
x
If a start date is missing the day and month 
o
Set to January 1st if study treatment began the year prior to the year of 
medication start  
o
Set to January 1st if the medication is known to start in a year prior to study 
treatment  
o
If the medication and the study treatment start the same year, the 
medication start date will be set to the study treatment start date.  
x
No medication end dates will be imputed 
x
No completely missing dates will be imputed. If, after imputation, it cannot 
be determined whether a medication was taken prior or concomitantly, it will 
be considered a concomitant medication.  
In general, the assumptions about the missing or partially missing dates, when 
needed, are made conservative to avoid overestimation of treatment effect and 
underestimation of adverse effects. 
4.3.7
Clinical Laboratory Values 
Clinical laboratory values collected as below or above a limit of quantitation (e.g. 
containing “<” or “>” in the laboratory value) will be analyzed according to the 
numeric value associated with the “>” or “<” symbol.  
 
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4.4
Treatment Groups 
Data displays for the Double-Blind Treatment period/Observational period will have 
columns for avatrombopag 60 mg dose and placebo groups, unless otherwise 
specified. Data displays for the optional OLE period will have 3 columns: subjects 
randomized to avatrombopag 60 mg dose, subjects randomized to placebo, and a 
total column (all subjects in the optional OLE period receive avatrombopag 60 mg). 
Data displays for the entire study will include subjects randomized to 
avatrombopag 60 mg only. 
Data listings will generally include Subject ID, Age/Sex/Race, and an indicator of 
whether the applicable record occurred during the Screening, Double-Blind, 
Observational, or OLE periods. 
5.
Study Patients 
5.1
Disposition of Patients 
Disposition will be summarized by treatment group and overall for the FAS 
population.  
A summary table will include the total number of subjects screened and 
randomized. The number and percentage of subjects in each analysis set will be 
presented by treatment group.  
The summary table will also contain the number and percentage of subjects who 
completed the Double-Blind/Observational period, discontinued the study during 
the Double-Blind/Observational period (along with reason), entered the OLE period, 
completed the OLE period, and discontinued the study during the OLE period (along 
with reason).  
Details of “Other” reason for discontinuation will be included in a disposition listing. 
A separate table summary and listing will also indicate the reasons subjects were 
screen failures for the Double-Blind period as well as the reasons subjects did not 
enter the OLE period.  
5.2
Protocol Deviations 
The number and percentage of subjects with major protocol deviations will be 
summarized by category by treatment group and overall for the FAS. Details of the 
major protocol deviations will be provided in a listing.  
The number and percentage of subjects who are excluded from the PPS will be 
summarized by treatment group, along with reasons for exclusion. Subjects 
excluded from PPS will also be presented in a data listing. 
5.3
Inclusion and Exclusion Criteria Not Met 
Details of inclusion/exclusion criteria not met for subjects in the FAS will be 
provided in a listing. The listing will separately note whether the inclusion/exclusion 
criteria not met was for the Double-Blind period or for the OLE period.  
5.4
Randomization 
For subjects in the FAS, a listing will be provided which details randomization 
information (including treatment group, date/time, number of eligible 
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chemotherapy agents) as collected in the Interactive Web Response System 
(IWRS), and kit number of the study drug assigned. 
6.
Demographic and other Baseline Characteristics 
Demographics and Baseline Characteristics will be summarized for subjects in the 
FAS for the Double-Blind period. If necessary, summaries will be repeated for 
subjects in the PPS. 
6.1
Demographics and Baseline Characteristics 
Descriptive statistics with respect to subject characteristics at baseline will be 
displayed by treatment group for the FAS. The variables to be summarized are: 
Demographics 
x
Age at enrollment (years) 
x
Age group at enrollment: <65 years, 65-<75 years, 75-<85 years, 85+ 
years 
x
Sex 
x
Race 
x
Ethnicity 
x
ECOG Performance Status 
x
Region (United States, Europe, China) 
Baseline subject characteristics  
x
Height (cm) 
x
Weight (kg) 
x
Body Mass Index (BMI) (kg/m2) 
x
Baseline platelet count (109/L) (defined as the lowest platelet count collected 
during the qualifying period in Cycle X and prior to first dose of study drug) 
x
Platelet count prior to study treatment start (i.e., the last platelet count 
collected prior to the first dose of study drug) 
x
Number of eligible chemotherapy agents recorded in IWRS 
 
A listing of demographic and baseline characteristics will also be provided. 
6.2
Medical and Surgical History 
Medical and surgical history will be coded using the Medical Dictionary for 
Regulatory Authorities (MedDRA) version 23.0. The coding version may be updated 
prior to database lock if a newer version is available. 
Medical and surgical history will be tabulated by MedDRA System Organ Class 
(SOC) and Preferred Term (PT) for the FAS. Subjects with more than one medical 
history event in a SOC or PT will only be counted once per SOC or PT.   
Medical history details will also be provided in a data listing.  
6.3
Oncology History 
Descriptive statistics with respect to oncology history and cancer characteristics will 
be displayed by treatment group for the FAS. The variables to be summarized are: 
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x
Primary Cancer Diagnosis: Ovarian, Non-small cell lung cancer, Small cell 
lung cancer, Bladder cancer 
x
Stage (I, II, III, IV) 
x
Time since diagnosis (years), defined as (Date of randomization – Date of 
Diagnosis)/365.25 
x
Cycle length of current regimen: 21-day or 28-day 
x
Cycle of Chemotherapy at Study Entry, both continuous and categorical  
x
Prior Surgery for Current Cancer (Yes/No) 
x
Prior Radiation for Current Cancer (Yes/No) 
x
Prior Chemotherapeutic Regimens for Current Cancer (Yes/No) and number 
of prior chemotherapy regimens (1 or 2)  
x
Number of Eligible Chemotherapy Agents recorded on eCRF (1, 2, 3, or 4) 
A listing of oncology history will be provided. 
7.
Prior and Concomitant Treatment 
Prior and Concomitant medications will be classified according to the World Health 
Organization (WHO) Drug Dictionary (March 2020, B3). The coding version may be 
updated prior to database lock if a newer version is available. Medications will be 
coded per the Anatomical Therapeutic Classification (ATC). All medications will be 
documented from the time of informed consent up to the Follow-up visit.  
Prior medications are those which start and stop before the first day of study 
treatment in the Double-Blind period. Concomitant medications for the Double-
Blind/Observational period are those which start on or after the first day of study 
treatment and prior to the first dose of the study drug in the OLE period. A 
medication which begins before the start of study treatment in the Double-Blind 
period and continues into the Double-Blind period will be considered as 
concomitant for the Double-Blind/Observational period.  
Concomitant medications for the OLE period are those which begin prior to the OLE 
period and continue into the OLE period or those which start on or after the first 
day of study treatment in the OLE period.  
Tabular summaries will display the number and percentage of subjects with at least 
one medication in ATC Level 2 and preferred term categories and overall. Subjects 
who have taken a medication more than once will only be summarized once per 
ATC Level 2 or preferred term.  
The tabular summaries to be provided are as follows: 
x
Prior Medications  
x
Concomitant Medications (Double-Blind/Observational period) 
x
Concomitant Medications (OLE period) 
x
Concomitant Medications taken as rescue for a bleeding event (Double-
Blind/Observational period) 
x
Concomitant Medications taken as rescue for a bleeding event (OLE period) 
An overall listing of medications will be provided. The listing will designate whether 
a medication is considered prior or concomitant. A separate listing will also be 
produced for concomitant medications taken as rescue for a bleeding event. 
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A data listing for the concomitant radiation therapy procedures will also be 
provided. 
Chemotherapy agents that the subjects received during Cycle X + 1 will be 
summarized by preferred name for FAS. The study chemotherapy data will also be 
provided in a data listing. 
8.
Efficacy Evaluation  
All primary and secondary efficacy endpoints will be analyzed using the FAS.  
8.1
Primary Efficacy Analysis 
The primary efficacy endpoint is the proportion of responders who meet all of the 
following criteria during the period after post-chemotherapy IP treatment in Cycle 
X+1 through Chemotherapy Day of Cycle X+2: 
• Not requiring a platelet transfusion; 
• Not requiring a chemotherapy dose reduction by ≥15% due to 
thrombocytopenia; and 
• Not requiring a chemotherapy delay by ≥4 days due to thrombocytopenia. 
Chemotherapy Day is defined as the latest among Day 1 to 3 of the subject’s 
chemotherapy regimen (eg, if chemotherapy is given on Day 1 and Day 2, Day 2 
will be the Chemotherapy Day). For subjects whose chemotherapy is on an 
intermittent schedule (eg, Days 1, 8, 15), Day 1 will be the Chemotherapy Day. 
If subjects had no post-chemotherapy IP dosing in Cycle X+1, the assessment 
period of the primary efficacy endpoint will start from the day after Chemotherapy 
Day in Cycle X+1 through Chemotherapy Day in Cycle X+2.  
If subjects had any post-chemotherapy IP dosing in Cycle X+1, the assessment 
period of the primary efficacy endpoint will start from the day after post-
chemotherapy IP dosing in Cycle X+1 through Chemotherapy Day in Cycle X+2.  
If the information on platelet transfusion or chemotherapy dose reduction or delay 
is missing (eg, due to early drop-out), the subject will be treated as a non-
responder in the primary analysis.  
The primary efficacy endpoint will be tested between avatrombopag and placebo 
using the Cochran-Mantel-Haenszel (CMH) 2-sided test at α=0.05, adjusting for 
number of eligible chemotherapy agents as collected in the IWRS (1 or ≥2 
permissible chemotherapy agents). The numbers and percentages of responders in 
each treatment group with the associated unadjusted exact (Clopper-Pearson) 95% 
CI, and the difference in proportion of responders between avatrombopag and 
placebo with the associated unadjusted exact (Clopper-Pearson) 95% CI will be 
calculated. The primary analysis will be performed based on the FAS and repeated 
on the PPS as a supportive analysis.  
8.2
Secondary Efficacy Analysis 
8.2.1
Secondary Efficacy Endpoints 
The key secondary efficacy endpoints include the following: 
x
Duration of severe thrombocytopenia defined as a platelet count <50 × 109/L 
during the period after post-chemotherapy IP treatment in Cycle X+1 through 
Chemotherapy Day of Cycle X+2 
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Duration of severe thrombocytopenia will be assessed as the total number of days 
with platelet count <50 x 109/L based on platelet counts taken from the day after 
the last post-chemotherapy IP in Cycle X + 1 through the Chemotherapy Day in 
Cycle X + 2. Platelet counts collected through the expected date of Cycle X+2 
Chemotherapy Day (based on 21- or 28-day cycle length after Cycle X+1 
Chemotherapy Day) or the end of study date, whichever is earliest, will be 
considered for this endpoint.  
The days between a platelet count <50 x 109/L and a subsequent platelet count 
assessment will be assumed to show severe thrombocytopenia and contribute to 
the duration, and days between a platelet count ≥50 x 109/L and a subsequent 
platelet count within Cycle X+1 will not contribute to the duration. If a scheduled 
platelet count assessment is missing, it will be considered that the platelet count 
was <50 × 109/L at that visit. 
x
Change in platelet count from baseline (qualifying chemotherapy cycle [Cycle 
X]) (nadir) to Cycle X + 1 (nadir) 
Change in platelet count from baseline is the difference between the lowest platelet 
value prior to the first dose of study treatment and the lowest value during Cycle 
X+1 (i.e., the lowest platelet value during the day after the last post-chemotherapy 
IP dose in Cycle X + 1 through the Chemotherapy Day of Cycle X + 2). 
Multiple imputation methods using a “jump to control” procedure will be 
implemented to address missing Cycle X+1 (nadir).  In this procedure, multiply 
imputed datasets will be produced using SAS PROC MI which assume that the 
subjects with missing Cycle X+1 (nadir) have platelet counts following a similar 
pattern of those subjects receiving placebo. The multiply imputed datasets are then 
combined using SAS PROC MIANALYZE to create a p-value for the assessment of 
the difference between avatrombopag and placebo groups in the mean change in 
platelet count from baseline. This p-value will be used in the hierarchical testing 
strategy defined in Section 8.2.2.  
x
Proportion of subjects who do not have major or non-major clinically relevant 
bleeding during the period after post-chemotherapy IP treatment in Cycle X+1 
through Chemotherapy Day of Cycle X + 2 
Subjects will be considered to NOT have major or non-major clinically relevant 
bleeding if no bleeding events were reported on the ISTH Non-surgical Bleeding 
Assessment CRF page that were classified as “Major Bleeding” or “Non-major 
clinically relevant bleeding” from the day after the last post-chemotherapy IP in 
Cycle X + 1 through the Chemotherapy Day in Cycle X+2. If information on the 
bleeding events is missing, subjects will be assumed to have had major or non-
major clinically relevant bleeding during that period. 
x
Proportion of subjects who do not receive platelet transfusion during the period 
after post-chemotherapy IP treatment in Cycle X+1 through Chemotherapy Day 
of Cycle X + 2  
Subjects will be considered to have not required a platelet transfusion if subjects 
did not require a platelet transfusion after taking the last post-chemotherapy IP in 
Cycle X + 1 through the Chemotherapy Day in Cycle X + 2. If information on 
platelet transfusion is missing, subjects will be assumed to have had a platelet 
transfusion during that period. 
The categorical variables (eg, proportion) will be summarized and analyzed in the 
same manner as the primary efficacy endpoint. If the data is sparse where the 
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approximative methods cannot be applied, the Fisher’s Exact test will be used 
instead. 
For continuous variables (eg, change from baseline in platelet count, duration of 
severe thrombocytopenia), the normality assumption of an analysis of covariance 
will be evaluated analytically using the Shapiro-Wilk test and visually using the 
residual plot.  
Plots will be created displaying platelet count values over time separately for the 
Double-Blind/Observational period, the OLE period, and the entire study. 
8.2.2
Hierarchical Testing Strategy for Secondary Efficacy Endpoints 
If the test of the treatment effect on the primary efficacy endpoint is statistically 
significant, the analysis of the key secondary efficacy endpoints will proceed using 
the following step-down closed testing procedure to maintain the family-wise Type 
I error rate at significance level α = 0.05 (2-sided): 
x
Step 1: Test the treatment effect at a significance level of 0.05 on duration of 
severe thrombocytopenia defined as a platelet count <50 × 109/L during the 
period after post-chemotherapy IP treatment in Cycle X+1 through 
Chemotherapy Day of Cycle X + 2; if successful, proceed to Step 2; otherwise 
stop at Step 1. 
x
Step 2: Test the treatment effect at a significance level of 0.05 on change in 
platelet count from baseline (qualifying chemotherapy cycle [Cycle X]) (nadir) 
to Cycle X + 1 (nadir); if successful, proceed to Step 3; otherwise stop at 
Step 2. 
x
Step 3: Test the treatment effect at a significance level of 0.05 on proportion 
of subjects who do not have major or non-major clinically relevant bleeding 
during the period after post-chemotherapy IP treatment in Cycle X+1 through 
Chemotherapy Day of Cycle X + 2; if successful, proceed to Step 4; otherwise 
stop at Step 3. 
x
Step 4: Test the treatment effect at a significance level of 0.05 on proportion 
of subjects who do not receive platelet transfusion during the period after 
post-chemotherapy IP treatment in Cycle X+1 through Chemotherapy Day of 
Cycle X + 2. 
8.3
Other Efficacy Analysis 
The other efficacy endpoints include the following during the period after post-
chemotherapy IP treatment in Cycle X+1 through Chemotherapy Day of Cycle 
X+2: 
• Proportion of subjects who do not have a chemotherapy dose reduction that is 
≥15% due to thrombocytopenia; 
• Proportion of subjects who do not have a chemotherapy delay that is ≥4 days 
due to thrombocytopenia; 
• Proportion of subjects with a pre-defined post-baseline nadir platelet count (i.e., 
subjects with the lowest platelet count <10, <25, <50, <75, <100, and ≥100 x 
109/L at any time); 
• Proportion of subjects achieving a pre-defined post-baseline maximum platelet 
count (i.e., subjects with the highest platelet count ≤400, >400, and >600 x 109/L 
at any time). 
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Categorical variables (eg, proportion) will be summarized and analyzed in the 
similar manner as the primary efficacy endpoint. If the data is sparse where the 
approximative methods cannot be applied, the Fisher’s Exact test will be used 
instead.  
8.4
Sensitivity Analysis of Primary Efficacy Endpoint 
The following sensitivity analyses will be performed for the primary efficacy endpoint: 
x
The difference in the proportion of responders between the avatrombopag 
and placebo groups will be tested using the Fisher’s Exact test; 
x
The primary efficacy analysis will be repeated using the observed case, i.e. 
missing data will be excluded from the analysis. 
8.5
OLE Period Efficacy Analysis 
For the OLE period (start of pre-chemotherapy IP dosing of Cycle X+3 and 
onward), the following efficacy endpoints will be summarized descriptively for 
subjects randomized to avatrombopag and subjects randomized to placebo 
separately and overall:  
x
Proportion of subjects who meet the primary efficacy criteria (i.e., no platelet 
transfusion, no chemotherapy delay by ≥4 days due to thrombocytopenia, no 
chemotherapy dose reduction by ≥15% due to thrombocytopenia) overall and 
in each cycle 
x
Proportion of subjects who do not receive a platelet transfusion overall and in 
each cycle 
x
Proportion of subjects who do not have a chemotherapy dose reduction 
(≥15%) due to thrombocytopenia overall and in each cycle 
x
Proportion of subjects who do not have a chemotherapy delay (≥4 days) due 
to thrombocytopenia overall and in each cycle  
x
Proportion of subjects who do not have major or non-major clinically relevant 
bleeding overall and in each cycle 
x
Duration of severe thrombocytopenia (i.e., platelet count <50 x 109/L) overall 
and in each cycle 
x
Actual and change from baseline values of platelet count in each cycle (nadir) 
These analyses and summaries will be provided in a similar manner to the Double-
Blind/Observational period. 
Similar analyses and summaries will be provided for the entire study (Double 
Blind/Observational Period + OLE) for subjects randomized to avatrombopag 60 
mg group only. 
8.6
Subgroup Analyses 
The primary efficacy analysis will be repeated for the following subgroups: 
x
Age (<65 years, 65-<75 years, 75-<85 years, 85+ years) 
x
Sex 
x
Race (White vs Non-White) 
x
Number of eligible chemotherapy agents (1 vs ≥2) 
x
Tumor type (ovarian cancer, lung cancer, bladder cancer) 
x
Previous chemotherapy regimens (0 vs 1 vs 2) 
x
Region (United States, Europe, China) 
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8.7
Interim Analysis 
No formal interim efficacy analysis is planned for this study. An independent Data 
Safety and Monitoring Board (DSMB) has been convened for this study to monitor 
safety on a periodic basis. A separate DSMB charter describes the scope of the 
DSMB’s data review as well as rules governing the DSMB.  
9.
Safety Evaluation 
Safety and tolerability will be assessed by examining exposure/treatment 
compliance, the incidence of adverse events, clinical laboratory parameters, vital 
signs, and other pertinent safety data using the SAF.  
9.1
Exposure and Treatment Compliance 
Exposure and treatment compliance will be separately summarized for the Double-
Blind period, the OLE period, and the entire study.  
The number of doses (both descriptively and categorically) will be summarized for 
each study period. 
Treatment compliance during the relevant study period per subject will be 
calculated as (number of tablets taken/number of tablets expected)*100. The 
treatment compliance will be summarized descriptively and also presented 
categorically (e.g. number and percentage of subjects with <80%, 80-100%, and 
>100%). Number of tablets taken will be determined as the number of tablets 
dispensed minus the number of tablets returned that are recorded in the eCRF. 
Duration of exposure (in days) will also be summarized descriptively per study 
period and computed as the last dose day – the first dose day +1. For the OLE 
period and entire study, duration will also be summarized by categories (≤10 days, 
11-20 days, 21-30 days, 31-40 days, etc.) 
The number and percentage of subjects receiving Cycle X+1 chemotherapy, Cycle 
X+2 chemotherapy, etc. will be summarized in the relevant study period tables. 
A data listing will provide details of subject exposure for the Double-Blind, the OLE 
periods, and the entire study. Listings of study drug administration for the Double-
Blind period and study drug accountability for the OLE period will also be provided.  
9.2
Adverse Events 
Adverse events (AEs) will be coded using MedDRA version 23.0. The coding may be 
updated according to newly released versions of the dictionary.  
Severity of AEs is categorized according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. 
For investigator determined relationship to study drug, AEs are classified as 
“Related” or “Not Related”. 
AEs leading to discontinuation of avatrombopag/placebo are AEs where action 
taken is designated as “Drug Withdrawn” in the eCRF.  
Two categories for Adverse Events of Special Interest (AESI) will be summarized 
and are defined as: 
1. Thromboembolic events - All adverse events with MedDRA PT belonging to 
SMQ ‘Embolic and thrombotic events’ 
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2. Bleeding Events - MedDRA PT belonging to 2nd level SMQ ‘Haemorrhage 
terms (excl laboratory terms)’ 
Tabular summaries of adverse events will be provided for the Double-
Blind/Observational period, OLE period, and the entire study separately and will 
only include treatment-emergent adverse events (TEAE). TEAEs are defined as AEs 
occurring after the first dose of study treatment.  
Listings will include all adverse events reported after the consent form is signed 
(both TEAE and non-TEAE). A flag will be included in the listings to designate 
whether an adverse event is treatment-emergent.  
Overview summary tables by treatment group will include the number and 
percentage of subjects with at least one: 
x
TEAE 
x
TEAE related to study drug 
x
Serious TEAE 
x
Grade 3+ TEAEs 
x
TEAE leading to study drug discontinuation 
x
TEAE of special interest 
x
Deaths 
Summary tables of TEAEs by System Organ Class (SOC) and Preferred Term (PT) 
will be provided for: 
x
TEAE (by SOC and PT and by descending frequency of PT) 
x
TEAEs related to study drug 
x
Grade 3+ TEAEs 
x
Serious TEAE 
x
TEAE of special interest 
x
TEAE leading to study drug discontinuation 
Listings of all adverse events by treatment group will be provided and will include 
information such as the patient identifier, SOC, PT, reported term, date of 
onset/stop, duration of the event, TEAE, seriousness, severity, action taken, 
outcome, causality and relationship.  
Listings of adverse events will be provided for the following categories: 
x
All Adverse Events 
x
AEs related to study drug 
x
Grade 3+ AEs  
x
Serious AEs 
x
AEs of special interest 
x
AEs leading to study drug discontinuation 
A listing of deaths will be provided which will include any death details available in 
the eCRF.  
 
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9.3
Clinical Laboratory Determination 
Clinical safety laboratory assessments will include tests from the serum chemistry, 
hematology, and coagulation categories. Where applicable, laboratory values will 
be graded according to the NCI-CTCAE v5.0.   
Local laboratories will be used to determine eligibility or when clinically needed; 
however, for the safety analysis of laboratory assessments, only laboratory values 
evaluated at a central laboratory will be used.  Unless otherwise specified, all the 
summaries of the laboratory tests will be presented by the Double-blind period, 
OLE period, and entire study. 
Shift tables of Baseline CTCAE grade to worst post-baseline CTCAE grade will be 
presented separately for gradable Hematology Parameters and Serum Chemistry 
Parameters. In the case of bi-directional toxicities, parameters will be presented 
separately (eg Calcium High, Calcium Low). For the purposes of tabulation, 
laboratory values which are not assigned NCI-CTCAE Grades 1, 2, 3, or 4 due to a 
toxicity will be assigned Grade 0 (within the normal range).  
All laboratory data (including Hematology parameters, Chemistry parameters, 
Coagulation parameters, and pregnancy tests) will be included in separate 
laboratory listings.  
A separate summary table for liver tests (ALT, AST, Alkaline Phosphatase, Direct 
Bilirubin, and Total Bilirubin) will be created. This table will indicate the number 
and percentage of subjects (presented by lab test) who have a highest post-
baseline lab value for the test that is CTCAE Grades 1, 2, 3, or 4.  
Observed values and changes from baseline for continuous Hematology and Serum 
Chemistry laboratory tests will be presented over time in box plots. Reference lines 
for the LLN and ULN will be included in the plots.  
9.4
Other Safety Measures 
9.4.1
Vital Signs 
By-visit summary tables will be created displaying the observed values and 
changes from baseline for vital sign parameters, separately for the Double-
Blind/Observational period and the OLE period. 
A listing of all vital signs entered in the eCRF will also be provided.  
9.4.2
ISTH Bleeding Information 
A tabular summary of ISTH Bleeding Information will be provided and will include 
the number and percentage of subjects in the Double-Blind/Observational period, 
OLE period, and entire study who have experienced bleeding in the following 
categories: any bleeding, major bleeding, non-major clinically relevant bleeding, 
and minor bleeding.  
A data listing of ISTH Bleeding information will also be provided which will include 
the criteria for major classification, major bleeding at a critical site, and non-major 
clinically relevant bleeding.  
9.4.3
Blood Transfusions 
A summary table will be created to display the frequency and percentage of 
subjects, separately for the Double-Blind/Observational period, OLE period, and 
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Page 23 of 28 
 
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TPL Version: 05 
Of SOP SA-02.07 
TPL Effective Date: 31 Mar 2016 
 
entire study who have blood transfusions (yes/no). The type of blood product (Red 
Blood Cells, Platelets, Cryoprecipitate) will be summarized (subjects may appear in 
more than one category) and the reason for transfusion (Thrombocytopenia, 
Bleeding Event, Adverse Event other than Bleeding Event, Other) will be 
summarized (subjects may appear in more than one category). The total number 
of packs/units received per transfusion will be summarized as a continuous 
variable.  
Details of any blood product transfusions occurring during the study will be 
presented in a listing. 
9.4.4
ECOG Performance Status   
The ECOG performance status will be presented in a listing.  
9.4.5
Long Term Follow-Up (LTFU) Period 
The number and percentage of subjects who entered (Yes vs No), completed (Yes 
vs No), and remain ongoing during the 5-year LTFU period will be summarized. The 
reasons for not entering the LTFU and the reasons for not completing the LTFU 
period will also be tabulated. The number and percentage of subjects who 
developed a secondary malignancy (Yes vs No), and the number and percentage of 
deaths occurring during the LTFU period along with the cause of death (if known) 
will be tabulated for all subjects who participated in the LTFU period. A data listing, 
with details of any secondary malignancies reported, will also be provided for all 
subjects in the LTFU period. 
9.4.6
COVID-19 Impact 
In April 2020, the eCRF was updated to add a page for collecting the extent to 
which study visits may have been affected by the COVID-19 global pandemic. This 
page collects a Yes/No answer of whether there was any impact. If the answer was 
yes, additional data as to the type of impact (Visit not done, Visit delay, Study drug 
not taken as planned, Study discontinuation, Lab sample collection, Study 
procedures, Other), visit impacted, cycle impacted, and description of impact were 
collected.  
The details of the COVID-19 Impact will be presented in a listing.  
9.5
Pharmacokinetics 
A listing of drug concentrations from pharmacokinetic (PK) samples will be 
provided.  
Further analysis relating to PK/PD modelling will be provided in a separate 
analytical plan.  
10. References 
International Conference on Harmonization (ICH) guideline “Statistical principles 
for Clinical trials”: E9, 1998. 
11. List of Tables, Listings, and Figures 
A separate document will detail the list of the planned tables, listings, and figures 
for the final statistical analysis. The document will also include the mock tables, 
listings, and figures. 
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Confidential 
 
Dova Pharmaceuticals – AVA-CIT-330 - SAP – V1.0/31AUG2020 
Page 24 of 28 
 
TPL N°: TPL SA-02-01 
TPL Version: 05 
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TPL Effective Date: 31 Mar 2016 
 
Appendix A: Time and Events Schedule 
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double-blind treatment period, all subjects will be assessed for platelet transfusions and chemotherapy dose reductions or delays. 
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Confidential 
 
Dova Pharmaceuticals – AVA-CIT-330 - SAP – V1.0/31AUG2020 
Page 25 of 28 
 
TPL N°: TPL SA-02-01 
TPL Version: 05 
Of SOP SA-02.07 
TPL Effective Date: 31 Mar 2016 
 
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Confidential 
 
Dova Pharmaceuticals – AVA-CIT-330 - SAP – V1.0/31AUG2020 
Page 26 of 28 
 
TPL N°: TPL SA-02-01 
TPL Version: 05 
Of SOP SA-02.07 
TPL Effective Date: 31 Mar 2016 
 
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Confidential 
 
Dova Pharmaceuticals – AVA-CIT-330 - SAP – V1.0/31AUG2020 
Page 27 of 28 
 
TPL N°: TPL SA-02-01 
TPL Version: 05 
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TPL Effective Date: 31 Mar 2016 
 
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Confidential 
 
Dova Pharmaceuticals – AVA-CIT-330 - SAP – V1.0/31AUG2020 
Page 28 of 28 
 
TPL N°: TPL SA-02-01 
TPL Version: 05 
Of SOP SA-02.07 
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Prot_000.pdf: 
C LI NI C A L  ST U D Y P R O T O C O L  
A R a n d o mize d, D o u ble- Bli n d, P l ac e b o-C o ntr olle d St u d y Wi t h a n 
O pe n- L a bel E xte nsi o n t o E v al u at e t he Effic ac y a n d S afet y o f 
A v atr o m b o p a g fo r t he T re at me nt o f C he m ot her a p y -I n d uce d 
T hr o m b oc yt o pe ni a i n S u bjects Wit h Acti ve N o n- He m at ol o gic al 
C a ncers 
I n vesti g ati o n al P r o d uct: A vatr o m b o pa g ta bl ets 
Pr ot oc ol  Nu m ber:  A V A - CI T- 3 3 0 
N C T  Nu m ber:  0 3 4 7 1 0 7 8  
S p o ns or:  
D o va P har mace uticals  
2 4 0 Lei g h Far m R d, S uite 2 4 5 
D ur ha m, N C 2 7 7 0 7 
U nite d  States 
Tele p h o ne: + 1  9 1 9- 7 4 8- 5 9 7 5 
Fa x : + 1  9 1 9- 7 4 8- 5 9 7 6 
Vers i o n Nu m ber:  2. 0 /  A me n d me nt 1  
D at e: 0 4 A pril  2 0 1 9 
Re places: V ersi o n 1. 0 / 2 3 Fe br u ar y 2 0 1 8 
C o nfi de nti alit y  St ate me nt 
T he inf or mati o n i n t his d oc u me nt is co nfi de ntial an d is n ot to be di scl ose d wit h o ut t he writte n 
c o nse nt of D o va P har mace uticals e x ce pt to t he exte nt that di scl os ure w o ul d be re q uire d b y la w 
a n d f or the p u r p ose of ev al uati n g a n d/ or c o n d uc ti n g a cli nical st u d y f or Do v a P har mace uticals . 
Y o u are all o we d t o discl ose the co nte nts of this d oc u me nt o nl y to y o ur I nstit uti o nal R e vie w 
B oar d o r I n dep e n de nt Et hics  Co m mittee  a n d st u d y pers o n nel di rectl y in v ol ve d wit h c o n d ucti n g 
t his pr ot oc ol. Pers o ns to w h o m the inf or mati o n is di scl ose d m ust be inf or me d t hat the 
i nf or mati o n is co nf i de ntial an d pr o priet ar y to D o v a P har mace uticals a n d t hat it ma y n ot be 
f urt her di scl ose d t o t hird parties. 




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I N V E S TI G A T O R A G R E E M EN T  
B y si g ni n g b el o w I a gree t hat:  
I h a ve rea d t his pr ot oc ol. I a p pr o ve t his d oc u me nt a n d I a gree t h at it c o ntai ns all necessar y details 
f or carr yi n g o ut t he st u d y as descri be d. I will c o n d uct t his st u d y i n acc or da n ce wit h t he desi g n a n d 
s pecific pr o visi o n of t his pr ot oc ol a n d will ma ke a reas o n a ble eff ort t o c o m plete t he st u d y wit hi n 
t he ti me desi g nate d. I will pr o vi de c o pies of t his pr ot oc ol a n d access t o all i nf or mati o n f ur nis he d 
b y D o v a P har mace uticals  t o st u d y pers o n nel u n d er m y s u p er visi o n. I will disc uss t his material 
wit h t he m t o e ns ur e t he y are f ull y i nf or m e d a b o ut t he st u d y pr o d u ct a n d st u d y pr oce d ures. I will 
let t he m k n o w t hat t his i nf or mati o n is c o nfi de ntial a n d pr o prietar y t o D o v a P har mace uticals a n d 
t hat it ma y n ot be f urt her discl ose d t o t hir d parties. I u n d ersta n d t hat t he st u d y ma y b e ter mi nate d 
or e nr o ll me nt s us pe n de d at a n y ti me b y D o v a P har mace uticals, wit h or wit h o ut ca use, or b y me if 
it bec o mes necessar y t o pr otect t he best i nterests of t he st u d y s u bjects.  
I a gree t o c o n d uct t his st u d y i n f ull acc or d a nce wit h I nstit uti o nal Re vie w B oar d/ Et hic s C o m mittee 
Re g ulati o ns a n d I nter n ati o nal C o u ncil f or Har m o nisati o n ( I C H) G ui deli nes f or G o o d Cli nical 
Practices.  
 
 
 
 
 
 
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I n v esti gat or’s Si g n at ure  
  
  
  
  
 
Date  
 
 
 
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I n v esti gat or’s Pri nte d Na me 
 
  


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S Y N O P SI S  
TI T L E:   A  Ra n d o mize d,  D o u ble -Bli n d,  Place b o -C o ntr olle d  St u d y  W it h  a n  O pe n-La bel 
E xte nsi o n  t o  E val uate  t he  Efficac y  a n d  Saf et y  of  A vatr o m b o pa g  f or  t he  Treat me nt  of  
C he m ot hera p y -I n d u ce d T hr o m b oc yt o p e nia i n S u bjects Wit h Acti ve N o n-He mat ol o gi cal Ca ncers  
P R O T O C O L N U M B E R:   A V A -CI T - 3 3 0 
I N V E S TI G A TI O N A L P R O D U C T:  A vatr o m b o pa g t a blets 
P H A S E:   3 
I N DI C A TI O N( S):  Tr eat me nt of c he m ot hera p y-i n d uce d t hr o m b oc yt o pe ni a ( CI T) 
O B J E C TI V E S:  
T he pri mar y o bjecti ve of t his st u d y is t o e val uat e t he efficac y of a v atr o m b o pa g i n i n creasi n g 
platelet c o u nts a n d t heref ore pre v e nti n g t he nee d f or a platelet tra nsf usi o n or c he m ot hera p y d ose 
re d uctio n or del a y i n s u bjects wit h CI T. 
T he sec o n d ar y o bjecti ves of t his st u d y are t he f oll o wi n g:  
•  T o e val uate t he s afet y of a vatr o m b o pa g i n s u bjects wit h CI T, a n d 
•  T o i n vesti gate t h e effect of a vatr o m b o pa g o n bl ee di n g i n s u bjects wit h CI T. 
P O P U L A TI O N:  
I ncl usi o n Criteri a  f or All S u bjects 
S u bjects w h o meet all of t he f oll o wi n g criteria will be eli gi ble t o partici pate i n t he st u d y:  
1.  S u bject is ≥1 8 years of a ge at t he ti me of i nf or me d c o nse nt; 
2.  S u bject wit h a dia g n o sis wit h o vari a n  ca ncer, l u n g ca n cer (s mall cell or n o n-s mall cell), or 
bla d der ca ncer, re q uiri n g s yste mic c h e m ot hera p y; 
3.  S u bject is c urre ntl y r ecei vi n g a c h e m ot hera p y re gi me n gi ve n i n a 2 1 -d a y  or 2 8- da y c ycle ( ot her 
c he m ot hera p y c ycl e le n gt hs are n ot all o w e d), i ncl u di n g 1 or m ore of t he f oll o wi n g a ge nts  or 
class of a ge nts : 
o  N ucle osi de a n al o g, i n cl u di n g ge mcita bi n e a n d fl u or o uracil; 
o  Car b o plati n or cis plati n; 
o  A nt hrac ycli ne;  or  
o  Al k ylati n g a ge nt;  
4.  S u bject  e x perie nce d  se v ere t hr o m b oc yt o pe nia,  d efi ne d  as  2 pl atelet   c o u nts  < 5 0 ×   1 09/ L 
meas ure d at least 2 4 h o urs a part, d uri n g t h e q ualif yi n g c h e m ot hera p y c ycl e ( C ycle X), of t heir 
c urre nt c h e m ot hera p y r e gi me n . Platelet c o u nts o btai ne d per sta n dar d of care d uri n g C ycle X 
pri or t o c o nse nt ma y be use d; 


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5.  S u bject  is  pla n ne d to r ecei ve  t he  sa m e  c h e m ot hera p y re gime n  a n d  t he  sa me  d ose(s)  o n  
C he m ot hera p y Da y ( Da ys 1 -3) of C ycl e X + 1 as was gi v e n i n t he q ualif yi n g c he m ot hera p y 
C ycle X;  
6.  S u bject has a n Easter n C o o perati ve O n c ol o g y Gr o u p ( E C O G) perf or ma n ce stat us ≤2; 
7.  S u bject has a life  e x pecta nc y > 1 2 w ee ks at Scree ni n g  a n d is a ble t o recei ve at least 2 a d diti o nal 
c ycles of t he c urr e nt c he m ot hera p y re gi me n ; 
8.  Fe males of c hil d beari n g p ote ntial m ust a gree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
(e g, t otal a bsti ne nce; a n i ntra uteri ne d e vice; h or m o nal c o ntra ce pti ve gi ve n orall y, b y i nj ecti o n , 
or b y i m pla nt; d o u ble barrier c o ntrace pti o n (i.e., c o n d o m + dia p hra g m) ; or has a vasect o mize d 
part ner wit h c o nfir m e d az o os per mia)  t hr o u g h o ut t he e ntire st u d y p eri o d a n d f or 3 0 da ys after 
i n vesti gati o nal pr o d uct (I P)  disco nti n uati o n. If c urre ntl y a bsti ne nt, t he s u b j ect m ust a gree t o 
use a n effecti ve met h o d as descri b e d a b o ve if s h e bec o mes s e x uall y acti ve d uri n g t he st u d y 
peri o d or f or 3 0 d a ys aft er I P disc o nti n uati o n.   
Male s u bjects m ust be eit he r s ur gicall y sterile or agree t o use a d o u ble barrier c o ntrace pti o n 
met h o d 
(c o m bi nati o n  of  male  c o n d o m  wit h  eit her  ca p,  dia p hra g m,  or  s p o n ge  wit h  a  
s per mici de) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after I P dis c o nti n uati o n; 
N ote: All fe male s u bjects  are c o nsi dere d t o be of c hil d beari n g p ote ntial  u nless t he y are  
p ost me n o pa usal ( at least 1 2 m o nt hs c o ns ec uti ve a me n orr h ea a n d wit h o ut a n ot her k n o w n or 
s us pecte d ca us e) or ha ve bee n sterilize d s ur gicall y (ie, bilateral t u bal li gati on, h yst erect o m y, 
or bilateral o o p h or ect o m y) at least 1 m o nt h bef ore d osi n g. 
9.  S u bject is willi n g a n d a bl e t o c o m pl y wit h all as p ects of t he pr ot oc ol; a n d  
1 0.  S u bject m ust pr o vi de writte n i nf or me d c o nse nt. 
E xcl usi o n Criteri a f or All S u bjects  
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will be e x cl u de d fr o m partici pati o n i n t he st u d y:  
1.  S u bject has e x perie nce d ≥ Gra de 2 CI T wit h a pl atelet c o u nt < 7 5 ×  1 09/ L ( ot her t ha n d uri n g 
t he c urr e nt c he m ot her a p y treat me nt re gi me n) wit hi n 6 m o nt hs of Scree ni n g; 
2.  S u bject has a  platelet c o u nt > 1 7 5 ×  1 09/ L at Visit 2 (- 1 da y); 
3.  S u bject  wit h  a n y  hist or y  of  h e mat ol o gic  mali g na n cies,  i ncl u di n g  le u ke mia,  m yel o ma,  
m yel o pr olif erati ve diseas e, l y m p h o ma, or m yel o d ys plastic diseas es; 
4.  S u bject w h o r ecei v e d > 2 pre vi o us li nes of c h e m ot hera p y (a dj u va nt/ ne o a dj u va nt t hera p y is 
c o nsi dere d a pr e vi o us li ne; i m m u n ot hera p y al o n e is n ot c o nsi dere d a pre vi o us li ne) or is 
recei vi n g w h ole brai n r a diati o n d uri n g t he st u d y treat me nt peri o d; 
5.  S u bject wit h  a n ala ni ne a mi n otra nsferase  ( A L T) or as partate a mi n otra nsferase  ( A S T) > 5 ×  
u p per li mit of n or mal or t otal bilir u bi n ≥3 ×  u p per li mit of n or mal; 
6.  S u bject has a k n o w n me dical hist or y of h u m a n i m m u n o deficie nc y vir us; 
7.  S u bject has a n y k n o w n cli nicall y si g nifica nt ac ute or acti ve blee di n g (e g, gastr oi ntesti nal or 
ce ntral ner v o us s yste m) wit hi n 7 da ys of Scree ni n g;  


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8.  S u bject has a k n o w n me dical hist or y of ge netic pr ot hr o m b otic s y n dr o mes  (e g, Fact or V 
Lei d e n, pr ot hr o m bi n G 2 0 2 1 0 A, or A TIII defi cie n c y);  
9.  S u bject has a rece nt hist or y ( wit hi n 3 m o nt hs of Scree ni n g) of si g nifica nt car di o vas c ular 
disease ( e g, c o n gesti ve h eart f ail ure e x acer bati o n , arr h yt h mia k n o w n t o i n creas e t he ris k of 
t hr o m b oe m b olic e ve nts [ e g, atri al fi brillati o n], c or o nar y arter y ste nt place me nt, a n gi o plast y, 
or c or o nar y art er y b y pass gr aft);  
1 0.  S u bject has a hist or y of arterial or ve n o us t hr o m b osis wit hi n 3 m o nt hs of Scree ni n g; 
1 1.  S u bject has use d vita mi n K a nta g o nists wit hi n 7 da ys of Scree ni n g ( us e of l o w m olec ular 
wei g ht h e pari n , X a i n hi bit ors, or t hr o m bi n i n hi bit ors is all o we d); 
1 2.  S u bject has a hist or y of c hr o nic platelet or bl ee d i n g dis or d ers or t hr o m b o c yt o pe nia d ue t o a n 
eti ol o g y ot her t ha n CI T ( e g, c hr o nic li ver disease or i m m u ne t hr o m b oc yt o p e nia p ur p ura); 
1 3.  S u bject has use d m o derate or str o n g i n d ucers of c yt o c hr o me P 4 5 0 ( C Y P) 2 C or C Y P 3 A 4/ 5 
(see A p p e n di x C ) wit hi n 7 da ys of Scree n i n g; 
1 4.  S u bject has recei ve d a t hr o m b o p oieti n rece pt or a g o nist (e g, eltr o m b o pa g or r o mi pl osti m) or 
rec o m bi na nt h u ma n t hr o m b o p oieti n f or t he treat me nt of CI T wit hi n 3 m o nt hs of Scree ni n g; 
1 5.  S u bject recei v e d a platel et tra nsf usi o n wit hi n 7 2 h o urs of ra n d o mizati o n; 
1 6.  S u bject is u na ble t o ta ke oral me dicati o n ; 
1 7.  S u bject  has  a n y  hist or y  of  a  c o nc o mita nt  m e dical  c o n diti o n  t hat,  i n  t h e  o pi ni o n  of  t h e  
I n v esti gat or, w o ul d c o m pr o mise t he su bject’s a bilit y t o safel y c o m plete t he st u d y, s uc h as 
u nsta ble a n gi na, re n al fail ure re q uiri n g he m o dial ysis, or acti ve i nfecti o n re q uiri n g i ntra ve n o us 
a nti bi otics; 
1 8.  Fe male  s u bjects  w h o  are  lactati n g  or  pre g na nt  at  Scree ni n g  or  t he  Baseli ne  Visit  (as 
d oc u me nte d b y a p ositi ve ser u m or uri n e  beta -h u ma n c h ori o nic g o na d otr o pi n [ β -h C G] test) ; 
1 9.  S u bje ct has h y p erse nsiti vit y t o a vatr o m b o pa g or a n y of its e x ci pie nts; or  
2 0.  S u bject is c urre ntl y e nr olle d i n a n ot her cli nical st u d y wit h a n y i n v esti gati o n al dr u g or de vi ce 
wit hi n 3 0 da ys of Scree ni n g; h o we v er, p artici pati o n i n o bser vati o nal st u dies is per mitte d. 
I ncl usi o n Criteri a f or S u bjects t o C o nti n ue I nt o t he O pti o n al O pe n-L a bel E xte nsi o n Peri o d  
S u bjects w h o meet all of t he f oll o wi n g criteria will be eli gi ble t o c o nti n ue i nt o t he o pti o nal 
O pe n -La b el E xte nsi o n ( O L E ) Peri o d : 
1.  S u bject is c urre ntl y r ecei vi n g t he sa me c h e m ot hera p y a ge nts as w ere gi ve n i n t he q ualif yi n g 
c he m ot hera p y C ycl e X;  
2.  S u bject has a n E C O G  perf or ma nce stat us ≤2; 
3.  Fe males of c hil d beari n g p ote ntial m ust a g ree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
as pre vi o usl y defi ne d. 
Male s u bjects m us t be eit her s ur gicall y sterile or a gree t o use a d o u ble barrier c o ntrace pti o n 
met h o d 
(c o m bi nati o n  of  male  c o n d o m  wit h  eit her  ca p,  dia p hra g m,  or  s p o n ge  wit h  a  
s permici de) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after I P dis c o nti n uati o n;  


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N ote:  Al l  fe male s u bjects  are c o nsi dere d t o be of c hil d beari n g p ote ntial  u nless t he y are  
p ost me n o pa usal (at l east 1 2 m o nt hs c o nsec uti ve a me n orr hea i n t he a p pr o priate a ge gr o u p a n d 
wit h o ut a n ot her k n o w n or s us pecte d ca use) or h a ve bee n sterilize d s ur gicall y (ie, bi lateral t u b al 
li gati o n, h yst erect o m y, or bilateral o o p h orect o m y) at least 1 m o nt h bef ore d osi n g. 
4.  S u bject is willi n g a n d a bl e t o c o m pl y wit h all as p ects of t he pr o t oc ol; a n d  
5.  S u bject m ust pr o vi de c o nse nt t o c o nti n ue i nt o t he O L E Peri o d. 
E xcl usi o n  Criteri a f or S u bjects t o C o nti n ue Int o  t he O pti o n al O pe n-L a bel E xte nsi o n Peri o d  
S u bjects w h o meet a n y of t he f oll o wi n g criteria will be e x cl u de d f r o m c o nti n ui n g i nt o t he o pti o nal 
O L E Peri o d:  
1.  S u bject has a pl atelet c o u nt > 1 7 5 ×  1 09/ L o n t he sc he d ule d first d a y of d os i n g of a v atr o m b o pa g 
pri or t o c he m ot her a p y; 
2.  S u bject wit h a n A L T  or A S T > 5 ×  u p per li mit of n or mal or t otal bilir u bi n ≥3 ×  u p per li mit  of  
n or mal; 
3.  S u bject has  a n y k n o w n cli nicall y si g nifica nt ac ute or acti ve blee di n g (e g, gastr oi ntesti nal or 
ce ntral ner v o us s yste m) wit hi n 7 da ys of pre- c he m ot hera p y I P treat me nt i n O L E c ycles ; 
4.  S u bject has use d vita mi n K a nta g o nists wit hi n 7 da ys of pre -c he m ot hera p y I P treat me nt i n 
C ycle X + 3 ( use of l o w m olec ular wei g ht h e pari n , Xa i n hi bit ors, or t hr o m bi n i n hi bit ors  is 
all o we d); 
5.  S u bject has use d m o der ate or str o n g i n d ucers of C Y P 2 C or C Y P 3 A 4/ 5 (see  A p p e n di x C ) 
wit hi n 7 da ys of pre- c he m ot hera p y I P treat me nt i n O L E c ycles ; 
6.  S u bject  is u na ble t o ta ke oral me dicati o n ; 
7.  Fe male s u bjects w h o ar e lactati n g or pre g na nt (as d oc u me nte d b y a  p ositi ve uri ne or ser u m  
test) 
S T U D Y D E SI G N A N D D U R A TI O N:  
T his is a P hase 3 ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y of t he efficac y a n d safet y of 
oral a vatr o m b o pa g i n s u bjects wit h CI T wit h acti ve n o n -he mat ol o gical ca n cers. T he st u d y c o nsists 
o f 4 peri o ds: a D o u ble -Bli n d Treat me nt Peri o d , a n O bser vati o nal Peri o d, a n opti o nal O L E  Peri o d , 
a n d a L o n g -T er m  F oll o w- U p Peri o d.  
T o be eli gi ble f or t he st u d y, s u bjects m ust ha ve e x perie nce d  t hr o m b oc yt o p e nia d uri n g t heir c urre nt 
c he m ot hera p y r e gi me n as des cri be d i n t he i ncl usi o n criteria. T he q ualif yi n g c h e m ot hera p y c ycle 
is define d as “ C ycl e X” . S u bjects m ust be scree ne d ≤2 8 da ys pri or t o t he Baseli ne Visit , u nless 
Scree ni n g a n d Baseli ne Visits are perf or me d o n t he sa me da y,  a n d be gi n treat me nt d uri n g C ycl e 
X.  
D o u ble -Bli n d Tre at me nt Peri o d  
At  t he  Bas eli ne  Visit,  eli gi ble  s u bjects  will  be  ra n d o mize d  i n  a  2: 1  rati o  t o  recei ve  eit her  
a vatr o m b o pa g  or  place b o  i n  a  d o u ble -bli n d  ma n ner  pri or  t o  a n d  d uri n g  t he  s u bse q ue nt  
c he m ot hera p y  c ycle,  C ycl e  X  +  1.  Ra n d o mizati o n  will  be  stratifie d  b y  t h e  n u m ber of 
c he m ot hera p y  a ge nts  t he  s u bject  is  recei vi n g ( 1  or  ≥2 per missi ble c he m ot hera p y  a ge nts  
[ n ucle osi de  a nal o g,  i n cl u di n g  ge mcita bi ne  a n d  fl u or o uracil;  car b o plati n  or  cis plati n;  


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a nt hrac ycli n e; or al k yl ati n g a ge nt] ). S u bject s will recei ve eit her a vatr o m b o pa g or place b o o nce 
dail y  f or  5  da ys  pri or  t o  C he m ot hera p y  Da y  i n  C ycle  X  +  1.  S u bjects  will  als o recei ve 
a vatr o m b o pa g  or  place b o  o nce  dail y  f or  5  da ys  i m me diatel y  f oll o wi n g  C he m ot hera p y  Da y.  
C he m ot hera p y Da y is defi ne d per p r ot o c ol as Da y 1 t o 3 of t he s u bject’s c he m ot hera p y re gi me n 
(e g, if c he m ot her a p y is gi ve n o n Da y 1 a n d Da y 2, t he sec o n d r o un d of a v atr o m b o pa g or place b o 
will  start  o n  Da y 3).  A vatr o m b o pa g  or  place b o  will  n ot  be  a d mi nistere d  c o nc urre ntl y wit h  
c he m ot hera p y o n  C he m ot hera p y  D a y.  C he m ot hera p y  re gi me ns  re q uiri n g  d osi n g  b e y o n d  
C he m ot hera p y Da y wit hi n t he 2 1 -da y or 2 8 -da y c ycle (e g, g e mcita bi ne o n Da y 8) are all o we d.  
T hese mi d -c ycle c he m ot hera p y d oses, after I P treat me nt, will be part of t he assess me nt of t he 
c o m posite pri mar y e n d p oi nt f or d ose m o dificati o ns or dela ys. 
O bser v ati o n al Peri o d  
C ycle X + 2 will be a n O bser vati o nal Peri o d. T he O bser v ati o nal Peri o d is desi g n e d   t o e na bl e 
assess me nt of  w het her t he s u bject s meet t he c h e m ot hera p y d ose m o difi cati o ns or d ose  de la y 
c o m p o ne nts of t he co m p osite pri mar y e n d p oi nt  o n C he m ot hera p y Da y w hile  re d u ci n g decisi o n-
ma ki n g bias f or c he m ot h era p y d o se m o dificati o ns or dela ys. S u bjects i n t he O bser vati o nal Peri o d 
will n ot recei ve a n y I P pr e - or p ost-C he m ot hera p y Da y i n C ycl e X + 2. 
F or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E Peri o d, a F oll o w -U p Visit will occ ur pri or t o 
(wit hi n 3 da ys) C he m ot h er a p y Da y i n C ycle X + 3. F or t h ese s u bjects, t heir partici pati o n i n t he 
O bser vati o nal Peri o d  will c o ncl u de after t h e y c o m plete t he F o ll o w-U p Visit a n d at t hat p oi nt t he y 
will e nter t he L o n g - T er m F oll o w- U p Peri o d. 
If C ycle X + 2 is t he s u bject’s last c h e m ot hera p y c ycle, a F oll o w -U p Visit will occ ur at 3 0 d a ys 
(± 3 da ys) after C he m ot h era p y D a y i n C ycl e X + 2.  
O pti o n al O pe n - L a bel E xte nsi o n Peri o d  
S u bjects w h o c o m plete t he D o u ble -Bli n d Treat me nt Peri o d a n d t he O bser vati o nal Peri o d will be 
eli gi ble t o e nter a n o pti o n al O L E  Peri o d at 5 da ys pri or t o C ycle X + 3 , if t he y f ulfill t he i ncl usi o n 
criteria a n d e x cl usi o n crit eria f or t he o pti o nal O L E Peri o d  a n d re mai n o n t h e sa me c he m ot hera p y 
a ge nts as prescri be d i n C ycle X . S u bjects m ust c onti n ue t o f ulfill the i n cl usi o n a n d e x cl usi o n 
criteria pri or t o pre -c he m ot hera p y a v atr o m b o pa g treat me nt i n eac h e nr olle d o pe n -la b el c ycle t o 
c o nti n ue i n t he O L E Per i o d. 
All s u bjects will recei ve a vatr o m b o pa g o nce dail y f or 5 d a ys pri or t o C he m ot hera p y D a y i n 
C ycle  X + 3 . S u bjects will als o recei ve a vatr o m b o p a g o nce dail y f or 5 da ys i m me diatel y f oll o wi n g 
C he m ot hera p y Da y. A vatr o m b o pa g will n ot be a d mi nistere d c o nc urre ntl y wit h c he m ot hera p y o n 
C he m ot hera p y Da y.  
S u bjects ma y re p eat t his treat me nt se q u e nce a n d c o nti n ue i n t he o pti o nal O L E Peri o d u ntil t he e n d 
of t heir c urre nt c h e m ot hera p y re gi me n.  
S u bjects will ha ve a F oll o w -U p Visit at 3 0 da ys ( ± 3 da ys) after t h e last d ose of a v atr o m b o pa g  
treat me nt of t he s u bject’s last c he m ot hera p y c ycle. 
L o n g -Ter m F oll o w -U p  Peri o d  
After t he F oll o w- U p Visit , all s u bjects will be c o ntacte d a p pr o xi matel y e ver y 6 m o nt hs f or u p t o 
5 years b y tele p h o ne d uri n g t he L o n g -Ter m F oll o w -U p Peri o d f or d oc u me ntati o n of vital stat us 
(if deat h occ urr e d, rec or d of date of d eat h) a n d o cc urre nce of sec o n dar y m ali g na n cies.  


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E n d of St u d y  
T he  e n d  of  st u d y ( “st u d y c o m pleti o n”)  is  defi ne d  as  t he  date  of  t he  last  pr ot oc ol-s pecifie d 
visit/assess me nt (i ncl u di n g t e le p h o ne c o ntact) f or t he l ast s u bject i n t he L o n g-T er m F oll o w -U p 
Peri o d . 
D O S A G E F O R M S A N D R O U T E O F A D MI NI S T R A TI O N:  
S u bjects  ra n d o mize d  t o  t he  i n vesti gati o nal  ar m  will  recei ve  6 0  m g  a vatr o m b o pa g  
( 3 ×  2 0 m g  ta blets) f or or al a d mi nistrati o n o nce dail y f or 5 da ys pri o r t o C he m ot hera p y D a y a n d 
f or 5 da ys i m me diatel y f oll o wi n g C he m ot hera p y Da y  d uri n g t he D o u ble -Bli n d Treat me nt Peri o d . 
S u bjects ra n d o mize d t o t he c o ntr ol ar m will recei ve matc hi n g place b o ta blets.  
S u bjects i n t he o pti o nal O L E  Peri o d will recei ve 6 0 m g a vatr o m b o pa g  ( 3 ×  2 0 m g  ta blets) f or oral 
a d mi nistrati o n o nce  dail y  f or  5  da ys  pri or  t o  C he m ot hera p y  D a y  a n d  f or  5  da ys  after  
C he m ot hera p y Da y.  
E F FI C A C Y V A RI A B L E S:  
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all  of t h e f ol l o wi n g 
criteria d uri n g  t he  p eri o d after  p ost -c he m ot h era p y I P  treat me nt  i n  C ycle  X + 1  thr o u g h  
C he m ot hera p y Da y  of C ycl e X + 2 : 
•  N ot r e q uiri n g a platel et tra nsf usi o n ; 
•  N ot r e q uiri n g a c h e m ot hera p y d ose re d ucti o n b y ≥1 5 % d ue t o t hr o m b oc yt o pe nia; a n d  
•  N ot r e q uiri n g a c h e m ot hera p y del a y b y ≥4 da ys d ue t o t hr o m b oc yt o p e nia. 
T he ke y sec o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  D urati o n of se v er e t hr o m b oc yt o p e nia  defi ne d as a platelet c o u nt < 5 0 ×  1 09/ L d uri n g t he peri o d 
after p ost -c he m ot her a p y I P treat me nt i n C ycle X + 1 t hr o u g h C he m ot hera p y D a y  of C ycl e X + 2 ; 
•  C ha n ge i n plat elet c o u nt fr o m baseli ne ( q u alif yi n g c he m ot hera p y c ycle [ C ycle X]) ( na dir) t o 
C ycle X + 1 ( n a dir);  
•  Pr o p orti o n of s u bjects  w h o d o n ot ha ve  maj or or n o n -maj or cli nicall y rel e va nt blee di n g  d uri n g 
t he peri o d after p ost -c he m ot hera p y I P treat me nt i n C ycle X + 1 thr o u g h C h e m ot hera p y D a y  of 
C ycle X + 2 ; a n d  
•  Pr o p orti o n of s u bjects w h o d o n ot recei ve platelet tra nsf usi o n  d uri n g t he peri o d after p ost -
c he m ot hera p y I P tr eat me nt i n C ycle X + 1 thr o u g h  C he m ot hera p y Da y  of C ycl e X + 2. 
T he ot her efficac y e n d p oi nts i ncl u de t he f oll o wi n g  d uri n g t he peri o d aft er p ost -c he m ot hera p y I P 
treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y D a y of C ycle X + 2 : 
•  Pr o p orti o n of s u bjects w h o d o n ot  ha ve a c he m ot hera p y d ose re d ucti o n t h at is ≥1 5 % d ue  t o 
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n  of  s u bjects  w h o  d o  n ot  ha ve  a  c he m ot hera p y  dela y  t hat  is  ≥4  da ys  d ue  t o  
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n of s u bjects wit h a pre -d efi ne d p ost- bas eli ne na dir platelet c o u nt;  a n d 


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•  Pr o p orti o n of s u bjects ac hie vi n g a pre -d efi ne d p ost -baseli ne ma xi m u m platelet c o u nt . 
P H A R M A C O KI N E TI C A N D P H A R M A C O D Y N A MI C V A RI A B L E S:  
Bl o o d  sa m ples  f or  p h ar mac o ki netic  a n d  p har mac o d y na mics  a n al ysis  will  be  c ollecte d.  
P har mac o ki netic sa m pli n g will occ ur t wice d uri n g t he st u d y wit h 4 sa m ples c ollecte d o n ea c h da y. 
P har mac o d y na mic sa m pl es  (ie, platelet c o u nts) will be c ollecte d t hr o u g h o ut eac h c ycl e of t he 
st u d y i ncl u di n g C ycl e X + 1, C ycl e X + 2, a n d eac h e nr olle d o pe n-l a bel c ycle. 
S A F E T Y V A RI A B L E S:  
Safet y v aria bl es will i ncl u de a d vers e e ve nts, a d v erse e v e nts  of s peci al i nterest ( A E SI), cli nical 
la b orat or y para meters, p h ysical e x a mi nati o n fi n di n gs, a n d vital si g ns. 
S T A TI S TI C A L A N A L Y S E S:  
A n al ysis  of Effic ac y  
All pri mar y a n d sec o n d ar y efficac y e n d p oi nts  will be a nal yz e d usi n g t he F ull A nal ysis Set ( F A S) . 
T he pr i mar y efficac y a n al ysis will be re peat e d f or t he Per-Pr ot oc ol A n al ysis Set ( P P S) as t he 
s u p p orti ve a nal ysis. 
A n al ysis of t he P ri m a r y E ffic ac y E n d p oi nt   
T he t reat me nt effect o n t he pri mar y effi cac y e n d p oi nt will be teste d bet w ee n a vatr o m b o pa g a n d 
place b o us i n g t he C oc hr a n-Ma ntel -H ae nszel test, a dj usti n g f or n u m ber of c he m ot hera p y a ge nts 
(1, or ≥2  per missi ble  c he m ot hera p y  a ge nts  [ n ucle osi de  a n al o g,  i ncl u di n g  ge mcita bi ne  a n d  
fl u or o uracil;  car b o plati n  or  cis plati n;  a nt hrac ycli ne;  or  al k ylati n g  a ge nt]).  T he  n u m bers  a n d  
perce nt a ges of res p o n d ers i n eac h treat me nt gr o u p, t he ass ociate d 9 5 % c o nfi de nce i nter vals ( CI), 
a n d t he 9 5 % CI f or t he differe n ce bet we e n a v atr o m b o pa g a n d place b o will be calc ulat e d. T he 
pri mar y a n al ysis will be perf or me d bas e d o n t he F A S a n d re p e ate d o n t he P P S. Ot her se nsiti vit y 
a nal ys es of t he pri mar y efficac y e n d p oi nt ma y be perf or me d as a p pr o priate.  
A n al ysis of t he K e y Sec o n d ar y E ffic ac y E n d p oi nts  
If t he test of t he treat me nt effect o n t he pri mar y efficac y e n d p oi nt is statisticall y si g nifica nt, t he 
a nal ysis of t he ke y s ec o n dar y efficac y e n d p oi nts will pr ocee d usi n g ste p-d o w n cl ose d testi n g 
pr oce d ur e i n t he f oll o wi n g or der t o mai ntai n t he fa mil y-wise T y pe I err or rate at si g nifica nce le vel 
al p ha = 0. 0 5 ( 2 -si de d): 
Ste p  1:  Test  t he  treat me nt  eff ec t  at  a  si g nifica nt  le v el  of  0. 0 5  o n  d urati o n  of  se vere  
t hr o m b oc yt o pe ni a  defi ne d  as  a  platelet  c o u nt  < 5 0  ×   1 09/ L d uri n g  t he  peri o d  after  p ost -
c hem o t hera p y I P treat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y D a y  of C ycle X + 2 ; if s uccessf ul, 
pr ocee d t o Ste p 2; ot h er wise st o p at Ste p 1.  
Ste p 2: Test t he tr eat me nt effect at a si g nifica nt le vel of 0. 0 5 o n c h a n ge i n platelet c o u nt fr o m 
baseli ne ( q u alif yi n g c h e m ot hera p y c ycle [ C ycle X]) ( na dir) t o C ycle X + 1 ( na dir); if s u ccessf ul, 
pr ocee d t o Ste p 3; ot her wise st o p at  Ste p 2. 
Ste p 3: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n pr o p orti o n of s u bjects w h o d o n ot 
ha ve maj or or n o n -maj or cli nicall y r ele va nt blee di n g  d uri n g t he peri o d aft er p ost -c he m ot hera p y 


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C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
1 1  
I P treat me nt i n C ycle X + 1 thr o u g h  C h e m ot hera p y D a y  of C ycle X + 2 ; if s uccessf ul, pr o cee d t o 
Ste p 4; ot her wise st o p at Ste p 3.  
Ste p 4: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n p r o p orti o n of s u bjects w h o d o n ot 
recei v e platelet tr a nsf usi o n d uri n g t he p eri o d after p ost -c he m ot hera p y I P treatme nt i n C ycle X + 1 
thr o u g h C he m ot her a p y D a y  of C ycle X + 2 . 
A n al ysis of O t her E ffic ac y E n d p oi nts:  
T he cate g orical v aria bles (e g, pr o p orti o n) will be s u m marize d a n d a nal yz e d i n t he sa me ma n ner 
as t he pri mar y efficac y e n d p oi nt. T he c o nti n u o us varia bles (e g, c h a n ge fr o m baseli ne i n platelet 
c o u nt) will be a nal yze d usi n g a nal ysis of c o varia n ce m o dels wit h treat me nt a n d t he ra n d o mizati o n 
stratificati o n fact or as mai n effects a n d t he baseli ne meas ure me nt  as a c o variate, a n d Wilc o x o n 
Ra n k S u m tests if t he n or malit y ass u m pti o n is vi olate d. 
T he effi cac y v aria bles c ollecte d  d uri n g t he o pti o nal O L E  Peri o d will be s u m marize d descri pti vel y.  
A n al ysis  of S af et y  
Safet y a n d t olera bilit y will be ass esse d b y e x a mi ni n g t he i n ci de nce of a d verse e ve nts, A E SI , 
cli nical la b orat or y p a r a meters, p h ysical e x a mi nati o n fi n di n gs, a n d vital si g ns o ver ti me usi n g t h e 
Saf et y A nal ysis Set.  
S A M P L E SI Z E D E T E R MI N A TI O N:  
Ass u mi n g t here is a 4 0 % res p o nse rate i n t he acti ve gr o u p a n d 1 0 % i n t he place b o gr o u p, a n d 
usi n g a 2: 1 ra n d o mizati o n, a 1 0 % pre ma t ure ter mi nati o n rate, a n d 9 0 % p o wer wit h 2-si de d 
al p ha = 0. 0 5, t he sa m ple size is 1 2 0 s u bjects ( 8 0 acti ve s u bjects a n d 4 0 place b o s u bjects).  
SI T E S:   A p pr o xi matel y 7 5 sites gl o ball y  
S P O N S O R:  
D o va P har mace uticals  
2 4 0 Lei g h Far m R d, S uite 2 4 5  
D ur ha m, N C 2 7 7 0 7 
U nite d States  
Tele p h o ne: + 1 9 1 9- 7 4 8- 5 9 7 5 
Fa x: + 1 9 1 9 -7 4 8 -5 9 7 6  


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C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
1 2  
T A B L E O F C O N T E N T S  
Si g nat ure Pa ge ................................................................................................................................ 2 
I n v esti gat or A gr ee me nt ................................................................................................................... 3 
S y n o psis .......................................................................................................................................... 4 
Ta ble of C o nte nts .......................................................................................................................... 1 2 
List of  Ta bl es  ................................................................................................................................ 1 6 
List of Fi g ures  ............................................................................................................................... 1 6 
List of A b br e viati o ns a n d Defi niti o n of Ter ms ............................................................................. 1 7 
1  I ntr o d u cti o n a n d Bac k gr o u n d I nf or mati o n ............................................................................. 1 8 
1. 1  
T hr o m b oc yt o p e nia ........................................................................................................ 1 8 
1. 2  
C he m ot hera p y -I n d u ce d T hr o m b oc yt o p e nia .................................................................. 1 8 
1. 3  
A vatr o m b o pa g ............................................................................................................... 1 9 
1. 4  
N o ncli nical St u dies  ....................................................................................................... 1 9 
1. 5  
Cli nical St u dies  ............................................................................................................. 1 9 
1. 5. 1  P hase 1 St u dies .................................................................................................. 2 0 
1. 5. 2  P hase 2 St u dies .................................................................................................. 2 0 
1. 5. 3  P hase 3  St u dies .................................................................................................. 2 1 
1. 6  
Rati o nale  ........................................................................................................................ 2 3 
1. 7  
Ris k/ Be nefit  ................................................................................................................... 2 4 
2  St u d y O bjecti ves  ..................................................................................................................... 2 5 
2. 1  
Pri mar y O bj ecti ve  ......................................................................................................... 2 5 
2. 2  
Sec o n dar y O bj ecti ves  .................................................................................................... 2 5 
3  St u d y Descri pti o n .................................................................................................................... 2 6 
3. 1  
S u m mar y of St u d y Desi g n ............................................................................................ 2 6 
3. 1. 1  Scree ni n g/ Q ualif yi n g C h e m ot hera p y Re gi me n ( C ycl e X)  ................................ 2 6 
3. 1. 2  D o u ble- Bli n d Tr eat me nt Peri o d ........................................................................ 2 6 
3. 1. 3  O bser vati o nal Peri o d ......................................................................................... 2 7 
3. 1. 4  O pti o nal O pe n- La b el E xte nsi o n Peri o d  ............................................................ 2 7 
3. 1. 5  L o n g -T er m F ol l o w- U p P eri o d .......................................................................... 2 8 
3. 2  
St u d y D urati o n a n d E n d of St u d y ................................................................................. 2 8 
3. 3  
Data a n d Saf et y M o nit ori n g B oar d ............................................................................... 2 8 


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Cli nical St u d y Pr ot oc ol A V A -CI T -3 3 0  
C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
1 3  
3. 4  
St u d y I n dicati o n  ............................................................................................................ 2 8 
4  Selecti o n a n d Wit h dra wal of S u bjects .................................................................................... 2 9 
4. 1  
I n cl usi o n Criteria f or All S u bjects  ................................................................................ 2 9 
4. 2  
E x cl usi o n Criteria f or All S u bjects  ............................................................................... 3 0 
4. 3  
I n cl usi o n Criteria f or S u bjects t o C o nti n ue I nt o t h e O pti o nal O pe n-La bel  
E xte nsi o n Peri o d ........................................................................................................... 3 1 
4. 4  
E x cl usi o n Criteria f or S u bjects t o C o nti n ue I nt o t h e O pti o nal O pe n- La bel  
E xte nsi o n Peri o d ........................................................................................................... 3 1 
4. 5  
Wit h dra wal Criteria  ....................................................................................................... 3 2 
4. 5. 1  S u bjects wit h I n vesti gati o nal Pr o d uct I nterr u pti o n or Disc o nti n uati o n ............ 3 2  
5  St u d y Treat me nts  .................................................................................................................... 3 3 
5. 1  
Treat me nt Gr o u ps .......................................................................................................... 3 3 
5. 2  
Rati o nale f or D osi n g ..................................................................................................... 3 3 
5. 3  
Ra n d o mizati o n a n d Bli n di n g ......................................................................................... 3 3 
5. 4  
Brea ki n g t he Bli n d  ........................................................................................................ 3 4 
5. 5  
Dr u g S u p plies ................................................................................................................ 3 4 
5. 5. 1  F or m ulati o n a n d Pac k a gi n g ............................................................................... 3 4 
5. 5. 2  I n v esti gati o nal Pr o d uct Dis pe nsi n g ................................................................... 3 4 
5. 5. 3  I n v esti gati o nal Pr o d uct A d mi nistrati o n ............................................................ 3 4 
5. 5. 4  Treat me nt C o m plia nce  ...................................................................................... 3 5 
5. 5. 5  St ora ge a n d A cc o u nta bilit y ............................................................................... 3 5 
5. 6  
Pri or a n d C o nc o mita nt Me dicati o ns a n d/ or Pr oce d ures ................................................ 3 5 
5. 6. 1  E x cl u de d Me dicati o ns a n d/ or Pr oce d ures ......................................................... 3 5 
5. 6. 2  All o we d Me dicati o ns a n d/ or Pr oce d ures .......................................................... 3 5 
5. 6. 3  D oc u me ntati o n of Pri or a n d C o nc o mita nt Me dicati o n Use .............................. 3 6  
6  St u d y Pr o ce d ur es  .................................................................................................................... 3 7 
6. 1  
I nf or me d C o nse nt .......................................................................................................... 3 7 
6. 2  
C ycle X ( Q ualif yi n g C he m ot hera p y C ycle)  .................................................................. 3 7 
6. 2. 1  Scree ni n g ( Visit 1, Da y - 2 8 t o Da y - 1) ............................................................. 3 7 
6. 2. 2  Baseli ne Visit ( Visit 2, First Da y [ or - 1 Da y] of t he 5-da y I n v esti gati o nal 
Pr o d uct Treat me nt)  ............................................................................................ 3 8 
6. 2. 3  Pre -C he m ot hera p y I n vesti gati o nal Pr o d uct Treat me nt ( Visit 3, Last D a y  
of t he 5- da y I n vesti gati o nal Pr o d uct Treat me nt) ............................................... 3 8 


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Versi o n 2. 0, 0 4 A pril 2 0 1 9  
1 4  
6. 3  
D o u ble- Bli n d Tr eat me nt Peri o d ( C ycl e X + 1)  ............................................................. 3 9 
6. 3. 1  C he m ot hera p y Da y ( Visit 4, C ycle X + 1 Da y 1 t o 3)  ...................................... 3 9 
6. 3. 2  P ost- C he m ot hera p y I n vesti gati o nal Pr o d uct Treat me nt ( Visit 5)  ..................... 3 9 
6. 3. 3  C ycle X + 1 D a ys 1 1 ( ± 1 da y), 1 5 ( ± 1 da y), a n d 1 8 ( ± 1 da y)  
( Visits 6, 7, a n d 8) ............................................................................................. 4 0 
6. 4  
O bser vati o nal Peri o d ( C ycle X + 2)  .............................................................................. 4 0 
6. 4. 1  C he m ot hera p y Da y i n C ycl e X + 2 ( Vis it 9) ..................................................... 4 0 
6. 4. 2  C ycle X  + 2 D a ys 1 1 (± 1 da y), 1 5 ( ± 1 da y), a n d 1 8 ( ± 1 da y)  
( Visits 1 0, 1 1, a n d 1 2) ....................................................................................... 4 1 
6. 4. 3  F oll o w- U p Visit ( F or s u bject s n ot c o nti n ui n g i nt o t he o pti o nal  
O pe n - La b el E xte nsi o n Peri o d) .......................................................................... 4 1 
6. 4. 3. 1  Pri or t o C he m ot hera p y D a y i n C ycle X + 3 ( Visit 1 7) ....................... 4 1  
6. 5  
O p ti o nal O pe n- La b el E xte nsi o n Peri o d ( C ycl e X + 3 a n d O n) ..................................... 4 1 
6. 5. 1  Pre - C he m ot hera p y A vatr o m b o pa g Treat me nt ( Visit 1 3) .................................. 4 1 
6. 5. 2  C he m ot hera p y Da y ( Visit 1 4, C ycle  X + 3 Da y 1 t o 3) .................................... 4 2 
6. 5. 3  P ost- C he m ot hera p y A vatr o m b o pa g Treat me nt ( Visit 1 5) ................................ 4 3 
6. 5. 4  C ycle X + 3 D a y 1 5 ( ± 1 da y) ( Visit 1 6)  ............................................................ 4 3 
6. 5. 5  F oll o w- U p Visit  ................................................................................................. 4 3 
6. 5. 5. 1  T hirt y da ys after l ast a vatr o m b o pa g d ose ( Visit 1 7) i n t he O L E 
Peri o d  .................................................................................................. 4 3 
6. 6  
Earl y Ter mi nati o n Visit a n d Wit h dra wal Pr oce d ures  ................................................... 4 4 
6. 7  
L o n g -T er m F oll o w -U p  .................................................................................................. 4 5 
7  Eff icac y Assess me nts.............................................................................................................. 4 6 
8  P har mac o ki netic a n d P har mac o d y na mic Ass ess me nts  ........................................................... 4 7 
8. 1  
P har mac o ki netic Assess me nts  ....................................................................................... 4 7 
8. 2  
P har mac o d y na mic Ass ess me nts  .................................................................................... 4 7 
9  Safet y Assess me nts  ................................................................................................................. 4 8 
9. 1  
A d verse E v e nts  .............................................................................................................. 4 8 
9. 1. 1  Assess me nt of A d vers e E ve nts b y t he I n vesti gat or .......................................... 4 9 
9. 1. 2  A d verse E v e nts of S peci al I nt erest  .................................................................... 5 0 
9. 1. 3  Efficac y E n d p oi nts ............................................................................................ 5 0 
9. 2  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E v e nts ............................. 5 0  
9. 3  
Seri o us A d verse E v e nts  ................................................................................................. 5 1 


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Cli nical St u d y Pr ot oc ol A V A -CI T -3 3 0  
C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
1 5  
9. 4  
Seri o us A d verse E v e nt Re p orti n g − Pr oce d ures f or I n vesti gat ors ................................ 5 1 
9. 5  
Pre g n a nc y Re p orti n g  ..................................................................................................... 5 2 
9. 6  
Re g ula t or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ................................ 5 2 
9. 7  
Cli nical La b or at or y E val uati o ns .................................................................................... 5 3 
9. 8  
Vital Si g ns ..................................................................................................................... 5 3 
9. 9  
P h ysical E x a mi nati o ns  .................................................................................................. 5 3 
1 0  Statistics  .................................................................................................................................. 5 4 
1 0. 1  A nal ysis P o p ulati o ns ..................................................................................................... 5 4 
1 0. 2  Statistical Met h o ds  ........................................................................................................ 5 4 
1 0. 2. 1  A nal ysis of Efficac y  .......................................................................................... 5 4 
1 0. 2. 1. 1  Pri mar y efficac y a nal ysi s .................................................................... 5 4 
1 0. 2. 1. 2  Ke y sec o n d ar y efficac y a nal ysis  ......................................................... 5 5 
1 0. 2. 1. 3  Ot her efficac y a nal ysis  ........................................................................ 5 5 
1 0. 2. 2  A nal ysis of Safet y  ............................................................................................. 5 6 
1 0. 2. 3  I nteri m A nal ysis ................................................................................................ 5 6 
1 0. 2. 4  Sa m p le Size Deter mi nati o n ............................................................................... 5 6 
1 1  Data Ma na ge me nt a n d R ec or d K ee pi n g  ................................................................................. 5 7 
1 1. 1  Data Ma na ge me nt  ......................................................................................................... 5 7 
1 1. 1. 1  Data Ha n dli n g  ................................................................................................... 5 7 
1 1. 1. 2  C o m p uter S yste ms  ............................................................................................. 5 7 
1 1. 1. 3  Data E ntr y  ......................................................................................................... 5 7 
1 1. 1. 4  Me dical I nf or mati o n C o di n g ............................................................................. 5 7 
1 1. 1. 5  Data Vali dati o n  ................................................................................................. 5 7 
1 1. 2  Rec or d Kee pi n g  ............................................................................................................. 5 8 
1 2  I n v esti gat or Re quire me nts a n d Q ualit y C o ntr ol ..................................................................... 5 9 
1 2. 1  Et hical C o n d uct of t he St u d y ........................................................................................ 5 9 
1 2. 2  I nstit uti o nal Re vie w B oar d/I n d e pe n d e nt Et hics C o m mittee ......................................... 5 9 
1 2. 3  Pr ot oc ol A me n d me nts ................................................................................................... 5 9 
1 2. 4  I nf or me d C o nse nt .......................................................................................................... 5 9 
1 2. 5  St u d y M o nit ori n g Re q uir e me nts  ................................................................................... 6 0 
1 2. 6  Discl os ure of D ata  ......................................................................................................... 6 0 
1 2. 7  Rete nti o n of Rec or ds ..................................................................................................... 6 0 


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Cli nical St u d y Pr ot oc ol A V A -CI T -3 3 0  
C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
1 6  
1 2. 8  P u blicati o n P olic y  ......................................................................................................... 6 1 
1 2. 9  Fi na ncial Discl os ur e  ...................................................................................................... 6 1 
1 2. 1 0  I ns ura nce a n d I n d e m nit y ............................................................................................... 6 1 
1 3  Refere n ces  ............................................................................................................................... 6 2 
A p pe n di x A:  Sc he d ule of Pr oce d ur es .......................................................................................... 6 4 
A p pe n di x B:  Cli nical La b orat or y A nal ytes ................................................................................. 6 9 
A p pe n di x C:  C yt oc hr o m e P 4 5 0 I n d u cers .................................................................................... 7 0 
A p pe n di x D:  I nter n ati o nal S ociet y o n T hr o m b osis a n d Hae m ostasis Blee di n g Defi niti o ns ....... 7 1  
A p pe n di x E:  Pr ot oc ol A me n d me nts ............................................................................................ 7 2 
 
 
LI S T O F T A B L E S  
Ta ble 1.  
Sc he d ule of Pr oce d ures ( D o u ble- Bli n d Treat me nt Peri o d)  ........................................ 6 4 
Ta ble 2.  
Sc he d ule of Pr oce d ures ( O bser vati o nal Peri o d) ......................................................... 6 6 
Ta ble 3.  
Sc he d ule of Pr oce d ures ( O pti o nal O pe n- La b el E xte nsi o n Peri o d)............................. 6 7  
Ta ble 4  
C yt o c hr o me P 4 5 0 I n d u cers ......................................................................................... 7 0 
Ta ble 5.  
I nter nati o nal S ociet y o n T hr o m b osis a n d Hae m ostasis Blee di n g Defi niti o ns............ 7 1 
 
 
LI S T O F FI G U R E S  
Fi g ure 1.  St u d y Desi g n  ............................................................................................................... 2 6 
Fi g ure 2.  Treat me nt Sc he d ul e f or D o u ble- Bli n d Treat me nt Peri o d  ........................................... 2 7 
Fi g ure 3.  Treat me nt Sc he d ul e f or O pti o nal O pe n- La b el E xte nsi o n Peri o d  ............................... 2 8 
 


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C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
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L I S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
A b bre viati o n  
Defi n iti o n 
2 1 C F R  
Title 2 1 of t he C o de of Fe deral Re g ul ati o ns  
A E SI  
A d verse e ve nts o f s pecial i nterest 
A L T  
Ala ni ne a mi n otra nsferas e  
A S T  
As partate a mi n otra nsferase  
β -h C G  
Beta -h u ma n c h ori o nic g o na d otr o pi n  
CI  
C o nfi de nce i nter v al  
CI T  
C he m ot hera p y -i n d uce d t hr o m b oc yt o p e nia 
C L D  
C hr o nic li ver disease  
C R A  
Cli nical researc h ass oci ate 
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
C Y P  
C yt o c hr o me P 4 5 0  
D S M B  
Data a n d Safet y M o nit ori n g B oar d  
e C R F 
Electr o nic case re p ort f or m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
E D C  
Electr o nic data ca pt ure  
F A S  
F ull A nal ysis Set  
G C P  
G o o d Cli nical Pra ctice  
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n  
I E C 
I n d e pe n de nt Et hics C o m mittee 
I P 
I n v esti gati o nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
I nteracti ve res p o nse t ec h n ol o g y 
I S T H 
I nter nati o nal S ociet y o n T hr o m b osis a n d Hae m ostasis  
I T P 
I di o pat hic/i m m u ne t hr o m b oc yt o pe ni c p ur p ura 
O L E  
O pe n -la bel e xte nsi o n 
P D  
P har mac o d y na mic  
P K  
P har mac o ki netic (s) 
P P S  
Per -Pr ot oc ol A nal ysis Set  
R DI  
Relati ve d ose i nte nsit y  
S A E  
Seri o us a d verse e ve nt  
S U S A R  
S us pecte d u ne x pecte d seri o us a d ver se reacti o n 
T P O  
T hr o m b o p oieti n  


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Cli nical St u d y Pr ot oc ol A V A -CI T -3 3 0  
C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
1 8  
1  
IN T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N  
1. 1  
T hr o m b oc yt o pe ni a 
T hr o m b oc yt es or p latel ets are a n i m p orta nt c o m p o ne nt of bl o o d t hat f u ncti o n t o mai ntai n n or mal 
he m ostasis. I n t he cas e of vessel i nj uries, platelets i m me diatel y c o nt r ol blee di n g b y a d h esi o n, 
acti vati o n, a n d a g gre gati o n, t here b y f or mi n g a st a ble cl ot i n c o nj u ncti o n wit h bl o o d c oa g ulati o n 
fact ors.  T hr o m b o p oieti n  ( T P O),  t he  pri n ci pal  p h ysi ol o gic  re g ulat or  of  platelet  pr o d u cti o n,  is  
pr o d uce d c o nstit uti vel y i n t he li ver, circ ulates i n t he bl o o dstrea m, a n d is deli vere d t o t he b o n e 
marr o w,  w her e  it  sti m ulates  t he  earl y  d e vel o p me nt  of  m ulti ple  he mat o p oietic  li nea ges  a n d  
me ga kar y o c yt o p oi esis. B o ne marr o w pr o d ucti o n of platelets is directl y affecte d b y T P O le vels.  
T he cir c ulati n g platelet c o u nt i n bl o o d is deter mi ne d b y t he rates of platelet pr o d ucti o n a n d platel et 
destr ucti o n. I n healt h y i n di vi d uals, t he a v era ge lifes pa n of platel ets is 7 t o 1 0 da ys, aft er w hic h 
t he y are d estr o ye d a n d r e place d wit h ne wl y-ge n erate d platelets. A n or mal bl o o d platelet c o u nt 
ra n ges fr o m 1 5 0 × 1 09/ L t o 4 5 0 × 1 09/ L, a n d p atie nts w h o ha ve less t ha n 1 5 0 × 1 09/ L h a ve t he 
c o n diti o n k n o w n as t hr o m b oc yt o pe ni a. T hr o m b o c yt o p e nia is a p ote ntiall y seri o us c o n diti o n t hat 
is c haracterize d b y a deficie nc y of pl atelets i n t h e circ ul at or y s yste m t hat is ass ociate d wit h a n 
i ncreas e d ris k of bl ee di n g. T hr o m b oc yt o pe nia ca n res ult fr o m decrease d pl atelet pr o d u cti o n i n t he 
b o ne  marr o w,  i ncr eas e d  platelet  destr ucti o n  i n  t he  bl o o d  (s uc h  as  fr o m  a ut o -a nti b o dies), or 
se q uestrati o n of platel ets i n t he s plee n.  
1. 2  
C he m ot her a p y -I n d uce d T hr o m b oc yt o pe ni a 
C he m ot hera p y -i n d uce d  t hr o m b oc yt o p e nia  ( CI T)  is  a  c o m m o n  t o xicit y  of  m yel os u p pressi ve  
c he m ot hera p y.  Occ urre nce  of  t hr o m b oc yt o p e nia  has  t he  p ote ntial  t o  create  si g nifica nt  
c o m plicati o ns . At platelet c o u nts < 1 0, 0 0 0/ µ L, s p o nta ne o us blee di n g ris k is i ncrease d. At platelet 
c o u nts  < 5 0, 0 0 0/ µ L,  pr oc e d ures  are  ofte n  c o m plicate d  b y  blee di n g.  At  platelet  c o u nts  
< 1 0 0, 0 0 0/ µ L,  c h e m ot hera p y  is  a d mi nistere d  wit h  ca uti o n  f or  fear  of  w orse ni n g  t he  
t hr o m b oc yt o pe ni a a n d i n creasi n g t he ris k of blee di n g.1 
Cli nicia ns’ res p o nses t o t hr o m b oc yt o p e nia i n a ca ncer p atie nt var y:  re d ucti o n of t he d ose i nte nsit y 
of c he m ot hera p y is c o m m o n, m ore effecti ve re gi me ns wit h t hr o m b oc yt o pe nic t o xicit y ma y b e 
a v oi de d, a n d tr eat me nt m a y e ve n be pr ecl u de d. Platelet tra nsf usi o ns are oft e n t he o nl y treat m e nt;1 ,2  
h o we ver, platelet tra nsf usi o ns create  t he a d diti o nal ris k of tra nsf usi o n reacti o ns or i nfecti o ns, a n d 
ma y l ea d t o t he d e vel o p me nt of platel et refract ori ness wit h re peat e d plat elet tra nsf usi o ns. T he 
latter i m p orta ntl y eli mi nates platelets as a n o pti o n f or f ut ure e mer ge nt nee ds i n t hese patie nts 
d uri n g t heir c he m ot her a p y r e gi me n or f or ot her e mer ge nt c o n diti o ns t hat ma y d e vel o p. 
T he i nci de nce, se v erit y, a n d d urati o n of t hr o m b oc yt o p e nia var y wit h t he c he m ot hera p y re gi me n. 
K uter,  2 0 1 5  pr o vi des  a n  o ver vie w  of  t he  re p orte d  fre q u e ncies  of  s e v ere  t hr om b oc yt o pe ni a 
( Gra d e 3 = 2 5, 0 0 0 t o < 5 0, 0 0 0/ µ L, Gra d e 4 ≤2 5, 0 0 0/ µ L) ass ociate d wit h vari o us c he m ot hera p y 
re gi me ns.1 


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T he reas o ns t hat s o me patie nts e x perie nce m ore se vere or pr ol o n ge d t hr o m b oc yt o p e nia after 
c he m ot hera p y ar e n ot well u n derst o o d a n d ca n b e diffic ult t o pre dict. T he mec ha nis ms b y w hic h 
c he m ot hera p y re gi me ns r es ult i n t hr o m b oc yt o pe ni a als o differ a n d i ncl u de t he f oll o wi n g: 
•  Al k ylati n g a ge nts s uc h as b us ulfa n affect pl uri p ot e nt ste m cells ; 
•  C ycl o p h os p ha mi d e  s par es  he mat o p oietic  ste m  cells,  b ut  affects  later  me ga kar y oc yte  
pr o ge nit ors; 
•  B ortez o mi b has n o effect o n ste m cells or me ga k ar y o c yt e mat urati o n b ut d oes i n hi bit n uclear 
fact or k a p pa B, a critical re g ulat or of plat elet s he d di n g; a n d 
•  C he m ot hera p y  ma y  e n h a nce  plat elet  cleara n ce  b y  i m m u ne  mec h a nis ms,  as  occ urs  wit h  
fl u dara bi ne. 
T here h as bee n  o ne a p pr o ve d pr o d uct f or t he treat me nt of CI T, o prel ve ki n ( Ne u me ga , Pfizer); 
h o we ver, d ue t o t h e t o xicit y pr ofile ass o ciate d wit h t his pr o d uct (a n a p h yla xis, fl ui d rete nti o n 
i ncl u di n g p ul m o nar y e d e ma, arr h yt h mias), p h ysicia ns c o nti n ue t o rel y o n platelet tra nsf usio ns i n 
t his patie nt p o p ulati o n. As a res ult, CI T re mai ns a c o n diti o n t hat is n ot a de q uatel y treate d wit h 
e xisti n g p har mac ol o gical a ge nts.  
1. 3  
A v atr o m b o p a g 
A vatr o m b o pa g maleate is a n orall y a d mi nistere d T P O rece pt or a g o nist t hat mi mics t he bi ol o gic 
effects of T P O i n vitr o a n d i n vi v o. T hr o m b o p oieti n e x erts its effect o n me ga kar y oc yt o p oie sis a n d 
t hr o m b oc yt o p oiesis t hr o u g h bi n di n g a n d acti vati o n of t he T P O rece pt or, w hic h is e x presse d o n 
he mat o p oietic  ste m  cells,  cells  of  t h e  me ga k ar y o c ytic  li nea ge,  a n d  pl atelets.  A vatr o m b o pa g  
acti vates t he h u ma n T P O rece pt or b y bi n di n g t o a differe nt site o n t he T P O rece pt or, b ut it is still 
ca pa ble of sti m ulati n g si g nal tra ns d u cti o n a n d mi mic ki n g t he bi ol o gic effects of T P O, res ulti n g i n 
a meas ur e d i ncrease i n pl atelet c o u nts.  
1. 4  
N o ncli nic al St u dies  
T he t o xicit y of a v atr o m b o pa g h as bee n e xte nsi vel y e v al uate d i n si n gl e- a n d re peate d -d os e oral 
t o xicit y st u dies i n mice, rats, d o gs, a n d c y n o m ol g us m o n ke ys (f or u p t o 1 3 wee ks i n mice, 
2 6 wee ks i n r ats, 4 wee ks i n d o gs, a n d 5 2 wee ks i n c y n o m ol g us m o n ke ys). T he ge n ot o xicit y of 
a vatr o m b o pa g was e val u ate d i n vitr o a n d i n vi v o. T w o -year carci n o ge nicit y st u dies h a ve bee n 
c o n d ucte d i n mice a n d rats. Re pr o d ucti ve a n d de v el o p me ntal t o xicit y w as e v al uate d b y c o n d ucti n g 
male a n d f e male f ertilit y st u dies i n rats, e m br y o -fetal de vel o p me nt t o xicit y st u dies i n rats a n d 
ra b bits, pre- a n d p ost -nat al de vel o p me nt st u dies i n rats, a n d a j u ve nile d ose ra n ge -fi n di n g st u d y i n 
rats. T he p ote ntial f or der mal a n d e ye irritati o n i n ra b bits, der mal s e nsitizati o n i n g ui n ea pi gs, a n d 
p h ot ot o xicit y  i n  pi g me nte d  rats  was  als o  e val u ate d.  N o ncli nical  st u dies  ha ve  i n dicate d  t hat  
a vatr o m b o pa g w as w ell t olerate d a n d data s u g gest t hat  a vatr o m b o pa g is a pr o misi n g ca n di date f or 
use i n t he treat me nt of t hr o m b oc yt o p e nia of di verse eti ol o gies, i ncl u di n g t he treat me nt of CI T . 
1. 5  
Cli nic al St u dies  
A vatr o m b o pa g has b ee n st u die d i n h u ma ns i n b ot h si n gle - a n d m ulti ple-d ose P hase 1, d ose -risi n g, 
safet y a n d t oler a bilit y st u dies a n d i n P hase 2 a n d P hase 3 efficac y a n d s afet y st u dies. A t otal of 
1 3 6 5 s u bjects ha ve bee n ra n d o mize d acr oss t he 2 4 c o m plete d st u dies i n t he a vatr o m b o pa g cli nical 
de vel o p me nt  pla n.  T he  t otal  safet y  d ata bas e  f or  a vatr o m b o p a g -treate d  s u bjects  i ncl u des 


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1 1 0 7 s u bjects i n t he c o m plete d cli nical st u dies. T his i ncl u des 52 0 healt h y v ol u nteers, 3 9 5  s u bjects 
wit h t hr o m b oc yt o pe nia ass ociate d wit h c hr o nic li ver disease ( C L D) pri or t o sc he d ule d s ur gi cal or 
dia g n ostic pr o ce d ur es, 6 4 s u bjects wi t h c hr o nic he patitis C vir us-relate d t hr o m b oc yt o pe ni a t o 
e na ble i nitiati o n a n d mai nte na nce of a nti viral treat me nt, a n d 1 2 8 s u bjects wit h c hr o nic i m m u ne 
t hr o m b oc yt o pe ni c p ur p ur a (I T P). 
1. 5. 1  
P h ase 1 St u dies  
T he cli nical p h ar mac ol o g y pr o gra m was d esi g n e d t o esta bl is h t he p h ar mac o ki netic ( P K) pr ofile of 
a vatr o m b o pa g,  t he  d eter mi nati o n  of  t he  eli mi nati o n  pat h wa ys,  t he  i n v esti gati o n  of  p ote ntial  
cli nicall y i m p orta nt dr u g -dr u g i nteracti o n s, t he effects of b ot h i ntri nsic a n d e xtri nsic fact ors o n 
P K,  a n d  t he  relati o ns hi p  bet wee n  P K  a n d  p har mac o d y na mic  ( P D)  effects  relate d  t o  cli nical  
efficac y.  I n  1 5  c o m plete d  P hase  1  st u dies  i n v ol vi n g  5 2 0 healt h y  v ol u nteers  e x p ose d  t o  
a vatr o m b o pa g, t he m ost c o m m o n a d verse e ve nt o cc urri n g i n 5 % or m ore of s u bjects treate d wit h 
a vatr o m b o pa g w as hea d ac he.  
A d diti o nal details are a v aila ble i n t he a vatr o m b o p a g I n vesti gat or’s Br o c h ure .3 
1. 5. 2  
P h ase 2 S t u dies 
In 6 4 I T P patie nts w h o were ra n d o mize d i n a d o u ble -bli n d, place b o -c o ntr olle d, P hase 2 efficac y 
a n d saf et y st u d y (St u d y C L -0 0 3), a vatr o m b o p a g de m o nstrate d s u peri or efficac y c o m pare d wit h 
place b o  as  meas ure d  b y  pl atelet  res p o nse  o n  Da y  2 8.  T his  res p o nse  was  d ose -relate d. 
A vatr o m b o pa g c o nti n ue d t o be effecti ve after a n a d diti o nal 6 m o nt hs of treat me nt as meas ure d b y 
d ura ble a n d o ver all platelet res p o nse rates i n 5 3 s u bjects w h o c o nti n ue d i nt o a 6 -m o nt h r oll o ver 
st u dy ( St u d y C L - 0 0 4). D ura ble pl atelet res p o nse was defi ne d as s u bjects w h o ha d at least 7 5 % of 
t heir meas ure d plat elet c o u nt val ues at res p o nse l e vel d uri n g t he last 1 4 wee ks of t he 2 4-wee k 
treat me nt peri o d a n d di d n ot recei ve res c ue t hera p y d uri n g t he st u d y. All s u bjects nee de d t o ha ve 
at least 3 platelet c o u nt assess me nts i n t he last 1 4 wee ks of St u d y C L -0 0 4. O verall res p o nse rate 
was defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve d eit her a d ura ble res p o nse or a tra nsie nt 
res p o nse (tra nsie nt r es p o nse was defi ne d as s u bjects w h ose platelet c o u nts were at a res p o nse le v el 
at 2 or m ore c o nsec uti ve a nal ysis wi n d o ws d uri n g t he 2 4 -wee k treat me nt peri o d o f St u d y C L - 0 0 4, 
wit h o ut ha vi n g ac hie ve d a d ura ble res p o nse). 
I n t he c o m bi ne d C L-0 0 3 a n d C L -0 0 4 st u dies, t he m o st c o m m o n treat me nt-e mer ge nt a d verse 
e ve nts  ( T E A Es),  occ urri n g  i n  5 %  or  m ore  of  s u bjects  treate d  wit h  a vatr o m b o pa g  w ere  ( b y  
decreasi n g  or der  of  fr e q ue nc y)  fati g u e,  hea dac he,  e pista xis,  c o nt usi o n,  art hral gia,  di arr h ea,  
t hr o m b oc yt o pe ni a,  gi n gi val  blee di n g,  bac k  pai n,  e de ma  peri p heral,  pet ec hiae,  platelet  c o u nt  
i ncreas e d,  v o miti n g,  d ys p nea,  n a usea,  u p per  res pirat or y  tract  i nfecti o n,  pai n  i n  e xtre mit y,  
ecc h y m osis,
 c o u g h,
 i ns o m nia,
 dizzi ness,
 p har y n g ol ar y n geal
 pai n,
 h y perli pi de mia,
 
nas o p har y n gitis, a n d platelet c o u nt decrease d. M ost T E A Es were Gra de 1 or Gra de 2, tra nsie nt, 
a n d c o m pletel y res ol v e d.  
A t otal of 1 3 0 s u bjects wit h t hr o m b oc yt o pe nia ass ociate d wit h C L D  w h o were sc h e d ule d t o 
u n der g o  electi ve  s ur gical  or  dia g n ostic  pr oce d ures  were  e nr olle d  i n  a  P hase  2,  ra n d o mize d,  
place b o -c o ntr olle d, d o u ble -bli n d, parallel -gr o u p st u d y ( St u d y 2 0 2). T he s u bjects were s plit i nt o 2 
c o h orts a n d recei ve d eit her a vatr o m b o pa g ( C o h ort A: first ge nerati o n f or m ulati o n; C o h ort B: 
sec o n d ge nerati o n f or m ulati o n) or place b o. T h e pri mar y a nal ysis of t he res p o n der rate i n t he 
o verall c o m bi ne d a vatr o m b o pa g gr o u p w as statisticall y si g nifi ca nt c o m p are d wit h t he o verall 
c o m bi ne d place b o gr o u p . A si milar statistical si g nifica nce was a gai n n ote d w he n t he d ata w ere 


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a dj uste d f or t h e eti ol o g y of li ver disease b y a C oc hra n -Ma ntel -Hae nszel test. Wit hi n C o h ort B, t he 
res p o nse rate i n platelet c o u nts b y D a y 8 i ncreas e d si g nifica ntl y i n s u bjects recei vin g treat me nt 
wit h a vatr o m b o pa g c o m pare d wit h place b o. I n a d diti o n, a statisticall y si g nifica nt re d ucti o n w as 
ac hie ve d  i n  t he  pr o p orti o n  of  s u bjects  recei vi n g  platelet  tra nsf usi o n  bef ore  electi ve  i n vasi ve  
pr oce d ur es i n C o h ort B c o m pare d wit h place b o. T he m ost c o m m o nl y re p orte d T E A Es, occ urri n g 
i n 5 % or m ore of s u bjects treate d wit h a vatr o m b o pa g were ( b y decreasi n g or d er of fre q u e nc y) 
na usea, fati g ue, h ea dac h e, p ortal h y p erte nsi ve gastr o pat h y, di arr h ea, dizzi ness, m uscle s pas ms, 
pr oce d ur al pai n, vari c es es o p h a geal, v o miti n g, a b d o mi nal pai n u p per, a n d e de ma peri p heral. 
St u d y 2 0 3 w as a P hase 2 m ultice nter, m ulti nati o nal, ra n d o mize d, place b o -c o ntr olle d, d o u ble-
bli n d, parallel -gr o u p st u d y t o d e m o nstrate t h e efficac y of  o n ce d ail y d osi n g wit h a vatr o m b o pa g 
c o m pare d t o place b o i n s u bjects  wit h c hr o nic he patitis C vir us -relate d t hr o m b oc yt o p e nia w h o were  
p ote ntial ca n di dates f or a nti viral treat me nt. Pri or t o t he i nitiati o n of a nti viral t hera p y, t h e m ost 
c o m m o nl y re p orte d T E A Es ( ≥5 % of s u bjects) i n t he c o m bi ne d a vatr o m b o p a g gr o u p were na usea 
a n d fati g ue. T he m ost c o m m o nl y re p orte d T E A Es ( ≥5 % of s u bjects) d uri n g t he C ore St u d y a n d 
E xte nsi o n  P hase  i ncl u de d  a ne mia,  ne utr o p e nia,  na usea,  fati g ue,  pr urit us,  le u k o pe nia,  c hills,  
i ns o m nia, hea dac he, r as h, diarr hea, i nfl ue n za-li ke ill ness, c o u g h, p yre xia, ast he nia, v o miti n g, 
irrita bilit y,  a b d o mi nal  pai n,  ascites,  i njecti o n  site  er yt h e ma,  e de ma  peri p heral,  e pista xis,  
a b d o mi nal pai n u p per, de pressi o n, l y m p h o pe ni a, d ys pe psia, he m orr h oi ds, n as o p har y n gitis, u p per 
res pirat or y  tract  i nfecti o n,  h y per urice mia,  dizzi ness,  d ys p nea,  a n d  d ys p nea  e x erti o nal.  T he  
maj orit y of t hese c o m m o nl y re p orte d T E A Es occ urre d after t he i nitiati o n of a nti viral treat me nt, 
a n d are c o nsiste nt wit h w hat is e x pecte d i n p atie nts  recei vi n g a nti viral t hera p y with i nterfer o n, 
ri ba viri n, a n d/ or tela pre vir. 
I n St u d y 2 0 4, a P hase 2, ra n d o mize d, place b o-c o ntr olle d, d o u ble-bli n d, parallel -gr o u p st u d y, a 
t otal of 3 9 J a pa n ese s u bjects wit h t hr o m b oc yt o pe ni a ass oci ate d wit h C L D  w ere ra n d o ml y  assi g n e d 
t o a st u d y gr o u p a n d recei ve d place b o or a vatr o m b o pa g. T h e pri mar y a n al ysis of t he res p o n d er 
rate (res p o n d ers wer e defi ne d as s u bjects wit h a platelet c o u nt ≥5 0 × 1 0 9/ L a n d w h o s h o we d at 
least 2 0 × 1 09/ L i n crease fr o m bas eli ne at Visit 4 [ Da ys 1 0  t o 1 3]) i n t he a v atr o m b o pa g 4 0 m g a n d 
6 0 m g gr o u ps w as statisticall y si g nifica nt c o m pare d wit h t he place b o gr o u p. T he m ost c o m m o nl y 
re p orte d T E A Es (≥5 % of s u bjects) i n t he a vatr o m b o pa g gr o u p were, b y decreasi n g or der o f 
fre q ue n c y, p ost-pr oce d ur al c o m plicati o n, p ost -e m b olisati o n s y n dr o me, diarr hea, bl o o d gl uc ose 
i ncreas e d, he m orr h a ge s u bc uta ne o us, c o nsti pati o n, a n d nas o p har y n gitis. 
1. 5. 3  
P h ase 3 St u dies  
F o ur P hase 3 efficac y a n d safet y st u dies ( St u dies 3 0 2, 3 0 5, 3 1 0, a n d 3 1 1) were c o n d ucte d. 
I n St u d y 3 0 2, a m ultice nter, ra n d o mize d, d o u ble-bli n d , place b o-c o ntr olle d, parallel -gr o u p st u d y 
wit h a n o pe n -la bel e xte nsi o n ( O L E) p has e treati n g t hr o m b oc yt o pe nia i n a d ults wit h c hr o nic I T P, 
s u bjects recei v e d oral a vatr o m b o pa g or matc hi n g place b o, wit h a starti n g d ose of 2 0 m g  o nce dail y 
a vatr o m b o pa g, f oll o w e d wit h d ose titrati o n u p t o a ma xi m u m d ose of 4 0 m g or d o w n t o a mi ni m u m 
d ose  of  5  m g.  T he  O L E  i ncl u de d  o nce  d ail y,  oral  d osi n g  wit h  a  st arti n g  d ose  of  2 0  m g  
a vatr o m b o pa g, f oll o we d wit h d ose titrati o n ( 5, 1 0, 2 0, 3 0, or 4 0 m g d oses). T he pri mar y efficac y 
e n d p oi nt was hi g hl y statisticall y si g nifi ca nt , fa v ori n g a v atr o m b o pa g ( p < 0. 0 0 0 1) c o m pare d wit h 
place b o. T h e me dia n of t he c u m ulati ve n u m ber of wee ks wit h platelet c o u nt ≥5 0 ×  1 09/ L d uri n g 
t he 6-m o nt h treat me nt was 1 2. 4 wee ks f or a v atr o m b o pa g a n d 0 wee ks f or  place b o. T he m ost 
c o m m o nl y re p orte d T E A Es ( ≥5 % of s u bjects) i n t he a vatr o m b o pa g gr o u p i n t he C ore St u d y were 


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hea dac he,  c o nt usi o n,  u p per  res pir at or y  tract  i nfecti o n,  art hral gia,  e pista xis,  fati g ue,  gi n gi val  
blee di n g, p etec hi ae, bac k pai n, i ns o m nia, m o ut h he m orr ha ge, nas o p har y n gitis, na usea, a ne mia, 
bl o o d gastri n i ncreas e d, c o u g h, h y perte nsi o n, i nfl ue nza, t hr o m b oc yt o p e nia, a n d v o miti n g. I n t he 
c o m bi ne d C ore St u d y a n d E xte nsi o n P hase  i n t he a vatr o m b o pa g gr o u p ( n =4 7), t he m ost c o m m o nl y 
re p orte d T E A Es (≥5 % of s u bjects) were c o nt usi o n, hea dac he, u p per res pirat or y tract i nfecti o n, 
t hr o m b oc yt o pe ni a,  e pista xis,  gi n gi val  blee di n g,  fati g ue,  petec hiae,  p h ar y n gitis,  art hral gia,  
h y perte nsi o n, nas o p h ar y n gitis, bac k pai n, i nfl u e n za, m o ut h he m orr ha ge, c o u g h, i ns o m nia, n a use a, 
pai n i n e xtre mit y, a n d uri nar y tract i nfecti o n. 
I n St u d y 3 0 5, a m ultice nter, ra n d o mize d, d o u ble-bli n d, a cti ve-c o ntr olle d, parallel -gr o u p st u d y 
wit h a n O L E p h ase i n a d ults wit h c hr o nic I T P, s u bjects recei ve d oral a v atr o m b o pa g at 5, 1 0, 2 0, 
3 0, or 4 0 m g, wit h a starti n g d ose of a vatr o m b o pa g 2 0 m g, f oll o we d wit h d ose titrati o n d o w n t o 5 
m g or u p t o 4 0 m g. A t otal of 2 3 s u bjects were ra n d o mize d i nt o t he st u d y pri or t o t he pre mat ure 
ter mi nati o n of t he st u d y d ue t o sl o w e nr oll me nt. T he m ost c o m m o nl y re p orte d TE A Es i n t he 
a vatr o m b o pa g gr o u p i n t he C ore St u d y were dizzi ness, hea dac he, i ns o m nia, m usc ul os keletal pai n, 
a n d na usea, ( 3 [ 2 5. 0 %] s u bjects eac h). D uri n g t he c o m bi ne d C ore St u d y a n d E xte nsi o n P hase, t he 
m ost  c o m m o nl y  re p ort e d  T E A Es  were  fati g u e  a n d  hea d ac h e ( 5 [ 2 9. 4 %] s u bjects  eac h)  a n d  
dizzi ness, i ns o m nia, a n d nas o p har y n gitis ( 4 [ 2 3. 5 %] s u bjects eac h). 
T w o ( 1 6. 7 %) s u bjects i n t he a vatr o m b o pa g gr o u p ha d seri o us a d verse e ve nts ( S A Es) d uri n g t he 
C ore St u d y. T he e ve nt of I T P w as n ot c o nsi dere d b y t h e I n v esti gat or t o be rel ate d t o treat me nt. 
T he  e ve nts  of  p ortal  v ei n  t hr o m b osis  a n d  t hr o m b o p hle bitis  se ptic  were  c o nsi dere d  b y  t he  
I n v esti gat or t o be p ossi bl y r elate d t o i n vesti gati o nal pr o d uct (I P). 
St u dies 3 1 0 a n d 3 1 1 e nr olle d a d ults wit h C L D  a n d se vere t hr o m b oc yt o p e nia ( mea n baseli ne 
platelet c o u nt < 5 0 ×  1 09/ L), sc he d ul e d t o u n der g o i n vasi ve pr oce d ures. C o h orts were defi ne d b ase d 
o n baseli ne platelet c o u nt ( C o h ort 1, < 4 0 ×  1 09/ L or C o h ort 2, 4 0 t o < 5 0 ×  1 09/ L), a n d patients 
were ra n d o mize d 2: 1 t o o nce dail y oral a va tr o m b o pa g ( 6 0 m g f or C o h ort 1, 4 0 m g f or C o h ort 2) 
or place b o f or 5 da ys, wit h t he pr oce d ure s c h e d ule d 5 t o 8 da ys after t heir last d ose. 
T he pri mar y efficac y e n d p oi nt was t he pr o p orti o n of patie nts n ot re q uiri n g platelet tra nsf usi o n or 
a n y blee di n g resc u e  pr o ce d ure u p t o 7 da ys p ost -pr oce d ure. Sec o n dar y e n d p oi nts assesse d t h e 
pr o p orti o n of patie nts ac h ie vi n g t he tar get platelet c o u nt (≥5 0 ×  1 09/ L), c h a n ge i n platelet c o u nt 
fr o m baseli ne t o Pr oce d ure Da y, a n d safet y. 
St u d y 3 1 0  ra n d o mize d  2 3 1  patie nts  t o  1  of  2 p ossi ble  c o h orts:  C o h ort  1  ( 9 0  a vatr o m b o pa g  
patie nts / 4 8 place b o patie nts ) or C o h ort 2 ( 5 9 a v atro m b o pa g p atie nts / 3 4 place b o patie nts ). Patie nts 
ha d a me dia n a ge of 5 7 years wit h 6 8 % of patie nts bei n g male a n d a bas eli ne me dia n platel et c o u nt 
of 3 8 ×  1 09/ L. T h e C L D  eti ol o g y of patie nts was 1 4 % alc o h ol, 6 2 % viral h e patitis, a n d 2 3 % ot her. 
St u d y 3 1 1  r a n d o mize d  2 0 4  patie nts  t o  1  of  2  p ossi ble  c o h orts:  C o h ort  1  ( 7 0  a v atr o m b o pa g 
patie nts / 4 3 place b o patie nts ) or C o h ort 2 ( 5 8 a v atr o m b o pa g p atie nts / 3 3 place b o pat ie nts). Patie nts 
ha d a me dia n a ge of 5 9 years wit h 6 2 % of patie nts bei n g male a n d a b aseli ne me dia n  platelet of 
3 9 ×  1 09/ L. T he C L D  eti ol o g y of patie nts w as 1 5 % alc o h ol, 5 3 % viral he patitis, a n d 3 3 % ot her. 
Si g nifica ntl y gr eater  pr o p orti o ns  of  a v atr o m b o pa g -treate d  patie nts  acr oss  all  c o h orts  di d  n ot  
re q uire platelet tra nsf usi o n or blee di n g resc u e pr oce d ures c o m pare d wit h place b o: St u d y 3 1 0: 
C o h ort 1, 6 6 % vers us 2 3 %; C o h ort 2, 8 8 % vers us 3 8 %; eac h p < 0. 0 0 0 1; St u d y 3 1 1: C o h ort 1, 6 9 % 
vers us 3 5 %, p = 0. 0 0 0 6; C o h ort 2, 8 9 % vers us 3 3 %, p < 0. 0 0 0 1. A vatr o m b o p a g was als o s u peri or t o 
place b o f or b ot h sec o n d ar y e n d p oi nts, i ncreasi n g mea n platel et  c o u nts o n Pr oce d ure Da y t o 
6 4 ×  1 09/ L i n C o h ort 1 a n d 8 5 ×   1 09/ L i n C o h ort 2. T he m ost c o m m o n T E A Es were p yre xia, 


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a b d o mi nal pai n, na usea, a n d hea dac he, w hic h w ere si milar f or place b o a n d a vatr o m b o pa g ar ms i n 
b ot h st u dies . M ost T E A Es wer e mil d t o m o derate i n se v erit y;  h o we v er, 1  t hr o m b otic T E A E 
occ urr e d i n C o h ort 2 ( 4 0 m g a vatr o m b o p a g) i n St u d y 3 1 1. T he st u dies c o n cl u de d a vatr o m b o p a g 
gi ve n o v er 5 d a ys si g nifi ca ntl y re d u ce d t he n ee d f or platelet tra nsf usi o ns or resc ue pr oce d ures f or 
blee di n g, a n d it was well t olerate d wit h a safet y pr ofile si milar t o place b o.   
1. 6  
R ati o n ale 
Data i n s u bjects wit h C L D  a n d I T P s u g gest t hat a vatr o m b o pa g is a pr o misi n g ca n di dat e f or use i n 
t he treat me nt of t hr o m b oc yt o p e nia of di verse eti ol o gies. A va tr o m b o pa g is bei n g de vel o pe d t o 
p ote ntiall y a d dress t he u n met me dical nee d of CI T. T he st u d y ai ms t o e val uate t he efficac y of 
a vatr o m b o pa g i n i ncreasi n g platelet c o u nts p ost- c he m ot hera p y t o a v oi d platelet tra nsf usi o ns a n d 
c he m ot hera p y  d ose  del a ys  or  d ose  r e d u cti o ns .  T he  safet y  of  a vatr o m b o pa g  i n  t his  s u bject  
p o p ulati o n will als o be assesse d t hr o u g h m o nit ori n g of a d vers e e ve nts, a d verse e v e nts of s pecial 
i nterest ( A E SI), cli nical la b orat or y p ara met ers, p h ysical e x a mi nati o n fi n di n gs, a n d vital si g ns.  
T hr o m b o c yt o p e nia occ urs at vari o us gra des of se v erit y i n s u bjects u n der g oi n g c h e m ot hera p y wit h 
m yel os u p pr essi ve a ge nts. Fre q u e ntl y, it is t he maj or d ose -li miti n g he mat ol o gic t o xicit y. T his is 
bec o mi n g  i ncreasi n gl y  i m p orta nt  gi ve n  t h e  rece nt  tre n d  t o w ar d  t he  use  of  d ose -i nte nsi ve 
c o m bi nati o n c he m ot hera p y r e gi me ns facilitate d b y s u p p orti ve he m at o p oietic c ol o n y -sti m ulati n g 
fact ors t o pr e ve nt c h e m ot hera p y-i n d uce d fe brile ne utr o pe nia. T h e sta n dar d treat me nt d uri n g t he 
c ycle of c h e m ot hera p y t o c orr ect platel ets is a t h e ra pe utic platelet tra nsf usi o n, es peciall y i n t he 
setti n g  of  a n  acti ve
 blee di n g  e v e nt.  T he  sta n dar d  pre ve nti ve  meas ure  a gai nst  
c he m ot hera p y-i n d uce d  d e pressi o n  of  platelets  i n  s u bse q ue nt  treat me nt  c ycl es  has  bee n  d ose  
re d ucti o n a n d/ or d ose d el a y.  
W hile plat elet tra nsf usi o ns ofte n resc ue s u bjects wit h ver y l o w platelet le vels, t he y are ass o ciate d 
wit h  t he  ris k  of  viral  a n d  bacterial  i nfecti o ns,  as  well  as  all oi m m u nizat i o n.  Platelet  d o n or  
recr uit me nt ca n als o be diffic ult a n d platelet tra nsf usi o n ca n be ver y ex pe nsi ve de pe n di n g o n t he 
s o urce of platelets. Ca ncer patie nts recei vi n g i nte nsi ve c he m ot hera p y or m yel oa bl ati ve re gi me ns 
ma y re q uir e m ulti ple platelet tra nsf usi o ns . F or t hese patie nts, alter n ate strate gies are n ee d e d s o 
t hat platelet tra nsf usi o ns ca n be si g nifi ca ntl y re d u ce d or eli mi nate d. As a res ult, f or t he p ur p oses 
of t h is st u d y, o ne c o m p o ne nt of t h e pri mar y e n d p oi nt will classif y a res p o n der as a s u bject w h o 
di d N O T re q uir e t he a d mi nistrati o n of a platelet tra nsf usi o n. 
Relati ve d ose i nte nsit y ( R DI) is a ter m t hat refers t o t he a m o u nt of a partic ular c he m ot hera p y gi ve n 
o ver a s pecific ti me i n relati o n t o w hat w as or d ere d ( or is c o nsi dere d st a n dar d). D ose d ela ys a n d 
d ose re d ucti o ns ca n de crease R DI a n d p ote ntiall y i ncrease t he ris k of disease pr o gressi o n   a n d 
m ortalit y. Retr os pecti ve a nal ys es of ra n d o mize d c o ntr olle d cli nical trials h a ve s u g geste d a str o n g 
ass ociati o n bet wee n R DI a n d disease -free a n d o verall s ur vi val, es peciall y f or l y m p h o ma a n d 
ca ncers of t he breast, l u n g, o var y, a n d c ol o n. D ata s h o w i ncreas e d s ur vi val f or s u bjects w h o recei ve 
≥8 5 % R DI a n d, c o n versel y, m ortalit y c ur v es si milar t o u ntreate d p o p ulati o ns w he n t his t hres h ol d 
R DI is n ot a d mi nistere d. As a res ult, f or t he p ur p oses of t h is st u d y, o n e c o m p o ne nt of t he pri mar y 
e n d p oi nt  will  classif y  a  res p o n d er  as  a  s u bject w h o  di d  N O T  h a ve  a  d ose  re d ucti o n  of  
c he m ot hera p y of ≥1 5 % (t o mai ntai n t he R DI > 8 5 %) .5 -9 , 1 1 -2 0 
I n a d diti o n, c h e m ot hera p y d os e del a y ( or t otal d urati o n of c he m ot hera p y) als o c o ntri b utes t o t h e 
o verall o utc o mes of s u bjects recei vi n g c h e m ot hera p y. W hile t here are fe w er st u dies i n vesti gati n g 
t he i m pact of c he m ot her a p y d ose del a y o n o utc o m es, o ne st u d y i n dicate d t h at a n e xte nsi o n of t he 


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ti me t o c o m plete t he e ntire c h e m ot hera p y re gi me n res ulte d i n p o orer o utc o mes .1 0 ,2 1  I n t hat st u d y, 
t he t otal dela y of treat me nt acr oss 5 c ycl es was 9 da ys. W hile a d ela y i n c he m ot hera p y i nitiati on 
of 7  da ys is a c o m m o n d urati o n of dela y d escri b e d i n t he literat ure, mai nl y d ue t o c o n ve nie nce of 
re-sc h e d uli n g  a  c he m ot hera p y  i nf usi o n,  t he  af ore me nti o ne d  st u d y  s u g gests  m ulti ple  s h orter  
d urati o n dela ys ma y res ult i n cli nicall y rele v a nt alterati o ns i n o utc o mes. As a res ult, f or t h e 
p ur p oses of t h is st u d y, on e  c o m p o ne nt of t he pri mar y e n d p oi nt will classif y a res p o n der as a s u bject 
w h o di d N O T h a ve a d os e dela y of c h e m ot hera p y of ≥4 da ys (t o mai ntai n t he o verall d urati o n of 
c he m ot hera p y as s h ort as p ossi ble t o mai ntai n o utc o mes).  
1. 7  
Ris k/ Be nefit  
C urre nt  treat me nt  o pti o ns  f or  patie nts  wit h  CI T  i ncl u de  c he m ot hera p y  d os e  re d u cti o ns,  
c he m ot hera p y d ose d ela ys, a n d platelet tra nsf usi o ns. W hile t he ris ks of si n gl e platelet tra nsf usi o ns 
are  ge n erall y c o nsi dere d  acce pt a ble,  t he y are  o nl y tra nsie ntl y effecti ve  at  i ncreasi n g  platelet  
c o u nts,  a n d  are  ass oci ate d  wit h  i m p orta nt  patie nt  ris ks  t hat  ca n  ha ve  si g nifica nt  healt h  a n d  
ec o n o mic c o nse q u e nces. I n a d diti o n t o t he p ote ntial ris ks of tra nsf usi o n reacti o ns a n d i nfecti o ns, 
w hic h i n rare cases ca n be fatal, t he de vel o p me nt of  a nti-platelet a nti b o dies  a n d t he res ulta nt 
refr act ori ness  t o  s u bse q ue nt  platelet  tra nsf usi o ns  are  of  partic ular  i m p orta nce.  Gi v e n  t hat  
a vatr o m b o pa g sti m ulates t he b o d y’s o w n me ga k ar y o c yt es t o pr o d uce platel ets, t here is n o ris k f or 
i nfecti o n,  a n d  n o  i m m u ne  res p o nse  a n d  t h us  n o  ris k  of  refract ori n ess.  T his  has  i m p orta nt  
i m plicati o ns i n preser vi n g t he utilizati o n of platelets f or e mer ge nt or f ut ure nee ds of t he patie nt, 
w hic h ma y n ot be a v aila ble if t he y b ec o me refract or y.  
A n orall y a d mi nistere d t hr o m b o p oietic a ge nt t hat ca n pre ve n t si g nifica nt t hr o m b oc yt o pe ni a d ue t o 
c he m ot hera p y a n d a v oi d a n y r e d ucti o ns i n d osa ge or dela ys i n c he m ot hera p e utic re gi me ns w o ul d 
pr o vi de a n i m p orta nt p u blic healt h be nefit. 


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S T U D Y O B J E C TI V E S  
2. 1  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve  of t his st u d y is t o e v al uate t he efficac y of a vatr o m b o pa g i n i ncreasi n g 
platelet c o u nts a n d t her ef ore pr e ve nti n g t he nee d f or a pl atelet tra nsf usi o n or c he m ot hera p y d os e 
re d ucti o n or del a y i n s u bjects wit h CI T. 
2. 2  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ve s of t his st u d y are t he f oll o wi n g: 
•  T o e val uate t he s afet y of a vatr o m b o pa g i n s u bjects wit h CI T, a n d 
•  T o i n vesti gate t h e effect of a vatr o m b o pa g o n bl ee di n g i n s u bjects wit h CI T. 
 








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S E L E C TI O N A N D WI T H D R A W A L O F S U B J E C T S  
4. 1  
I ncl usi o n Criteri a f or All S u bjects 
S u bjects w h o meet all of t he f oll o wi n g criteria will be eli gi ble t o partici pate i n t he st u d y:  
1.  S u bject is ≥1 8 years of a ge at t he ti me of i nf or me d c o nse nt; 
2.  S u bject wit h a dia g n osis  wit h o varia n ca ncer, l u n g ca n cer  (s mall cell or n o n-s mall cell), or 
bla d der ca ncer, re q uiri n g s yste mic c h e m ot hera p y;  
3.  S u bject is c urre ntl y recei vi n g a c h e m ot hera p y re gi me n gi ve n i n a 2 1 -da y or 2 8 -da y c ycl e ( ot her 
c he m ot hera p y c ycl e le n gt hs are n ot all o we d), i n cl u di n g 1 or m ore of t he f oll o wi n g a ge nts or 
class of a ge nts:  
o  N ucle osi de a n al o g, i n cl u di n g ge mcita bi n e a n d fl u or o uracil; 
o  Car b o plati n or cis plati n; 
o  A nt hrac ycli ne; or  
o  Al k ylati n g a ge nt;  
4.  S u bject  e x perie nce d  se v ere  t hr o m b oc yt o pe ni a,  defi ne d  as  2  platelet  c o u nts  < 5 0  ×   1 09/ L 
meas ure d at leas t 2 4 h o urs a part, d uri n g t he q ualif yi n g c he m ot hera p y c ycle ( C ycle X), of t heir 
c urre nt c he m ot her a p y re gi me n. Platelet c o u nts o btai ne d per sta n d ar d of care d uri n g C ycle X 
pri or t o c o nse nt ma y be use d; 
5.  S u bject  is  pla n ne d t o recei ve  t he  sa me  c he m ot hera p y re gime n  a n d  t he  sa me  d ose(s)  o n  
C he m ot hera p y Da y  ( Da ys 1-3) of C ycle X + 1 as wa s gi ve n i n t he q ualif yi n g c h e m ot hera p y 
C ycle X;  
6.  S u bject has a n Easter n C o o perati ve O n c ol o g y Gr o u p ( E C O G) perf or ma n ce stat us ≤2; 
7.  S u bject has a life e x pecta nc y > 1 2 w ee ks at Scree ni n g  an d is a ble t o recei ve at least 2 a d diti o nal 
c ycles of t he c urr e nt c he m ot he ra p y re gi me n; 
8.  Fe males of c hil d beari n g p ote ntial m ust a gree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
(e g, t otal a bsti ne nce; a n i ntra uteri ne de vice; h or m o nal c o ntrace pti ve gi ve n orall y, b y i njecti o n, 
or b y i m pla nt; d o u ble barrier c o ntr ace pti o n (i.e., c o n d o m + dia p hra g m) ; or has a vasect o mize d 
part ner wit h c o nfir me d az o os per mia) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after 
i n vesti gati o nal pr o d uct (I P) disc o nti n uati o n. If c urre ntl y a bsti ne nt, t he s u bject m ust a gree t o 
use a n eff ecti ve met h o d as descri be d a b o v e if s h e bec o m es se x uall y acti v e d uri n g t he st u d y 
peri o d or f or 3 0 d a ys aft er I P disc o nti n uati o n.   
Male s u bjects m ust be eit her s ur gi call y sterile or a gree t o use  a d o u ble barrier c o ntrace pti o n 
met h o d 
(c o m bi nati o n  of  male  c o n d o m  wit h  eit her  ca p,  dia p hra g m,  or  s p o n ge  wit h  a  
s per mici de) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after I P dis c o nti n uati o n; 
N ote:  All  fe mal e  s u bjects  are  c o nsi dere d  t o  be  of  c hil d beari n g p ote nti al  u nless  t he y are  
p ost me n o pa usal (at least 1 2 m o nt hs c o nsec uti ve a me n orr h ea a n d wit h o ut a n ot her k n o w n or 
s us pecte d ca use) or ha v e bee n sterilize d s ur gicall y (i e, bilateral t u bal li gati o n, h ysterect o m y, 
or bilateral o o p h or ect o m y) at least 1 m o nt h bef ore d osi n g. 
9.  S u bject is willi n g a n d a bl e t o c o m pl y wit h all as p ect s of t he pr ot oc ol; a n d  


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1 0.  S u bject m ust pr o vi de writte n i nf or me d c o nse nt. 
4. 2  
E xcl usi o n Criteri a f or All S u bjects  
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will be e x cl u de d fr o m partici pati o n i n t he st u d y:  
1.  S u bject has e x perie nce d ≥ Gra de 2 CI T wit h a pl atel et c o u nt < 7 5 ×  1 09/ L ( ot her t ha n d uri n g 
t he c urr e nt c he m ot her a p y treat me nt re gi me n) wit hi n 6 m o nt hs of Scree ni n g; 
2.  S u bject has a platelet c o u nt > 1 7 5 ×  1 09/ L at Visit 2 (- 1 da y); 
3.  S u bject  wit h  a n y  hist or y  of  he mat ol o gic  mali g na n cies,  i ncl u di n g  le u ke mia,  m yel o ma, 
m yel o pr olif erati ve diseas e, l y m p h o ma, or m yel o d ys plastic diseas es; 
4.  S u bject w h o recei ve d > 2 pre vi o us li nes of c he m ot hera p y (a dj u va nt/ ne o a dj u va nt t hera p y is 
c o nsi dere d a pre vi o us li ne; i m m u n ot hera p y al o ne is n ot c o nsi d ere d a pre vi o us li ne) or is 
recei vi ng w h ole brai n r a diati o n d uri n g t he st u d y treat me nt peri o d; 
5.  S u bject wit h a n ala ni ne a mi n otra nsferase  ( A L T) or as partat e a mi n otra nsferase  ( A S T) > 5 ×  
u p per li mit of n or mal or t otal bilir u bi n ≥3 ×  u p per li mit of n or mal; 
6.  S u bject has a k n o w n me dical hist or y of h u m a n i m m u n o deficie nc y vir us; 
7.  S u bject has a n y k n o w n cli nicall y si g nifica nt ac ut e or acti ve blee di n g (e g, gastr oi nte sti nal or 
ce ntral ner v o us s yste m) wit hi n 7 da ys of Scree ni n g; 
8.  S u bject
 has
 a
 k n o w n
 me dical
 hist or y
 of
 ge n etic
 pr ot hr o m b otic
 s y n dr o mes
 
(e g, Fact or V Lei de n, pr ot hr o m bi n G 2 0 2 1 0 A, or A TIII deficie nc y); 
9.  S u bject has a rece nt hist or y ( wit hi n 3 m o nt hs of Scree ni n g ) of si g nifica nt car di o vasc ular 
disease ( e g, c o n gesti ve h eart fail ure e x acer b ati o n , arr h yt h mia k n o w n t o i n creas e t he ris k of 
t hr o m b oe m b olic e ve nts [ e g, atrial fi brillati o n], c or o nar y arter y ste nt place me nt, a n gi o plast y, 
or c or o nar y art er y b y pass gr aft);  
1 0.  S u bject has a hist or y of arterial or ve n o us t hr o m b osis wit hi n 3 m o nt hs of Scree ni n g; 
1 1.  S u bject has use d vita mi n K a nta g o nists wit hi n 7 da ys of Scree ni n g ( us e of l o w m olec ular 
wei g ht h e pari n , X a i n hi bit ors, or t hr o m bi n i n hi bit ors is all o we d); 
1 2.  S u bject has a hist or y of c hr o nic platel et or blee di n g dis or d ers or t hr o m b oc yt o pe nia d ue t o a n 
eti ol o g y ot her t ha n CI T ( e g, c hr o nic li ver disease or i m m u ne t hr o m b oc yt o p e nia p ur p ura); 
1 3.  S u bject has use d m o derat e or str o n g i n d ucers of c yt oc hr o me P 4 5 0 ( C Y P) 2 C or C Y P 3 A 4/ 5 (see 
A p p e n di x  C) wit hi n 7 da ys of Scree ni n g; 
1 4.  S u bject has recei ve d a t hr o m b o p oieti n rece pt or a g o nist (e g, eltr o m b o pa g or r o mi pl osti m) or 
rec o m bi na nt h u ma n t hr o m b o p oieti n f or t he treat me nt of CI T wit hi n 3 m o nt hs of Scree ni n g; 
1 5.  S u bject recei v e d a platel et tra nsf usi o n wit hi n 7 2 h o urs of ra n d o mizati o n; 
1 6.  S u bject is u na ble t o ta ke oral me dicati o n ; 
1 7.  S u bject  has  a n y  hist or y  of  a  c o n c o mita nt  me di cal  c o n diti o n  t hat,  i n  t h e  o pi ni o n  of  t he  
I n v esti gat or, w o ul d c o m pr o mise t he s u bject’s a bilit y t o safel y c o m plete t he st u d y, s uc h as 
u nsta ble a n gi na, re n al f ail ure r e q uiri n g he m o dial ysis, or acti ve i nfecti o n re q uiri n g i ntra ve n o us 
a nti bi otics; 


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1 8.  Fe male  s u bj ects  w h o  are  lactati n g  or  pre g n a nt  at  Scree ni n g  or  t he  Baseli ne  Visit  (as 
d oc u me nte d b y a p ositi ve ser u m or uri n e  beta - h u ma n c h ori o nic go na d otr o pi n [ β -h C G] test)  ; 
1 9.  S u bject has h y p erse nsiti vit y t o a vatr o m b o pa g or a n y of its e x ci pie nts; or  
2 0.  S u bject is c urr e ntl y e nr olle d i n a n ot her cli nical st u d y wit h a n y i n vesti gati o nal dr u g or de vice 
wit hi n 3 0 da ys of Scree ni n g; h o we v er, p artici pati o n i n o bs er vati o nal st u dies is per mitte d . 
4. 3  
I ncl usi o n Criteri a f or S u bjects t o C o nti n ue I nt o t he O pti o n al O pe n-L a bel 
E xte nsi o n Peri o d  
S u bjects w h o meet all of t he f oll o wi n g criteria will be eli gi ble t o c o nti n ue i nt o t he o pti o nal O L E 
Peri o d : 
1.  S u bject is c urre ntl y recei vi n g t he sa me c he m ot hera p y a ge nts as w ere gi ve n i n t he q ualif yi n g 
c he m ot hera p y C ycl e X;  
2.  S u bject has a n E C O G  perf or ma nce stat us ≤2; 
3.  Fe males of c hil d beari n g p ote ntial m ust a gree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
as pre vi o usl y d efi ne d.  
Male s u bjects m ust be eit her s ur gi call y sterile or a gree t o use a d o u ble barrier c o ntrace pti o n 
met h o d 
(c o m bi nati o n  of  male  c o n d o m  wit h  eit her  ca p,  dia p hra g m,  or  s p o n ge  wit h  a  
s per mici de) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after I P dis c o nti n uati o n;  
N ote:  All  fe mal e  s u bjects  are  c o nsi dere d  t o  be  of  c hil d beari n g p ote nti al  u nless  t he y are  
p ost me n o pa usal (at least 1 2 m o nt hs c o nsec uti ve a me n orr hea i n t he a p pr o priate a ge gr o u p a n d 
wit h o ut a n ot her k n o w n or s us pecte d ca us e) or h a ve bee n sterilize d s ur gi cal l y (ie, bilateral t u bal 
li gati o n, h yst erect o m y, or bilateral o o p h orect o m y) at least 1 m o nt h bef ore d osi n g. 
4.  S u bject is willi n g a n d a bl e t o c o m pl y wit h all as p ects of t he pr ot oc ol; a n d  
5.  S u bject m ust pr o vi de c o nse nt t o c o nti n ue i nt o t he O L E Peri o d. 
4. 4  
E xcl usi o n Criteri a f or S u bjects t o C o nti n ue I nt o t he O pti o n al O pe n -L a bel 
E xte nsi o n Peri o d  
S u bjects w h o me et a n y of t he f oll o wi n g criteri a will be e x cl u de d fr o m c o nti n ui n g i nt o t he 
o pti o nal O L E Peri o d: 
1.  S u bject has a pl atelet c o u nt > 1 7 5 ×  1 09/ L o n t h e sc he d ule d first d a y of d osi n g of a v atr o m b o pa g 
pri or t o c he m ot her a p y; 
2.  S u bject wit h a n A L T  or A S T > 5 ×  u p p er li mi t of n or mal or t otal bilir u bi n ≥3 ×  u p per li mit of 
n or mal; 
3.  S u bject has a n y k n o w n cli nicall y si g nifica nt ac ut e or acti ve blee di n g (e g , gastr oi ntesti nal or 
ce ntral  ner v o us s yste m) wit hi n 7 da ys of pre-c he m ot hera p y I P treat me nt i n O L E c ycles ; 
4.  S u bject has use d vita mi n K a nta g o nists wit hi n 7 da ys of pre -c he m ot hera p y I P treat me nt i n 
C ycle X + 3 ( use of l o w m olec ular wei g ht h e pari n , Xa i n hi bit ors, or t hr o m bi n i n hi bit ors  is 
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5.  S u bject has use d m o derate or str o n g i n d ucers of C Y P 2 C or C Y P 3 A 4/ 5 (see  A p pe n di x C ) 
wit hi n 7 da ys of pre- c he m ot hera p y I P treat me nt i n O L E c ycles ; 
6.  S u bjec t is u na ble t o ta ke oral me dicati o n ; 
7.  Fe male s u bjects w h o are l actati n g or pre g n a nt (as d oc u me nte d b y a p ositi ve uri ne or ser u m  
test). 
4. 5  
Wit h dr a w al Criteri a  
Partici pati o n of a s u bject i n t his cli nical st u d y ma y be disc o nti n ue d f or a n y of t he f oll o wi n g 
reas o ns: 
•  T he s u bject wit h dra ws c o nse nt or re q u ests disc o nti n uati o n fr o m t he st u d y f or a n y reas o n; 
•  O cc urre nce of a n y me di cal c o n diti o n or circ u msta nce t hat e x p oses t he s u bject t o s u bsta ntial 
ris k a n d/ or d oes n ot all o w t he s u bject t o a d here t o t he re q uire m e nts of t he pr ot oc ol; 
•  A n y seri o us  a d verse  e v e nt  (S A E ),  cli nicall y  si g nifica nt  a d v erse  e v e nt,  se vere  la b orat or y 
a b n or malit y, i nterc urre nt ill ness, or ot her me dical c o n diti o n w hic h i n dicates t o t he I n vesti gat or 
t hat c o nti n ue d partici pati o n is n ot i n t he best i nterest of t he s u bject; 
•  Pre g n a nc y;  
•  Re q uire me nt of pr o hi bite d c o nc o mita nt me dicati o n;  
•  S u bject fail ur e t o c o m pl y wit h pr ot oc ol re q uire me nts or st u d y- relate d pr o ce d ures; or  
•  Ter mi nati o n of t he st u d y b y t he S p o ns or or t h e re g ulat or y a ut h orit y. 
If a s u bject wit h dra ws pr e mat urel y fr o m t he st u d y d u e t o t he a b o ve criteria or a n y ot her reas o n, 
st u d y staff s h o ul d ma k e e ver y eff ort t o c o m plet e t he f ull pa nel of ass ess me nts sc he d ule d f or 
Visit  1 3 (f or s u bjects n ot i n t he o pti o nal O L E Peri o d) or Visit  1 7 (f or s u bjects partici pati n g i n  t he 
o pti o nal O L E Peri o d) . All s u bjects s h o ul d c o nti n ue i nt o t he L o n g -Ter m F oll o w -U p  Peri o d u nless 
c o nse nt has b ee n wit h dr a w n. T he reas o n f or s u bject wit h dra w al m ust b e d oc u me nte d i n t he 
electr o nic case re p ort f or m (e C R F).  
I n t he case of s u bjects  l ost  t o f oll o w-u p, atte m pts t o c o ntact  t he s u bject  m ust  be ma de a n d 
d oc u me nte d i n t he s u bject ’s me dical rec or ds. 
4. 5. 1  
S u bjects wit h I n vesti g ati o n al Pr o d uct I nterr u pti o n or Disc o nti n u ati o n 
S u bjects w h o disc o nti n ue st u d y dr u g will be f oll o we d f or t he e ntire st u d y d urati o n t hr o u g h t he 
L o n g -t er m F oll o w- U p Peri o d  ( u nless t he s u bject wit h dra ws c o nse nt), a n d all pr oce d ures s h o ul d be 
f oll o we d acc or di n g t o t he pr ot oc ol. 
If a s u bject disc o nti n ues st u d y dr u g d ue t o a n a d verse e ve nt, t he I n vesti gat or will atte m pt t o f oll o w 
t he e ve nt u ntil it has res ol ve d or sta bilize d. 
If a s u bject misses a d ose of st u d y dr u g, te m poraril y i nterr u pts treat me nts ( w het her d ue t o a n 
a d verse e v e nt or ot her reas o n), t he I n vesti gat or s h o ul d c o ntact t he Me dical M o nit or re gar di n g h o w 
t o ha n dle treat me nt r e-i nitiati o n or if per ma ne nt st u d y dr u g disc o nti n uati o n is re q uire d. 


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S T U D Y T R E A T M E N T S  
5. 1  
Tr e at me nt Gr o u ps  
T his is a P hase 3 ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y of t he efficac y a n d safet y of 
oral a vatr o m b o pa g i n s u bjects wit h CI T wit h acti ve n o n -he mat ol o gical ca ncers. T he st u d y c o nsists 
of 4 peri o ds: a D o u ble-Bli n d Treat me nt Peri o d , a n O bser vati o nal Peri o d, a n o pti o nal O L E Peri o d, 
a n d a L o n g- T er m F oll o w - U p Peri o d. 
S u bjects i n t he D o u ble-Bli n d Treat me nt Peri o d will be ra n d o mize d t o o ne of 2 st u d y ar ms: 6 0 m g 
a vatr o m b o pa g ( 3 ×  2 0 m g ta blets) o n ce d ail y  or pl ace b o  ( 3 t a blets).  
S u bject s i n t he O bser vati o nal Peri o d will n ot recei ve a n y I P. 
S u bjects i n t he o pti o nal O L E  Peri o d will recei v e 6 0 m g a vatr o m b o pa g ( 3 ×  2 0 m g  ta blets) o n ce 
dail y.  
S u bjects i n t he L o n g- T er m F oll o w -U p Peri o d will n ot recei ve a n y I P.  
5. 2  
R ati o n ale f or D osi n g 
A P K/ P D m o de l was de vel o pe d t o si m ulate platelet res p o nse t o a vatr o m b o pa g a d mi nistrati o n i n 
or der t o sel ect a d os e r e gi me n f or t his st u d y. Usi n g data fr o m h ealt h y v ol u nt eers a n d s u bjects wit h 
C L D , t h e P K/ P D m o del e val uate d t he relati o ns hi p of a v atr o m b o pa g c o nce ntrati ons t o i ncreases i n 
platelet c o u nts. As a part of t his m o del , t he effect of car b o plati n d ose o n platelet c o u nt o btai ne d 
fr o m p o p ulati o n P K/ P D m o deli n g of eltr o m b o pa g i n s u bjects wit h a d va nce d s oli d t u m ors wit h CI T 
was als o i nc or p orate d.4  Si m ulati o ns were perf or me d ass u mi n g t he bas eli ne platelet c o u nt ra n ge d 
bet wee n 2 5 a n d 1 5 0  ×  1 09/ L wit h a g oal t o i ncrease t he platelet c o u nt t o le vels > 1 0 0 ×  1 09/ L f or 
t he d urati o n of c he m ot hera p y tr eat me nt t o pre ve nt platelet tra nsf usi o n a n d t o all o w t he s u bject t o 
recei v e t he  sa me  d ose  a n d  sc h e d ule of c h e m ot hera p y as  prescri be d  i n  C ycl e X. Si m ulati o ns 
s u g geste d t hat 6 0 m g a v atr o m b o pa g a d mi nistere d o nce dail y f or 5 da ys pri or t o c he m ot hera p y a n d 
o nce dail y f or 5 d a ys f oll o wi n g c h e m ot hera p y w as t he m ost a p pr o priate f or mai ntai ni n g platel et 
c o u nts a b o ve t his t hres h ol d w hile pre ve nti n g platelet c o u nts fr o m ele v ati n g a b o ve t he u p p er li mit 
of n or mal. 
T o e ns ure t he acc ur ac y of t he pre dicti o ns, platelet res p o nse data will be re vie we d b y t he D S M B 
as descri be d i n  Secti o n 3. 3 , a n d if necessar y, d osa ge a dj ust me nts ma y be ma de f oll o wi n g t hese 
data re vie ws.  
5. 3  
R a n d o miz ati o n a n d Bli n di n g  
T his is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y. F or t he D o u ble -Bli n d Treat me nt 
Peri o d, s u bjects w h o meet t he i ncl usi o n criteria a n d e x cl usi o n criteria will be ra n d o mize d t o 
recei v e eit her a v atr o m b o pa g 6 0 m g or place b o i n a 2: 1 rati o at t he Baseli ne Visit. Ra n d o mizati o n 
will be stratifie d b y t he n u m ber of c he m ot hera p y a ge nts t he s u bject is recei vi n g  ( 1, ≥2 per missi ble 
c he m ot hera p y a ge nts [ n ucle osi de a n al o g, i ncl u di n g ge mcita bi ne a n d fl u or o uracil; car b o plati n or 
cis plati n; a nt hrac ycli ne; or al k yl ati n g a ge nt] ). Ra n d o mizati o n assi g n me nt will be perf or m e d usi n g 
i nteracti ve  r es p o nse  tec h n ol o g y  (I R T).  F oll o wi n g  ra n d o mizati o n,  I P will  be  dis pe nse d  i n  a  
d o u ble- bli n d ma n ner. T he S p o ns or a n d desi g nate d cli nical site pers o n nel (I n v esti gat or a n d st u d y 
c o or di nat or) will be bli n de d t o t he treat me nt gr o u p f or eac h  s u bject. S ubjects will als o be bli n de d 
t o t he treat me nt t he y recei ve. 


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5. 4  
Bre a ki n g t he Bli n d  
At t he i nitiati o n of t he st u d y, t he I n vesti gat or will be i nstr ucte d o n t he met h o d f or brea ki n g t he 
bli n d. T he  b li n d  is  n ot  t o  be  br o ke n  d uri n g  t he  st u d y  u nless  c o nsi dere d  necessa r y  b y  t h e  
I n v esti gat or f or e mer ge n c y sit uati o ns f or reas o ns of s u bject safet y. U n bli n di n g at t h e cli nical site 
f or a n y ot her reas o ns will be c o nsi der e d a pr ot o c ol de viati o n. T he I n vesti gat or s h o ul d c o ntact t he 
Me dical M o nit or bef or e brea ki n g t he bli n d, if ti me per mits. W he n t he bli n d is br o ke n, t he reas o n 
m ust be f ull y d oc u me nt e d.  
5. 5  
Dr u g S u p plies  
5. 5. 1  
F or m ul ati o n a n d P ac k a gi n g 
A vatr o m b o pa g will be pr o vi de d as fil m -c oat e d ta blets , wit h eac h ta bl et c o ntai ni n g  a v atr o m b o pa g 
maleate (e q ui v ale nt t o  2 0 m g of  a v atr o m b o pa g) a n d t he f oll o wi n g e x ci pie nts: lact ose m o n o h y drate, 
c oll oi dal  silic o n  di o xi de,  cr os p o vi d o ne,  ma g nesi u m  stearate,  micr ocr ystalli ne  cell ul ose,  a n d  
O pa dr y II 8 5 F 4 2 2 4 4.  
Matc hi n g place b o ta bl ets, c o ntai ni n g lact ose m o n o h y drate ( 2 3. 6 m g), will be pr o vi de d. 
I n vesti gati o nal pr o d uct will be pac ka ge d i n bli n de d blister pac ka ges , eac h c o ntai ni n g 1 5 ta blets. 
F or t he o pti o nal O L E Peri o d, a vatr o m b o pa g will be pac ka ge d i n o pe n -la bel blister pac ka ges, eac h 
c o ntai ni n g 1 5 ta bl ets of a vatr o m b o pa g. 
5. 5. 2  
I n vesti g ati o n al Pr o d uct Di s pe nsi n g 
T he I n vesti gat or or desi g nee will pr o vi de s u bjects wit h s ufficie nt I P t o c o m plete eac h 5-d a y c o urse 
of st u d y dr u g d uri n g  t he D o u ble-Bli n d Treat me nt Peri o d  (eac h 5-da y c o urse t o b e dis pe nse d o n 
se parat e  occasi o ns  as  a p pr o priate).  If  s u bj ects  c o nti n ue  i nt o  t he  o pti o nal O L E  Peri o d,  t h e  
I n v esti gat or or desi g n ee will pr o vi de s u bjects wit h a d diti o nal I P t o c o m plete t he o pti o nal O L E 
Peri o d . 
5. 5. 3  
I n vesti g ati o n al Pr o d uct A d mi nistr ati o n  
S u bjects  ra n d o mize d  t o  t he  i n vesti gati o nal  ar m  will  recei ve  6 0  m g  a v atr o m b o pag 
( 3 ×  2 0 m g  ta blets) f or or al a d mi nistrati o n o nce d ail y f or 5 da ys pri or t o C h e m ot hera p y D a y a n d 
f or 5 da ys i m me diatel y f oll o wi n g C he m ot hera p y Da y  d uri n g t he D o u bl e-Bli n d Treat me nt Peri o d . 
S u bjects ra n d o mize d t o t he c o ntr ol ar m w ill recei ve matc hi n g placeb o ta blets.  
S u bjects i n t he o pti o nal O L E  Peri o d will recei ve 6 0 m g a vatr o m b o p a g ( 3 ×  2 0 m g  ta blets) f or oral 
a d mi nistrati o n o nce d ail y f or 5 da ys pri or t o C he m ot hera p y D a y a n d f or 5 d a ys after C he m ot hera p y 
Da y.   
At sc he d ule d st u d y visits, I P ma y b e a d mi nistere d at t he site or t he s u bject ma y self - d ose e x ce pt 
f or Visits 3 a n d 5 w he n s u bjects will be d ose d at t he site a n d serial P K sa m ples will be c ollecte d 
pre - a n d p ost -d os e of I P . S u bjects will self-d ose at all ot her ti mes. S u bjects will be i nstr ucte d t o 
ta ke I P wit h f o o d.  
D uri n g t he st u d y, if t he s u bject has a platelet c o u nt > 4 0 0 ×   1 09/ L, I P d osi n g will be st o p p e d 
te m p oraril y. D osi n g m a y be restart e d f oll o wi n g disc ussi o n wit h t he Me dical M o nit or.  


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T he n u m ber of ta bl ets t o be ta ke n will be t hree 2 0 m g a v atr o m b o pa g t a blets or 3 mat c hi n g place b o 
ta blets o nce dail y . 
Act ual date a n d ti me of c he m ot hera p y d oses will als o be ca pt ure d. 
5. 5. 4  
Tre at me nt C o m pli a nce  
A t sc he d ule d st u d y visits, I P ma y b e a d mi nistere d at t he site or t he s u bject ma y self- d ose e x ce pt 
f or Visits 3 a n d 5 w he n s u bjects will be d ose d at t he site a n d serial P K sa m ples will  be c ollecte d 
pre - a n d p ost -d ose of I P . S u bjects will self-d ose at all ot her ti mes. W he n ta ki n g I P at h o me  f or t he 
d o u ble- bli n d p hase of t he st u d y, s u bjects will be as ke d t o rec or d t he date a n d ti me of eac h I P d ose 
i n t he d osi n g diar y.  
C o m plia nce wit h I P a d mi nistrati o n will be assesse d b y c o u nti n g ret ur n e d I P p ac ka ges a n d a n y 
u n use d I P i n a d diti o n t o re vie wi n g t he d osi n g diar y e ntries of I P i nta k e. A n y discre pa n cies bet wee n 
ret ur ne d I P n u m b er a n d d osi n g i n t he d osi n g diar y will be dis c usse d wit h t he s u bject f or w h o m a 
discre pa n c y was see n a n d rec or d e d i n t he s o urce d oc u me nts. N u m ber of ta blets dis pe nse d a n d 
n u m ber of ta blets r et ur ne d will be rec or d e d o n t he a p pr o priate dr u g acc o u nt a bi lit y e C R F. 
5. 5. 5  
St or a ge a n d Acc o u nt a bilit y 
In v esti gati o nal p r o d uct s h o ul d be st ore d at c o ntr olle d r oo m te m perat ure ( 2 0˚ C t o 2 5˚ C/ 6 8˚ F t o 
7 7˚ F) wit h e x c ursi o ns per mitte d t o 1 5˚ C t o 3 0˚ C ( 5 9˚ F t o 8 6˚ F)  i n a s ec ure l ocati o n a n d i n t h e 
c o ntai ners pr o vi de d.  
Rec or ds  will be mai ntai ne d i n dicati n g t he recei pt a n d dis pe nsa ti o n of all I P s u p plies. At t he 
c o ncl usi o n of t he st u d y, a n y u n use d I P will be ret ur ne d t o t he S p o ns or or t he S p o ns or’s desi g n ee  
or ma y b e d estr o ye d at t he site if a p pr o priate pr o ce d ures are i n place . If n o s u p pl y re m ai ns, t his 
will be i n dicate d i n t he Dr u g Acc o u nta bilit y L o g.  
5. 6  
Pri or a n d C o nc o mit a nt Me dic ati o ns a n d/ or Pr o ce d ures  
5. 6. 1  
E xcl u de d Me dic ati o ns a n d/ or Pr oce d ures  
T he f oll o wi n g m e dicati o ns a n d/ or pr oce d ures are e x cl u de d: 
•  Use of vita mi n K a nta g o nists ; 
•  Use of t hr o m b o p oieti n rece pt or a g o nists or rec o m bi na nt h u ma n t hr o m b o p oieti n; 
•  Use of m o der ate or str o n g i n d ucers of C Y P 2 C or C Y P 3 A 4/ 5 (see A p pe n di x C ); a n d 
•  C urre ntl y e nr olle d i n a n ot her cli nical st u d y wit h a n y i n v esti gati o nal dr u g or d e vice wit hi n 
3 0 da ys o f Scree ni n g; h o we ver, p artici pati o n i n o bser vati o nal st u dies is per mitte d.  
5. 6. 2  
All o w e d Me dic ati o ns a n d/ or Pr oce d ures  
•  U se of pac k e d re d bl o o d cell tra nsf usi o ns, er yt hr o p oieti n, or gra n ul oc yt e -c ol o n y sti m ulati n g 
fact or, as or der e d b y t h e ma na gi n g o nc ol o g y ser vice, is acce pta ble a n d d oes n ot precl u de 
partici pati o n ; a n d  
•  Use of l o w m olec ular wei g ht he pari n, Xa i n hi bit ors, or t hr o m bi n i n hi bit ors is all o we d. 


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5. 6. 3  
D oc u me nt ati o n of Pri o r a n d C o nc o mit a nt Me dic ati o n Use 
A ll c o nc o mita nt me dicati o ns (i ncl u di n g c o n c urre nt t hera pies a n d c o nc urre nt pr oce d ures) will be 
d oc u me nte d fr o m t he ti me of i nf or me d c o nse nt t o t he F oll o w-U p Visit . D ose, i n dicati o n f or 
a d mi nistrati o n, a n d dates of me dicati o n a d mi nistrati o n will als o be ca pt ure d i n s o urce d oc u me nts 
a n d o n t he a p pr o priate e C R F . 


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6  
S T U D Y P R O C E D U R E S  
A sc he d ule of pr o ce d ur es i n ta b ular f or mat is pr o vi de d i n Ta ble 1 , Ta ble 2 , a n d Ta ble 3  i n 
A p pe n di x A .  
L ocal la b or at ories ma y  be use d t o det er mi ne st u d y eli gi bilit y; h o w e ver, f or st u d y a nal ysis a n d 
re p orti n g p ur p oses, o nl y val ues deter mi ne d at a central la b orat or y will be use d wit h t he e x ce pti o n 
of platelet c o u nt. Platelet c o u nt a nal yses will be p erf or me d usi n g l ocal la b orat or y res ults. L o cal 
la b orat ories ma y b e use d if i m me diate res ults are cli nicall y nee d e d (e g,  Bas eli ne  Visit ). 
6. 1  
I nf or me d C o nse nt 
Pri or t o c o n d ucti n g a n y st u d y- r elate d acti vities, writte n i nf or me d c o nse nt m ust be si g ne d a n d 
date d b y t he s u bject. See  Secti o n 1 2. 4  f or a d diti o nal i nf or mati o n o n i nf or m e d c o nse nt. 
6. 2  
C ycle X ( Q u alif yi n g C he m ot her a p y C y cle) 
6. 2. 1  
Scree ni n g ( Visit 1, D a y - 2 8 t o D a y - 1) 
T he Scree ni n g Visit ma y be c o m bi ne d wit h t he  Baseli ne Visit o n t he da y pri or t o I P treat me nt 
( Da y -1) .  
T he f oll o wi n g pr oce d ures will be perf or me d at t he Scree ni n g Visit : 
•  O btai n i nf or me d c o nse nt pri or t o scree ni n g pr oce d ures; 
•  C o ntact I R T t o r e gister t he s u bject i n t he st u d y  
•  C o n d uct eli gi bilit y asses s me nt base d o n i ncl usi o n/e x cl usi o n criteria;  
•  O btai n de m o gr a p hics   (i ncl u di n g race), a n d me dical  hist or y (t o i ncl u de  c he m ot hera p y a n d 
ca ncer hist or y); 
•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale;  
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m f ull p h ysical e x a mi nati o n; 
•  Rec or d vital si g ns (i ncl u des hei g ht, wei g ht, b o d y te m perat ure, bl o o d press ure, a n d p ulse rate) ; 
a n d 
•  Perf or m pre g n a nc y test ( ser u m or uri ne) f or fe mal e s u bjects of c hil d beari n g p ote ntial o nl y; 
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts (if Scree ni n g Visit occ urs o n the sa me 
da y as t he Baseli ne Visit, o nl y t he Baseli ne l a b orat or y assess me nts s h o ul d be perf or me d): 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts). L ocal plat elet c o u nts ma y be re p eate d as nee de d ; 
a n d 
o  Ser u m c he mistr y  


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6. 2. 2  
B aseli ne Visit ( Visit 2 , First  D a y [or - 1 D a y] of t he 5 - d a y I n vesti g ati o n al Pr o d uct 
Tre at me nt ) 
T he Bas eli ne Visit ma y occ ur o ne da y pri or t o I P treat me nt, a n d ma y be c o m bi ne d wit h t he 
Scree ni n g Visit.  
Eli gi ble s u bjects will recei ve eit h er a v atr o m b o p a g or place b o o nce dail y f or 5 da ys pri or t o 
C he m ot hera p y D a y i n C ycl e X + 1. T h e f oll o wi n g pr oce d ures will be perf or me d at t he Bas eli ne 
Visit pri or t o I P d osi n g: 
•  C o n d uct eli gi bilit y assess me nt base d o n i ncl usi o n/e x cl usi o n criteria;  
•  C o ntact I R T t o r a n d o mize t he s u bject; 
•  Perf or m I nter na ti o nal S ociet y o n T hr o m b osis a n d Hae m ostasis (I S T H) bl ee di n g assess me nt 
(see A p p e n d i x D); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m s y m pt o m -dir ect e d p h ysical e x a mi nati o n (if n ot pre vi o usl y p erf or me d wit hi n 1 wee k 
of Bas eli ne Visit);  
•  Rec or d vital si g ns  (i ncl u des wei g ht, b o d y te m perat ure, bl o o d press ure, a n d p ulse rate). O nl y 
Scree ni n g vital si g ns will be rec or de d if c o m bi ne d wit h t he Scree ni n g Visit ; 
•  C ollect bl o o d sa m ples f or t he f oll o wi n g asses s me nts: 
o  He mat ol o g y (i ncl u di n g platelet c o u nts);  
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Perf or m pre g n a nc y test (ser u m or uri ne) f or fe mal e s u bjects of c hil d beari n g p ote ntial o nl y; 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e;  
•  Dis pe nse I P;  
•  Dis pe nse d osi n g di ar y; a n d 
•  A d mi nister or self -d ose I P  wit h f o o d , if t he Baseli ne Visit occ urs  o n t he first da y of t he 5 -da y 
I P treat me nt. 
6. 2. 3  
Pre - C he m ot her a p y I n v esti g ati o n al Pr o d uct Tre at me nt ( Visit 3, L ast D a y of t he 
5- d a y I n vesti g ati o n al Pr o d uct Tre at me nt) 
T he f oll o wi n g pr oce d ures will be p erf or m e d o n t he last da y of t he 5 -da y pre -c h e m ot hera p y I P 
treat me nt at Visit 3: 
•  C o ntact I R T;  
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  


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•  C ollect bl o o d sa m ples f or t he f oll o wi n g a ssess me nts: 
o  He mat ol o g y (i ncl u di n g platelet c o u nts); a nd 
o  P K sa m pli n g at pre - d ose ( wit hi n 3 0 mi n utes of I P d osi n g) a n d 0. 5 t o 2, 2 t o 4, a n d 4 t o 
6 h o urs p ost - d ose. Eac h sa m ple m ust be c ollecte d at least o ne h o ur a part fr o m a djace nt 
sa m ples. 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e; 
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n; 
•  A d mi nister I P  i n t he cli ni c wit h f o o d after t he first P K sa m pli n g;  
•  Re vie w d osi n g diar y; a n d 
•  C ollect u n use d I P, if a p plica ble. 
6. 3  
D o u ble -Bli n d Tre at me nt Peri o d  ( C y cle X + 1) 
6. 3. 1  
C he m ot her a p y D a y ( Visit 4, C ycle X + 1 D a y 1 t o 3) 
T he f oll o wi n g pr oce d ures will be perf or me d o n C ycle X + 1 , Da y 1  at Visit 4 pri or t o c he m ot hera p y 
d osi n g: 
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D ); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e  e ve nts;  
•  Perf or m s y m pt o m-dir ect e d p h ysical e x a mi nati o n; 
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate);  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); a n d  
o  Ser u m c he mistr y;  
•  Assess c he m ot her a p y d ose  m o dificati o ns /sc he d ul e; a n d  
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n. 
T he f oll o wi n g pr o ce d ures will be perf or me d p ost- c he m ot hera p y d osi n g (t h ese pr o ce d ures will be 
perf or me d o n t h e last C he m ot hera p y D a y of t he c ycl e): 
•  Dis pe nse I P; a n d  
•  Dis pe nse d osi n g di ar y. 
6. 3. 2  
P ost - C he m ot her a p y In v esti g ati o n al Pr o d uct T re at me nt ( Visit 5) 
S u bjects will als o recei ve a vatr o m b o pa g or pl ace b o o nce dail y f or 5 da ys i m me diatel y f oll o wi n g 
C he m ot hera p y Da y . T h e f oll o wi n g pr o ce d ures will be perf or me d  o n t he last da y of t he 5 -da y 
p ost- c he m ot hera p y I P tr eat me nt at Visit 5:  
•  C o ntact I R T;  


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•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D ); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  He mat ol o g y (i ncl u di n g platelet c o u nts); a n d  
o  Ser u m C he mistr y;  
o  C oa g ulati o n; a n d  
o  P K sa m pli n g at pre - d ose ( wit hi n 3 0 mi n utes of I P d osi n g) a n d 0. 5 t o 2, 2 t o 4, a n d 4 t o 
6 h o urs p ost - d ose. Eac h sa m ple m ust be c ollecte d at least o ne h o ur a part fr o m a djace nt 
sa m ples. 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e;  
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n; 
•  A d mi nister I P i n t he cli ni c wit h f o o d after t he first P K sa m pli n g;  
•  Re vie w d osi n g diar y; a n d 
•  C ollect u n use d I P, if a p plica ble. 
6. 3. 3  
C ycle X + 1 D a ys 1 1 ( ± 1 d a y), 1 5 ( ± 1 d a y) , a n d 1 8 (± 1 d a y) ( Visits 6, 7, a n d 8 ) 
T he f oll o wi n g pr o ce d ures will be perf or m e d o n C ycl e X + 1 , Da y s 1 1, 1 5, a n d 1 8 at Visit s 6, 7, 
a n d 8: 
•  Rec or d c o n c o mita nt me dicati o ns ; 
•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or platelet c o u nts ; 
•  Assess c he m ot her a p y d ose m o dif icati o ns/sc he d ul e; a n d  
•  Assess w het her s u bjec t r e q uire d platelet tra nsf usi o n. 
6. 4  
O bser v ati o n al Peri o d ( C ycle X + 2) 
If C he m ot her a p y D a y i n C ycl e X + 2 is del a ye d, rec or d t h e reas o n f or d ela y i n t he e C R F. If t he 
dela y is d ue t o la b orat or y res ults, rec or d t he rel eva nt res ults i n t he e C R F. 
6. 4. 1  
C he m ot her a p y D a y i n C ycle X + 2 ( Visit 9) 
T he  f oll o wi n g  pr o ce d ur es  will  be  perf or me d  o n C ycl e  X  +  2 , Da y  1  at  Visit 9 pri or  t o  
c he m ot hera p y d osi n g: 
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 
•  Rec or d c o n c o mita nt me dicat i o ns; 
•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale;  


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•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts pri or t o c he m ot hera p y d osi n g: 
o  He mat ol o g y (i ncl u di n g plat elet c o u nts);  
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e; a n d  
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n. 
6. 4. 2  
C ycle X + 2 D a ys 1 1 ( ± 1 d a y), 1 5 ( ± 1 d a y) , a n d 1 8 (± 1 d a y) ( Visits 1 0, 1 1, a n d 1 2) 
T he f oll o wi n g pr oce d ures will be perf or me d o n C ycl e X + 2 , Da y s 1 1, 1 5, a n d 1 8 at Visits 1 0, 1 1, 
a n d 1 2: 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  Platelet c o u nts ; 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e; a n d  
•  Assess w het her s u bject r e q uire d platelet tra nsf us i o n. 
6. 4. 3  
F oll o w- U p Visit  ( F o r s u bjects n ot c o nti n ui n g i nt o t he o pti o n al O pe n-L a bel 
E xte nsi o n Peri o d)   
6. 4. 3. 1  
Pri or t o C he m ot her a p y D a y i n C ycle X + 3 ( Visit 1 7) 
F or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E Peri o d, a F oll o w -U p Visit will occ ur pri or t o 
(wit hi n 3 da ys)  C he m ot hera p y  Da y  i n  C ycle  X  +  3.  If  C ycle  X  +  2  is  t he  s u bject’s  last  
c he m ot hera p y c ycl e, a F oll o w -U p Visit will occ ur at 3 0 da ys ( ± 3 da ys) aft er C he m ot hera p y Da y 
i n C ycle X + 2.  S u bjects will c o m plete Visit 1 7 pr oce d ures i n  Secti o n  6. 5. 5 . 
6. 5  
O pti o n al O pe n - L a bel E xte nsi o n Peri o d ( C ycle X + 3 a n d O n) 
6. 5. 1  
Pre - C he m ot her a p y A v atr o m b o p a g Tre at me nt ( Visit 1 3) 
S u bjects  will  recei ve  a vatr o m b o pa g  o nce  d ail y  f or  5  da ys  pri or  t o  C he m ot hera p y  Da y  i n  
C ycle  X + 3 ( Visit 1 3). F or C ycl e X + 4, t his visit will be de n ote d Visit 1 3. 1 a n d f or C ycle X + 5, 
t his visit will be de n ote d Visit 1 3 . 2. T his n u m beri n g sc h e me will c o nti n ue f or s u bse q ue nt e nr olle d 
o pe n- la bel c ycles.  
T he f oll o wi n g pr o ce d ur es will be  perf or me d o n t he first d a y of  pre -c he m ot hera p y a vatr o m b o pa g 
treat me nt at Visit 1 3 pri or t o a vatr o m b o pa g d osi n g: 
•  C o n d uct eli gi bilit y assess me nt base d o n O L E  i ncl usi o n/e x cl usi o n criteria; 
•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale;  


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•  C o ntact I R T;  
•  Perf or m I S T H blee di n g as sess me nt (see A p p e n d i x D); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate);  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts pri or t o I P d osi n g: 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); 
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Perf or m pre g n a nc y test ( uri ne  or ser u m ) f or fe mal e s u bjects of c hil d beari n g p ote ntial o nl y; 
•  Assess c he m ot her a p y d ose  m o dificati o ns /sc he d ul e; 
•  Assess w het her s u bject r e q uire d platel et tra nsf usi o n; 
•  Dis pe nse a vatr o m b o pa g;  
•  A d mi nister or self - d ose a vatr o m b o pa g wit h f o o d. 
6. 5. 2  
C he m ot her a p y D a y ( Visit 1 4, C ycle X + 3 D a y 1 t o 3) 
F or C ycle X + 4, t his visit will be de n ote d Visit 1 4 . 1 a n d f or C ycle X + 5, t his visit will be de n ote d 
Visit 1 4. 2. T his n u m beri n g sc h e me will c o nti n ue f or s u bse q ue nt e nr olle d o pe n- la bel c ycles.  
T he  f oll o wi n g  pr oce d ur es  will  be  perf or me d  o n  C ycl e  X  +  3 , Da y 1 at Visit 1 4 pri or  t o  
c he m ot hera p y d osi n g: 
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m s y m pt o m-dir ect e d p h ysical e x a mi nati o n;  
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate);  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts) 
•  Assess c he m ot her a p y d ose  m o dificati o ns /sc he d ul e; 
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n; a n d 
•  C ollect u n use d a vatr o m b o pa g , if a p plica ble. 
T he f oll o wi n g pr o ce d ures will be perf or me d o n p ost- c he m ot hera p y d osi n g  (t hese pr oce d ures will 
be perf or me d o n t he last C he m ot hera p y Da y of t he c ycle) : 
•  Dis pe nse a vatr o m b o pa g 


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6. 5. 3  
P ost - C he m ot her a p y A v atr o m b o p a g Tre at me nt  ( Visit 1 5) 
F or C ycle X + 4, t his visit will be de n ote d Visit 1 5. 1 a n d f or C ycle X + 5, t his visit will be de n ote d 
Visit 1 5. 2. T his n u m beri n g sc h e me will c o nti n ue f or s u bse q ue nt e nr olle d o pe n- la bel c ycles.  
T he f oll o wi n g pr oce d ur es will be perf or me d o n t he last da y of t he 5-d a y p ost -c he m ot hera p y 
a vatr o m b o pa g tr eat me nt at Visit 1 5: 
•  C o ntact I R T;  
•  Perf or m I S T H blee di n g a ssess me nt (see A p p en di x D) ; 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); 
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e;  
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n; 
•  A d mi nister or self - d ose a vatr o m b o pa g wit h f o o d; a n d 
•  C ollect u n use d a vatr o m b o pa g , if a p plica ble. 
6. 5. 4  
C ycle X + 3  D a y 1 5 (± 1 d a y)  ( Visit 16) 
F or C ycle X + 4, t his visit will be de n ote d Visit 1 6. 1 a n d f or C ycle X + 5, t his visit will be de n ote d 
Visit 1 6. 2. T his n u m beri n g s c he me will c o nti n ue f or s u bse q u e nt e nr olle d o pe n -la bel c ycles. T he 
f oll o wi n g pr o ce d ur es will be perf or m e d o n C ycle X + 3 , Da y 1 5 at Visit 1 6: 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 
•  C ollect bl o o d sa m ple s f or platelet c o u nts; 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e;  a n d  
•  Assess w het her s u bjec t r e q uire d platelet tra nsf usi o n. 
6. 5. 5  
F oll o w- U p Visit  
6. 5. 5. 1  
T hi rt y da ys after last a vatr o m b o pa g d ose ( Visit 17) i n t he O L E Peri o d 
T he f oll o wi n g pr oce d ures will be perf or m e d 3 0 d a ys (± 3 d a ys) after last a vatr o m b o pa g d ose at 
Visit 1 7: 
•  C o ntact I R T;  
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 


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•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale; 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m f ull p h ysical e x a mi nati o n; 
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate);  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts:  
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); 
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Perf or m pre g n a nc y test ( uri ne) f or fe male s u bj ects of c hil d beari n g p ote ntial o nl y; a n d  
•  Assess w het her s u bjec t r e q uire d platelet tra nsf usi o n. 
6. 6  
E arl y Ter mi n ati o n Visit a n d Wit h dr a w al Pr oce d ures  
F or s u bjects w h o are wit h dra w n fr o m t he st u d y pri or t o t he F oll o w -U p Visit , all Visit 1 3 (f or 
s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E Peri o d) or Visit 1 7 (f or s u bjects c o nti n ui n g i nt o t he 
o pti o nal  O L E  Peri o d)  pr oce d ur es  will  be  perf or me d  at  a n  Earl y  Ter mi nati o n  Visit.  T hese  
pr oce d ur es i ncl u de t he f oll o wi n g: 
•  C o ntact I R T;   
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D ); 
•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale;  
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m f ull p h ysical e x a mi nati o n; 
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate); 
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts:  
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); 
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Perf or m pre g n a nc y test ( uri ne) f or fe male s u bj ects of c hil d beari n g p ote ntial o nl y; 
•  Assess w het her s u bjec t r e q uire d platelet tra nsf usi o n; a n d 
•  C ollect u n use d I P, if a p p lica ble. 


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6. 7  
L o n g- Ter m F oll o w -U p  
After t he F oll o w -U p Visit, all s u bjects will be c o ntacte d a p pr o xi matel y e ver y 6 m o nt hs f or u p t o 
5 years b y tele p h o n e d uri n g t he L o n g -T er m F oll o w -U p Peri o d f or d o c u me ntati o n of vital stat us (if 
deat h occ urre d, rec or d of date of  deat h) a n d occ urre nce of sec o n d ar y mali g n a ncies.  If a sec o n d ar y 
mali g na n c y h as occ urre d , t he f oll o wi n g i nf or mati o n will be c ollecte d: date of o nset a n d t y pe of 
mali g na n c y, as w ell as a writte n narr ati ve fr o m t he cli nical site s u m marizi n g t he c o urs e of e ve nts 
lea di n g u p t o dia g n osis of t he sec o n d ar y mali g na n c y. 


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7  
E F FI C A C Y A S S E S S M E N T S  
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all of t he f oll o wi n g criteria  
d uri n g t he p eri o d after p ost -c he m ot hera p y I P treat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y D a y  
of C ycl e X + 2 : 
•  N ot re q uiri n g a platel et tra nsf usi o n; 
•  N ot re q uiri n g a c h e m ot hera p y d ose re d ucti o n b y ≥1 5 % d ue t o t hr o m b oc yt o pe nia; a n d 
•  N ot re q uiri n g a c h e m ot hera p y del a y b y ≥4 da ys d ue t o t hr o m b oc yt o p e nia. 
T he ke y sec o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  D urati o n of s e ver e t hr o m b oc yt o p e nia defi ne d as a platelet c o u nt < 5 0 ×  1 09/ L d uri n g t he p eri o d 
after p ost -c he m ot her a p y I P tr eat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y Da y  of C ycl e X + 2 ; 
•  C ha n ge i n platelet c o u nt fr o m baseli ne ( q ualif yi n g c he m ot hera p y c ycle [ C ycl e X]) ( n a dir) t o 
C ycle X + 1 ( n a dir);  
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve maj or or n o n- maj or cli nical l y rele v a nt blee di n g d uri n g 
t he peri o d after p ost -c h e m ot hera p y I P treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y Da y  of 
C ycle X + 2 ; a n d  
•  Pr o p orti o n of s u bjects w h o d o n ot recei ve a platelet tra nsf usi o n d uri n g t he peri o d after p ost -
c he m ot hera p y I P tr eat me nt i n C ycle X + 1 thr o u g h  C he m ot hera p y Da y  of C ycl e X + 2 . 
T he ot her efficac y e n d p oi nts i ncl u de t he f oll o wi n g  d uri n g t he peri o d after p os t-c he m ot hera p y I P 
treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y D a y of C ycle X + 2 : 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c h e m ot hera p y d ose re d ucti o n t h at is ≥1 5 % d ue t o 
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n  of  s u bjects  w h o  d o  n ot  ha ve  a  c he m ot hera p y  dela y  t hat  is  ≥4 da ys  d ue  t o  
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n of s u bjects wit h a pre -d efi ne d p ost- bas eli ne na dir platelet c o u nt; a n d  
•  Pr o p orti o n of s u bjects ac hie vi n g a pre -d efi ne d p ost- baseli ne ma xi m u m platelet c o u nt  
Bl o o d  sa m ples  t o  assess  platelet  c o u nt  will be c ollecte d  a s i n dicate d  i n  A p pe n di x  A . L o cal  
la b orat ories ma y  b e use d t o deter mi ne st u d y eli gi bilit y; h o we ver, f or st u d y a nal ysis a n d re p orti n g 
p ur p oses, o nl y v al ues d eter mi ne d at a ce ntral la b orat or y will be use d wit h t h e e x ce pti o n of pl atelet 
c o u nt. L o cal la b or at ories ma y b e use d if i m me diat e res ults are cli nicall y nee de d.   
W het her a s u bject  re q uir es a platelet tra nsf usi o n will be deter mi ne d b y t h e I n v esti gat or or treati n g 
p h ysicia n.  
Blee di n g will be e val uat e d b y t h e I n v esti gat or usi n g t he n o n-s ur gical I S T H blee di n g defi niti o ns 
descri be d i n A p p e n di x D . 


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P H A R M A C O KI N E TI C A N D P H A R M A C O D Y N A MI C A S S E S S M E N T S  
8. 1  
P h ar m a c o ki netic Assess me nts  
Bl o o d sa m ples f or P K a n al ysis will be c ollecte d as i n dicate d i n A p pe n di x A . A d diti o nal ti me p oi nts 
ma y b e c o llecte d as necessar y.  
P har mac o ki netic sa m pli n g will occ ur t wice d uri n g t he st u d y wit h 4 sa m ples c ollecte d o n e ac h da y.  
8. 2  
P h ar m a c o d y n a mi c Ass ess me nts  
Bl o o d s a m ples f or P D a n al ysis will be c ollecte d as i n dicate d i n A p pe n di x A.  
P har mac o d y na mic s a m ples (ie, platele t c o u nts) will be c ollecte d t hr o u g h o ut eac h c ycle of t he 
st u d y i ncl u di n g C ycl e X + 1, C ycl e X + 2, a n d eac h e nr olle d o pe n-l a bel c ycle. 
 


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S A F E T Y A S S E S S M E N T S  
9. 1  
A d verse E ve nts  
A n a d verse e v e nt is defi ne d as a n y u nt o w ar d m e dical occ urre nce i n a s u bject a d mi nister e d a 
p har mace utical pr o d u ct, w hic h d oes n ot n ecess aril y h a ve a ca usal relati o ns hi p wit h t his treat me nt. 
A n a d verse e ve nt ca n t h eref or e be a n y u nfa v ora ble a n d/ or u ni nte n d e d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass o ciate d wit h t he us e of a n i n vesti gati o nal 
me dici nal pr o d uct, w het her or n ot rel ate d t o t he i n vesti gati o nal me dici n al pr o d uct. All a d vers e 
e ve nts, i ncl u di n g o bs er ve d or v ol u nteere d pr o ble ms, c o m plai nts, or s y m pt o ms, are t o be rec or de d 
o n t he a p pr o priat e e C RF. 
A d verse  e v e nts,  w hic h  i ncl u de  cli nical  la b orat or y  test  varia bles,  will  be  m o nit ore d  a n d  
d oc u me nte d fr o m t he ti me of i nf or me d c o ns e nt u ntil t he F oll o w- U p Visit occ urri n g pri or t o (wit hi n 
3 da ys)  C he m ot hera p y Da y i n C ycle X + 3 (f or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E 
Peri o d) a n d t he F oll o w- U p Visit occ urri n g 3 0 da ys aft er last d ose of I P (f or s u bjects c o nti n ui n g 
i nt o t he o pti o nal O L E Peri o d). S u bjects s h o ul d b e i nstr ucte d t o re p ort a n y a d verse e ve nt t h at t he y 
e x perie nce t o t he I n vesti gat or. Be gi n ni n g wit h t he Scree ni n g Visit, In vesti gat ors s h o ul d ma ke a n 
assess me nt f or a d verse e ve nts at e ac h visit a n d rec or d t he e ve nt o n t he a p pr o priate a d verse e ve nt 
e C R F. E ve nts ass o ciate d wit h d isease pr o gressi o n s h o ul d n ot be re p orte d as a d verse e ve nts/S A E s. 
H o we ver, if i n t he I n vesti gat or’s o pi ni o n t he disease pr o gressi o n is ma nifesti n g i n a n u n us ual o r 
u nc haracteristic ma n n er, t he ass ociate d e ve nts s h o ul d be re p orte d as a d verse e v e nts/ S A Es, as 
a p pr o priate. 
W here ver p ossi ble, a s p ecific diseas e or s y n dr o me (ie, dia g n osis) rat her t ha n i n di vi d ual ass ociate d 
si g ns a n d s y m pt o ms s h o ul d be i de ntifie d b y t he In vesti gat or  a n d rec or de d o n t he e C R F.  H o w e ver, 
if a n o bser ve d or re p orte d si g n or s y m pt o m is n ot c o nsi dere d a c o m p o ne nt of a s pecific disease or 
s y n dr o me b y t he I n v esti gat or, it s h o ul d be rec or de d as a s e parate a d vers e e ve nt o n t he e C R F. 
A d diti o nall y, t he c o n diti o n t hat le d t o a me dical or s ur gical pr o ce d ure ( e g, s ur ger y, e n d os c o p y, 
t o ot h e xtracti o n, or tra nsf usi o n) s h o ul d be rec or de d as a n a d verse e v e nt, n ot t he pr oce d ure.  
A n y me dical  c o n diti o n alrea d y pr ese nt at t he S cree ni n g Visit  s h o ul d n ot be re p orte d as a n a d v ers e 
e ve nt u nless t he me dical c o n diti o n or si g ns or s y m pt o ms prese nt at baseli ne c ha n ges i n se verit y, 
fre q ue n c y, or seri o us ness at a n y ti me d uri n g t h e st u d y. I n t his case, it s h o ul d be re p orte d as a n 
a d verse e ve nt.  
Cli nicall y si g nifica nt a b n or mal  la b orat or y or ot her e x a mi nati o n fi n di n gs t hat are det ecte d d uri ng 
t he st u d y or are prese nt at t he Scree ni n g Visit a n d si g nifica ntl y w ors e n d uri n g t he st u d y s h o ul d be 
re p orte d  as  a d v erse  e ve nts.  T he  I n vesti gat or will  e x ercise  his  or  her  me dical  a n d  s cie nti fic 
j u d g me nt i n deci di n g w het her a n a b n or m al la b orat or y fi n di n g or ot her a b n or mal assess me nt is 
cli nicall y  si g nifi ca nt.  Cli nicall y  si g nifica nt  a b n or mal  la b orat or y  val u es  occ urri n g  d uri n g  t he  
cli nical st u d y will be f oll o we d u ntil re peat tests ret ur n t o n or m al, sta bilize, or are n o l o n ger 
cli nicall y si g nifica nt. La b orat or y a b n or malities are n ot c o nsi dere d a d vers e e ve nts u nless t he y are 
ass ociate d wit h cli nical si g ns  or s y m pt o ms, or re q uire me di cal i nter v e nti o n. A n y a b n or mal test 
t hat is deter mi ne d t o be a n err or d o es n ot re q uire re p orti n g as a n a d v erse e v e nt. 
Cli nicall y  si g nifica nt a b n or mal fi n di n gs i n p h ysical e x a mi nati o ns will be re p ort e d as a d v erse 
e ve nts. 


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9. 1. 1  
Assess m e nt of A d verse E ve nts b y t he I n vesti g at or 
T he I n v esti gat or will assess t he s e verit y (i nte nsit y) of eac h a d vers e e ve nt a n d will als o cate g orize 
eac h a d vers e e ve nt as t o its p ote ntial relati o ns hi p t o I P usi n g t he cate g ories of yes or n o. 
Assess me nt of Se veri t y: 
T he se verit y of all a d verse e v e nts s h o ul d be gra de d acc or di n g t o t he C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E v e nts ( C T C A E). F or t h ose a d vers e e ve nts n ot liste d i n t he C T C A E, t he 
f oll o wi n g gr a di n g s yste m s h o ul d be use d: 
•  Mil d ( C T C A E Gra de 1): Tra nsie nt s y m pt o ms, a ware ness of si g n/s y m pt o m, b ut easil y t olerate d 
a n d n o i nterfere nce wit h s u bject’s dail y acti vities.  
•  M o derate  ( C T C A E  Gr a de  2):  Mar k e d  si g ns/s y m pt o ms  t hat  i nterfere  wit h  s u bject’s  us ual  
acti vities, b ut still acce pta ble.  
•  Se vere  ( C T C A E  Gr a de  3):  I nca pacitati n g  si g ns/s y m pt o ms  w hi c h  ca use  c o nsi dera ble  
i nterfer e nce wit h t he s u bject’s dail y acti vities, u nacce pta bl e.  
•  Lif e -t hreate ni n g (C T C A E Gra de 4): Life -t hreate ni n g or disa bli n g a d v erse e ve nt. 
•  Deat h ( C T C A E Gr a de 5):  Deat h -r elate d a d v erse e ve nt. 
Ca usalit y Assess me nt : 
T he relati o ns hi p of a n a d verse e ve nt t o t he a d mi nistrati o n of t he I P is t o be assesse d acc or di n g t o 
t he f oll o wi n g defi niti o ns: 
•  N o ( u nrelate d, n ot relate d, n o relati o n) – T he ti me c o urse bet wee n t he a d mi nistrati o n of I P a n d 
t he occ urr e nce or w orse ni n g of t he a d vers e e ve nt r ules o ut a ca usal relati o nshi p a n d a n ot her 
ca use ( c o nc o mita nt dr u gs, t hera pies, c o m plicati o ns, etc.) is s us pecte d. 
•  Yes (r elate d) – T he ti m e c o urs e bet wee n t he a d mi nistrati o n of I P a n d  t he occ urre n ce or 
w orse ni n g of t he a d vers e e v e nt is c o nsiste nt wit h a ca usal relati o ns hi p a n d n o ot her ca us e 
(c o nc o mita nt dr u gs, t her a pies, c o m plicati o ns, etc.) ca n be i d e ntifie d. 
T he defi niti o n i m plies a reas o na bl e p ossi bilit y of a ca usal relati o ns hi p bet wee n t h e e ve nt a n d t he 
I P. T his mea ns t hat t here are f acts ( e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p. 
T he f oll o wi n g fact ors s h o ul d als o be c o nsi dere d: 
•  T he te m p oral se q u e nce fr o m I P a d mi nistrati o n - 
o  T he e ve nt s h o ul d occ ur after t he I P is gi ve n. T h e le n gt h of ti me fr o m I P e x p os ure t o e ve nt 
s h o ul d be e val uate d i n t h e cli nical c o nte xt of t he e ve nt. 
•  U n derl yi n g, c o nc o mita nt, i nterc urr e nt diseases- 
o  Eac h re p ort s h o ul d be e val uate d i n t he c o nte xt of t he nat ural hist or y a n d c o urse of t he 
disease bei n g treate d a n d a n y ot h er diseas e t he s u bject ma y ha ve.  
•  C o nc o mita nt dr u g- 
o  T he ot her dr u gs t he s u bject is ta ki n g or t he treat me nt t he s u bject recei ves s h o ul d be 
e x a mi ne d t o deter mi ne w het her a n y of t he m mi g ht be rec o g nize d t o ca use t he e ve nt i n 
q uesti o n. 


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•  K n o w n res p o nse p atter n f or t his class of I P- 
o  Cli nical a n d/ or precli nical data ma y i n dicate w het h er a partic ul ar res p o nse is li kel y t o b e a 
class eff ect.  
•  E x p os ure t o p h ysi cal a n d/ or me ntal stresses - 
o  T he e x p os ure t o str ess mi g ht i n d uce a d v erse c ha n ges i n t he reci pie nt a n d pr o vi de a l o gical 
a n d better e x pl a nati o n f or t he e ve nt. 
•  T he p har mac ol o g y a n d P K  of t he I P- 
o  T he k n o w n p h ar mac ol o gi c pr o perties (a bs or pti o n, distri b uti o n, meta b olis m, a n d e x creti o n) 
of t he I P s h o ul d b e c o nsi dere d. 
9. 1. 2  
A d verse E ve nts of S peci al I nterest  
T he I n vesti gat or will m o nit or eac h s u bject  f or cli nical a n d la b orat or y e vi de nce f or pre-d e fi ne d 
A E SI t hr o u g h o ut t heir p artici pati o n i n t his st u d y. T he p ur p ose f or s pecif yi n g t hes e A E SI is t o 
e na ble f urt her c haracteri zati o n of t he cli nical c o urse a n d ma na ge m e nt of t hese e ve nts. A n A E SI 
ma y or m a y n ot be t he c o nse q ue nce of treat me nt wit h a vatr o m b o pa g. 
T he A E SI defi n e d i n t his pr ot oc ol i ncl u de: 
•  T hr o m b oe m b olic e ve nts (a n y t hr o m b otic or e m b olic e ve nt, w het her arterial or ve n o us); a n d  
•  Blee di n g e v e nts (a n y cli nica ll y si g nifica nt bl o o d l oss). 
T hese e ve nts will be rec or de d i n t he a d verse e ve nt e C R F pa ge.  T he I n v esti gat or will assess a n d 
rec or d a n y a d diti o nal i nf or mati o n o n t he A E SI i n detail o n a S A E f or m ( w het her or n ot t he e ve nt 
meets seri o us ness criteria i n Secti o n 9. 3 ), t o be s u b mitte d wit hi n 2 4 h o urs of a ware ness of t he 
e ve nt. D uri n g t he c o urse of t he st u d y, a d diti o nal A E SI ma y b e i de ntifie d b y t he S p o ns or. 
9. 1. 3  
Effic ac y E n d p oi nts 
E fficac y e n d p oi nts, as descri be d i n Secti o n 7 , s h o ul d n ot be re p orte d as a d verse e v e nts u nless i n 
t he  o pi ni o n  of  t he  I n vesti gat or  t he  e ve nt  is  ca usall y  ass o ciate d  wit h  t he  I P.  F or  e x a m ple,  
t hr o m b oc yt o pe ni a, platel et tra nsf usi o ns f or t hr o m b oc yt o p e nia, a n d c he m ot hera p y d ose re d ucti o ns 
or dela ys s h o ul d n ot be re p orte d as a d verse e ve nts; h o we ver, cli nical l y si g nifica nt blee di n g e ve nts 
(a sec o n d ar y e n d p oint) s h o ul d be al wa ys be re p orte d as a n A E SI.  
9. 2  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E ve nts  
A d verse e ve nts will be re p orte d b y t he s u bject ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or 
t he partici pa nt's le gall y a ut h orize d re prese nt ative). Care will be ta ke n n ot t o i ntr o d uce bias w he n 
detecti n g a d v erse e ve nts a n d/ or S A Es. O p e n -e n d e d a n d n o n -lea di n g v er b al q uesti o ni n g of t he 
partici pa nt is t he preferre d met h o d t o i n q uire a b o ut a d verse e ve nt occ urre nces. 


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9. 3  
Seri o us A d verse E ve nt s 
A n a d vers e e v e nt or a d verse reacti o n is c o nsi dere d seri o us if, i n t he vie w of eit her t he I n vesti gat or 
or S p o ns or, it res ults i n a n y of t he f oll o wi n g o ut c o mes: 
•  D eat h, 
•  A life -t hreate ni n g a d vers e e ve nt, 
o  N O T E: A n a d verse e ve nt or a d vers e reacti o n is c o nsi dere d  “life-t hreate ni n g” if, i n vi e w of 
eit her t he I n vesti gat or or S p o ns or, its occ urre n ce places t he s u bject at i m me diate ris k of 
deat h. It d o es n ot i n cl u de a n e ve n t t hat, ha d it o cc urre d i n a m ore s e vere f or m, mi g ht h a ve 
ca use d deat h.  
•  Re q uires h os pitalizati o n  or pr ol o n gati o n of e xisti n g h os pitalizati o n, 
o  N O T E: A n y h os pital a d missi o n e ve n if a d mitte d a n d disc h ar ge d t he s a me da y  will be 
c o nsi dere d  a n  i n patie nt  h os pitalizati o n.  A n  e mer ge nc y  r o o m  visit  wit h o ut  h os pital  
a d missi o n will n ot be r ec or de d as a n S A E  u n d er t his criteri o n, n or will h os pitalizati o n f or 
a  pr o ce d ur e  sc h e d ule d  or  pla n n e d  b ef ore  si g ni n g  of  i nf or m e d  c o nse nt.  H o we v er,  
u ne x pecte d c o m plicati o ns a n d/ or pr ol o n gati o n of h os pitalizati o n t hat occ ur d uri n g electi ve 
s ur ger y s h o ul d be rec or d e d as a d verse e vent s a n d assesse d f or seri o us n ess. A d missi o n t o 
t he h os pital f or s o cial or sit uati o nal reas o ns (i e, n o place t o st a y, li ve t o o far a wa y t o c o me 
f or h os pital visits) will n ot be c o nsi dere d i n p atie nt h os pitalizati o ns.  
•  A  persiste nt  or  si g nifica nt  disa bilit y/i nca p acit y  or  s u bsta ntial  disr u pti o n  of  t he  a bilit y t o  
c o n d uct n or mal life f u n cti o ns, 
•  A c o n ge nital a n o mal y/ birt h defect , 
•  A n i m p orta nt me dical e v e nt, or 
o  N O T E: I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life -t hreate ni n g, or re q uire 
h os pitalizati o n  ma y  b e  c o nsi dere d  a n  S A E  w he n,  base d  u p o n  a p pr o priate  me dical  
j u d g me nt, t he y ma y j e o p ar dize t he s u bject or ma y re q uire me dical or s ur gi cal i nter v e nti o n 
t o pre ve nt o ne of t he o utc o mes liste d a b o ve. E x a m ples of s uc h me dical e ve nts i ncl u de 
aller gic br o nc h os p as m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, 
bl o o d d yscr asias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o ns, or t he 
de vel o p me nt of dr u g d e p e n de nc y. 
•  A n y s us pecte d tr a ns missi o n via a me dici nal pr o d u ct of a n i nfecti o us a ge nt. 
9. 4  
Seri o us A d verse E ve nt Re p orti n g − Pr oce d ures f or I n vesti g at ors  
I nitial Re p orts: 
All S A Es occ urri n g fr o m  t he ti me of i nf or me d c o nse nt u ntil pri or t o ( wit hi n 3 da ys) C he m ot hera p y 
Da y i n C ycle X + 3 (f or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E Peri o d) a n d 3 0 da ys 
f oll o wi n g t he last a dmi nistrati o n of I P (f or s u bjects c o nti n ui n g i nt o t he o pti o nal O L E Peri o d) m ust 
be re p orte d wit hi n 2 4 h o urs of t he k n o wle d ge of t he occ urre nce (t his refers t o a n y a d v erse e v e nt 
t hat meets a n y of t h e af ore me nti o ne d s eri o us criteria). All S A Es  t hat t he I n vesti gat or b ec o mes 
a war e of a n d c onsi ders r elate d t o I P occ urri n g after t he 3 0 -da y F oll o w- U p Peri o d  m ust be re p orte d 
t o t he S p o ns or. 


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T o re p ort t he S A E, c o m plete t he S A E Re p ort F or m a n d fa x or e m ail as i nstr ucte d o n t he f or m . It 
is ver y i m p orta nt t hat t h e f or m b e fille d o ut as c o m pletel y as p ossi ble at t he ti me of t he i nitial 
re p ort. T his i ncl u des t he I n v esti gat or’s assess me nt of ca usalit y. Preli mi nar y S A E re p orts s h o ul d 
be f oll o we d as s o o n as p ossi ble b y d etaile d des cri pti o ns i ncl u di n g c o pies of h os pital disc ha r ge 
s u m maries, a ut o ps y re p orts, a n d ot her d oc u me nts re q ueste d b y t h e S p o ns or or desi g nee. T he 
I n v esti gat or  m ust  n otif y  his/ her  I nstit uti o nal  Re vie w  B o ar d  (I R B)  or  I n de p e n de nt  Et hics  
C o m mittee  (I E C) of t he occ urr e nce of t he S A E, i n writi n g, if re q uire d b y t heir i nstit uti o n. A c o p y 
of t his c o m m u nicati o n m ust be f or war de d t o t he S p o ns or t o be file d i n t he S p o ns or’s Trial Master 
File.  
F oll o w- U p Re p orts: 
T he I n vesti gat or m ust c o nti n ue t o f oll o w t he s u bject u ntil t he S A E has s u bsi de d or u ntil t he 
c o n diti o n bec o me s c hr o nic i n nat ure, sta bilizes (i n t he case of persiste nt i m pair me nt), t he s u bject 
dies , or t he s u bject is l ost t o f oll o w- u p. 
Wit hi n 2 4 h o urs of recei pt of f oll o w -u p i nf or mati o n, t he I n vesti gat or m ust u p date t he S A E Re p ort 
F or m f or t he st u d y a n d s u b mit a n y s u p p orti n g d o c u me ntati o n ( e g, s u bject disc har ge s u m mar y or 
a ut o ps y r e p orts) via fa x or e- mail.  
9. 5  
Pre g n a nc y Re p orti n g  
If t h e s u bject bec o mes pre g na nt d uri n g t he st u d y or wit hi n 3 0 da ys of disc o nti n ui n g I P, t he 
I n v esti gat or will c o m plete  t he P re g na n c y R e p or t F or m wit hi n 2 4 h o urs of bei n g n otifie d   a n d 
f or war d it t o t he S p o ns or.  
A s u bject bec o mi n g pre g na nt w hile o n I P will i m me diatel y be wit h dra w n fr o m t he st u d y a n d earl y 
ter mi nati o n st u d y pr oce d ures will be perf or me d. 
T he s u bject  s h o ul d be f oll o we d b y t h e I nv esti gat or  u ntil c o m pleti o n of t he pre g n a nc y. If t he 
pre g na nc y e n ds f or a n y r eas o n bef ore t h e a ntici pat e d date, t he I n vesti gat or s h o ul d n otif y Saf et y b y 
c o m pleti n g a n d f or w ar di n g t he Pre g n a nc y Re p ort F or m wit h t he u p date d i nf or mati o n wit hi n 
2 4 h o urs of bei n g n otifie d. At t he c o m pleti o n of t he pre g na n c y, t he I n vesti gat or will d oc u me nt t he 
o utc o me of t he pre g na n c y. If t h e o utc o me of t h e pre g n a nc y m eets t he criteria f or i m me diate 
classificati o n as a n S A E ( ie, p ost part u m c o m plicati o n, s p o nta ne o us a b orti o n, still birt h, ne o natal 
deat h, or c o n ge nital a n o mal y), t h e I n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g a n S A E 
a n d als o u p date t he Pr e g na nc y Re p ort F or m. 
9. 6  
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts  
Re g ulat or y re p orti n g r e q uire me nts f or S A Es i ncl u de t he f oll o wi n g: 
•  Pr o m pt n otificati o n b y t he I n vesti gat or t o t he S p o ns or or desi g nee of a n S A E is esse ntial s o 
t hat le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of s u bj ects a n d t he s afet y 
of a st u d y i nter ve nti o n u n der cli nic al i n vesti gati o n are met.  
•  T h e S p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ul at or y a ut h orit y a n d ot her 
re g ulat or y a ge n cies a b o ut t he saf et y of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n. T h e 
S p o ns or or desi g n ee will c o m pl y wit h c o u ntr y- s pecific re g ulat or y re quire me nts relati n g t o 
safet y re p orti n g t o t he re g ulat or y a ut h orit y, I R Bs/I E C, a n d I n vesti gat ors. 


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•  I n v esti gat or safet y r e p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
( S U S A R) acc or di n g t o l ocal re g ulator y re q uire me nts a n d S p o ns or p olic y a n d f or w ar de d t o 
I n v esti gat ors as necessar y. 
•  A n I n vesti gat or w h o recei ves a n I n vesti gat or s afet y re p ort descri bi n g a S U S A R  or ot her 
s pecific saf et y i nf or m ati o n (e g, s u m mar y or listi n g of SU S A R s) fr o m t he S p o ns or will re vie w 
a n d  t he n  file  it  al o n g  wit h  t he  I n vesti gat or’s  Br oc h ure  a n d  will  n otif y  t he  I R B/I E C,  if  
a p pr o priate acc or di n g t o l ocal re q uire me nts. 
9. 7  
Cli nic al L a b or at or y E v al u ati o ns 
Cli nical safet y la b orat or y assess me nts will i ncl u de ser u m c he mistr y, he mat ol o g y, a n d c o a g ulati o n 
a n d will be o btai ne d as i n dicate d i n  A p pe n di x A . See A p pe n di x B  f or a c o m plete list of a nal ytes. 
9. 8  
Vit al Si g ns  
Vital si g n meas ure me nts will i ncl u de hei g ht (at t h e Scree ni n g Visit o nl y), we i g ht ( Scree ni n g a n d 
Baseli ne Visits o nl y) , b o d y te m perat ure ( Scree ni n g a n d Bas eli ne Visits o nl y), bl o o d press ure, a n d 
p ulse rate , a n d will be meas ure d after resti n g f or 5  mi n utes as i n dicate d i n  A p pe n di x A . 
9. 9  
P h ysic al E x a mi n ati o ns  
P h ysical e x a mi nati o ns will c o nsist of t he f oll o wi n g: ge neral a p peara n ce, hea d a n d nec k, e yes a n d 
ears, n os e a n d t hr oat, c h est, l u n gs, heart, a b d o m e n, e xtre mities a n d j oi nts, l y m p h n o des, s ki n, a n d 
ne ur ol o g y. F ull a n d s y m pt o m -directe d p h ysical e x a mi nati o ns w ill be perf or me d as i n dicate d i n 
A p pe n di x A . 


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S T A TI S TI C S  
1 0. 1  
A n al ysis P o p ul ati o ns 
F ull A nal ysis Set ( F A S): T he F A S will i ncl u de all ra n d o mize d s u bjects.  
Per -Pr ot oc ol A nal ysis Set ( P P S): T he P P S will i ncl u de t he s u bset of s u bjec ts fr o m t he F A S w h o 
d o n ot ha ve  a n y maj or de viati o ns. A f ull list of maj or pr ot oc ol de viati o ns will be fi nalize d pri or t o 
data base l oc k a n d u n bli n di n g.  
Safet y A nal ysis Set: T he Safet y A n al ysis Set will i ncl u de all s u bjects w h o recei v e at least 1 d ose 
of I P.  
1 0. 2  
S t atistic al Met h o ds 
T he st u d y d ata will be cl ea ne d a n d l oc ke d after t h e last s u bject fi nis hes t he O pti o nal O pe n -La bel 
E xte nsi o n Peri o d. T he st u d y will t he n b e u n bli n de d a n d fi nal a n al ysis will be c o n d ucte d. T he d ata 
f or L o n g- Ter m F oll o w-U p Peri o d will b e re p orte d o nce a v aila ble.  
1 0. 2. 1  
A n al ysis of Effic ac y  
A ll pri mar y a n d sec o n d ar y efficac y e n d p oi nts will be a nal yze d usi n g t he F A S. T he pri mar y 
efficac y a n al ysis will be re peat e d f or  t he P P S as t he s u p p orti ve a nal ysis. 
1 0. 2. 1. 1  
Pri mar y efficac y a nal ysis  
T he pri mar y effica c y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all of t he f oll o wi n g criteria  
d uri n g t he p eri o d after p ost -c he m ot hera p y I P treat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y D a y  
of C ycl e X + 2 : 
•  N ot re q uiri n g a platel et tra nsf usi o n; 
•  N ot re q uiri n g a c h e m ot hera p y  d ose re d ucti o n b y ≥1 5 % d ue t o t hr o m b oc yt o pe nia; a n d 
•  N ot re q uiri n g a c h e m ot hera p y del a y b y ≥4 da ys d ue t o t hr o m b oc yt o p e nia 
S u bjects wit h o ut s ufficie nt data f or t he deter mi nati o n of res p o nse stat us (ie, res p o n der ver s us 
n o n- res p o n der) will be treate d as n o n-res p o n ders i n t he a nal ysis. E ver y eff ort s h o ul d be ma d e 
d uri n g t he c o n d u ct of t he st u d y t o li mit t he e xte nt of missi n g data wit h s u bjects w h o pre mat urel y 
disc o nti n ue I P b ut re mai n i n t he st u d y f or c ollecti o n of data, u nless t he s u bject wit h dra ws c o nse nt.  
T he treat me nt effect o n t he pri mar y efficac y e n d p oi nt will be teste d bet wee n a v atr o m b o pa g a n d 
place b o usi n g t he C oc hra n -Ma ntel -Hae nszel test, a dj usti n g f or n u m ber of c h e m ot hera p y a ge nts ( 1 
or ≥2  per missi ble  c he m ot h era p y  a ge nts  [ n ucle osi de  a nal o g,  i ncl u di n g  ge m cita bi ne  a n d  
fl u or o uracil;  car b o plati n  or  cis plati n;  a nt hrac ycli ne;  or  al k ylati n g  a ge nt]).  T he  n u m bers  a n d  
perce nt a ges of res p o n ders i n eac h treat me nt gr o u p, t he ass ociate d 9 5 % c o nfi de nce i nter vals ( CI), 
a n d t he 9 5 % CI f or t he differe n ce bet wee n a vatr o m b o pa g a n d pl ace b o will be cal c ulate d. T h e 
pri mar y a n al ysis will be perf or me d bas e d o n t h e F A S a n d re p eate d o n t he P P S. Ot her se nsiti vit y 
a nal ys es of t he pri mar y efficac y e n d p oi nt ma y be perf or me d as a p pr o priate. 


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K e y sec o n d ar y efficac y a nal ysis  
T he ke y se c o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g:  
•  D urati o n of s e ver e t hr o m b oc yt o p e nia defi ne d as a platelet c o u nt < 5 0 ×  1 09/ L d uri n g t he p eri o d 
after p ost -c he m ot her a p y I P tr eat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y Da y  of C ycl e X + 2 ; 
•  C ha n ge i n platelet c o u n t fr o m baseli ne ( q ualif yi n g c he m ot hera p y c ycle [ C ycl e X]) ( n a dir) t o 
C ycle X + 1 ( n a dir);  
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve maj or or n o n- maj o r cli nicall y rele v a nt blee di n g d uri n g 
t he peri o d after p ost -c h e m ot hera p y I P treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y Da y  of 
C ycle X + 2 ; a n d  
•  Pr o p orti o n of s u bjects w h o d o n ot recei ve pl atelet tra nsf usi o n d uri n g t he peri o d after p ost -
c he m ot hera p y I P tr eat me nt i n C ycle X + 1 thr o u g h  C he m ot hera p y Da y  of C ycl e X + 2 .  
If t he test of t he treat me nt effect o n t he pri mar y efficac y e n d p oi nt is statisticall y si g nifica nt, t he 
a nal ysis of t he ke y s ec o n dar y efficac y e n d p oi nts will pr ocee d usi n g ste p-d o w n cl ose d testi n g 
pr oce d ur e i n t he f oll o wi n g or der t o mai ntai n t he fa mil y-wise  T y pe I err or rate at si g nifica nce le vel 
al p ha = 0. 0 5 ( 2-si de d): 
•  Ste p  1:  Test  t he  treat me nt  eff ect  at  a  si g nifica nt  le v el  of  0. 0 5  o n  d urati o n  of  s e vere  
t hr o m b oc yt o pe ni a  defi n e d  as  a  platelet  c o u nt  < 5 0  ×   1 09/ L d uri n g  t h e  peri o d  after  p ost -
c he m ot hera p y I P  treat m e nt  i n  C ycle  X + 1  t hr o u g h C he m ot hera p y  D a y  of  C ycl e  X + 2;  if  
s uccessf ul, pr o cee d t o Ste p 2; ot her wise st o p at Ste p 1.  
•  Ste p 2: Test t he treat me nt eff ect at a si g nifi ca nt le vel of 0. 0 5 o n c ha n ge i n platelet c o u nt fr o m 
baseli ne  ( q ualif yi n g  c he m ot hera p y  c yc le  [ C ycl e  X])  ( na dir)  t o  C ycle  X  +  1  ( na dir);  if  
s uccessf ul, pr o cee d t o Ste p 3; ot her wise st o p at Ste p 2. 
•  Ste p 3: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n pr o p orti o n of s u bjects w h o d o 
n ot  ha ve  maj or  or  n o n -maj or  cli nicall y  rele v a nt  blee di n g d uri n g  t he  peri o d  after  p ost -
c he m ot hera p y I P  treat m e nt  i n  C ycle  X + 1  t hr o u g h C he m ot hera p y  D a y  of  C ycl e  X + 2 ;  if  
s uccessf ul, pr o cee d t o Ste p 4; ot her wise st o p at Ste p 3. 
•  Ste p 4: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n pr o p orti o n of s u bjects w h o d o 
n ot recei v e platelet tr a nsf usi o n d uri n g t he p eri o d after p ost-c he m ot hera p y I P treat me nt i n C ycl e 
X + 1 t hr o u g h C he m ot her a p y Da y  of C ycl e X + 2 . 
1 0. 2. 1. 3  
O t her efficac y a nal ysis  
T he ot her efficac y e n d p oi nts i ncl u de t he f oll o wi n g  d uri n g t he peri o d after p os t-c he m ot hera p y I P 
treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y D a y of C ycle X + 2 : 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c h e m ot hera p y d ose re d ucti o n t h at is ≥1 5 % d ue t o 
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n  of  s u bjects  w h o  d o  n ot  ha ve  a  c he m ot hera p y  dela y  t hat  is  ≥4  da ys  d ue  t o  
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n of s u bject s wit h a pre -d efi ne d p ost- bas eli ne na dir platelet c o u nt ; a n d 
•  Pr o p orti o n of s u bjects ac hie vi n g a pre -d efi ne d p ost- baseli ne ma xi m u m plat elet c o u nt.  


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T he cate g orical varia bl es (e g, pr o p orti o n) will be s u m marize d a n d a nal yze d i n t he sa me m a n ner 
as t he pri mar y e ffi cac y e n d p oi nt. T he c o nti n u o us varia bles (e g, c ha n ge fr o m baseli ne i n platelet 
c o u nt) will be a nal yze d usi n g a nal ysis of c o varia n ce m o dels wit h treat me nt a n d t he ra n d o mizati o n 
stratificati o n fact or as mai n effects a n d t he baseli ne meas ure m e nt as a c o vari ate, a n d Wilc o x o n 
Ra n k S u m tests if t he n or malit y ass u m pti o n is vi olate d.  
T he efficac y vari a bles c ollecte d  d uri n g t he o pti o nal O L E  Peri o d will be s u m marize d descri pti vel y.  
A d diti o nal efficac y a n al ys es will be perf or me d if dee me d necess ar y. T he details of t he a nal yses 
will be descri be d i n t he Statistical A nal ysis Pla n t hat will be fi nalize d pri or t o data base l oc k.   
1 0. 2. 2  
A n al ysi s of S af et y 
S afet y a n d t olera bilit y will be assesse d b y e x a mi ni n g t he i nci de nce of a d verse e v e nts, A E SI , 
cli nical la b or at or y para m eters, p h ysical e x a mi nati o n fi n di n gs, a n d vital si g ns  o ver ti me usi n g t he 
Safet y A nal ysis Set.  
1 0. 2. 3  
I nterim  A n al ysis 
N o f or mal i nteri m a nal ysis is pla n ne d f or t his st u d y. A D S M B will be c o n ve ne d f or t his st u d y, 
pri maril y t o m o nit or safet y  at re g ular i nter vals . A D S M B c harter, detaili n g all as pects of t he 
D S M B’s sc o pe of re vi e w a n d pr oce d ures will be d escri be d i n a s e parate d o c u me nt.  
1 0. 2. 4  
S a m ple Size D eter mi n ati o n  
A ss u mi n g t here is a 4 0 % res p o nse rate i n t he acti ve gr o u p a n d 1 0 % i n t he place b o gr o u p, a n d usi n g 
a 2: 1 ra n d o mizati o n, a 1 0 % pre mat ure ter mi nati o n rate, a n d 9 0 % p o wer wit h 2 -si de d al p ha = 0. 0 5, 
t he sa m ple size is 1 2 0 s u bjects ( 8 0 acti ve s u bjects a n d 4 0 place b o s u bjects). 
T he ass u m pti o ns f or t he res p o nse rat es f or t he n ull a n d alter nati ve h y p ot h eses were base d u p o n 
res ults fr o m a st u d y i n CI T c o m plete d wit h o prel ve ki n ( Ne u me ga, Pfizer). T he st u d y d esi g n f or 
o prel ve ki n was si milar i n t hat s u bjects were ra n d o mize d t o acti ve o r place b o f oll o wi n g occ urre n ce 
of se ver e t hr o m b oc yt o p e nia ( platelet c o u nt ≤2 0 ×   1 09/ L i n a pre vi o us c ycle [C ycl e X ]). T he 
pri mar y e n d p oi nt of t he st u d y assesse d t he a bilit y of o prel v e ki n t o eli mi nate t he nee d f or platelet 
tra nsf usi o ns.  I n  t he  place b o  gr o u p ( n = 3 0),  9 3 %  of  s u bjects  re q uire d  a  platelet  tra nsf usi o n 
( 7 % res p o n d er  r ate)  a n d  7 2 %  of  acti ve  su bj ects  ( n = 2 9)  re q uire d  a  p latelet  tra nsf usi o n  
( 2 8 % res p o n d er rate). T h e res p o n d er rates ass u me d f or t he n ull a n d alter nati ve h y p ot hes es i n t he 
A V A -CI T -3 3 0 st u d y wer e base d u p o n t he res p o n d er rates i n t his si milarl y d esi g ne d st u d y wit h a n 
ass u m pti o n f or a sli g htl y hi g her r es p o nse rate d u e t o t he i ncl usi o n of s u bj ects wit h a platel et c o u nt 
i n C ycle X of < 5 0 ×  1 09/ L, r at her t ha n ≤2 0 ×  1 09/ L. 


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D A T A M A N A G E M E N T A N D R E C O R D K E E PI N G  
1 1. 1  
D at a M a n a ge me nt 
1 1. 1. 1  
D at a H a n dli n g 
D ata will be rec or d e d at t he site o n e C R Fs a n d re vie we d b y t h e cli nical researc h ass oci ate  ( C R A) 
o n a n o n g oi n g basis a n d d uri n g m o nit ori n g visits. T he C R As will verif y data rec or d e d i n t he 
electr o nic data ca pt ure ( E D C ) s yste m wit h s o urce d oc u me nts. All c orrecti o ns or c ha n ges ma de t o 
a n y st u d y d ata m ust be a p p r o priatel y trac ke d i n a n a u dit trail i n t he E D C s yste m. A n e C R F will be 
c o nsi dere d c o m plete w he n all missi n g, i nc orrect, a n d/ or i nc o nsiste nt data has bee n acc o u nte d f or  
a n d rec o n ciliati o n bet wee n ot her data b ases (e g, safet y, I R T) is c o m plete . 
1 1. 1. 2  
C o m p uter S yst e ms  
D ata will b e pr o cesse d usi n g a v ali date d c o m p uter s yste m c o nf or mi n g t o re g ulat or y re q uire me nts.  
1 1. 1. 3  
D at a E ntr y  
D ata m ust be rec or de d usi n g t he E D C s yste m as t he  st u d y is i n pr o gress. All site pers o n nel m ust 
l o g i nt o t he s yste m usi n g t heir sec ur e user na m e a n d pass w or d i n or der t o e nter, re vie w, or c orrect 
st u d y data. T hese pr oce d ures m ust c o m pl y wit h Title 2 1 of t he C o de of Fe d eral Re g ulati o ns 
( 2 1 C F R ) Part 1 1 a nd ot her a p pr o priate i nter nati o nal re g ulati o ns. All pass w or ds will be strictl y 
c o nfi de ntial. 
1 1. 1. 4  
Me di c al I nf or m ati o n C o di n g 
F or me dical i nf or mati o n, t he f oll o wi n g t hes a uri will be use d:  
•  Me dical Dicti o nar y f or R e g ul at or y Acti vities  f or me dical hist or y a n d a d v erse e ve nts, a n d  
•  W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y f or pri or a n d c o n c o mita nt me dicati o ns. 
1 1. 1. 5  
D at a V ali d ati o n 
V ali dati o n  c hec ks  pr o gr a m me d  wit hi n  t he  E D C  s yste m,  as  w ell  as  s u p ple me ntal  vali dati o n  
perf or me d via r e vie w of t he d o w nl oa de d data, will be a p plie d t o t he data i n or der t o e ns ure 
acc ur ate, c o nsiste nt, a n d relia ble data. Data i d e ntifie d as er r o ne o us, or data t hat are missi n g, will 
be ref err e d t o t he i n vesti gati ve site f or res ol uti o n t hr o u g h d ata q ueri es. 
T he e C R Fs m ust be re vi e we d a n d el ectr o nicall y  si g ne d b y t h e I n vesti gat or. 


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1 1. 2  
Rec or d Kee pi n g  
Rec or ds of s u bjects, s o ur ce d oc u m e nts, m o nit ori n g visit l o gs, e C R Fs, i n v e nt or y of st u d y pr o d u ct, 
re g ulat or y d oc u m e nts, a n d ot her S p o ns or c orres p o n de nce p ertai ni n g t o t he st u d y m ust be ke pt i n 
t he a p pr o pri ate st u d y files at t he site. S o urce data are d efi ne d  as all i nf or m ati o n i n ori gi nal rec or ds 
a n d certified c o pies of ori gi nal r ec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her acti vities i n a 
cli nical st u d y necessar y f or t he e val uati o n a n d rec o nstr ucti o n of t he cli nical st u d y. S o urce d ata are 
c o ntai ne d i n  s o urce d oc u me nts ( ori gi nal rec or ds or certifi e d c o pi es). T h ese rec or ds will be retai ne d 
i n a sec ur e file f or t he p eri o d as set f ort h i n t h e Cli nical St u d y A gree me nt. Pri or t o tra nsfer or 
destr ucti o n of t hese rec or ds, t he S p o ns or m ust b e n otifie d i n writi n g a n d be gi v e n t he o p p ort u nit y 
t o f urt her st ore s u c h rec or ds.  


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1 2  
IN V E S TI G A T O R R E Q UI R E M E N T S A N D Q U A LI T Y C O N T R O L  
1 2. 1  
Et hic al C o n d uct of t he St u d y  
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol a n d all re g ul at or y re q uire me nts, i n 
acc or d a nce  wit h  G o o d  Cli nical  Practice  ( G C P),  i ncl u di n g  I nter n ati o nal  C o nfere n ce  o n  
Har m o nisati o n (I C H) g ui deli nes, a n d i n ge n eral c o nf or mit y wit h t he m ost rece nt v ersi o n of t he 
Declar ati o n  of  Helsi n ki.  D o va  P har mace uticals  Q ualit y  Ass ura nce  or  desi g nee  ma y  verif y  
a d here n ce t o t hes e practices a n d pr o ce d ures t hr o u g h a u dit a n d i ns pecti o n. 
1 2. 2  
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee 
T he I R B/I E C will re vie w all a p pr o priate st u d y d oc u me ntati o n i n or der t o safe g uar d t he ri g hts, 
safet y, a n d w ell-bei n g of s u bjects. T he st ud y will o nl y b e c o n d uct e d at sites w here I R B /I E C 
a p pr o val h as bee n o btai n e d. T he pr ot oc ol, I n v esti gat or’s Br oc h ure, I nf or m e d C o nse nt For m  (I C F), 
a d vertise me nts (if a p plica ble), writte n i nf or mati o n gi ve n t o t he s u bjects, safet y u p dat es, a n n ual 
pr o gress re p orts, a n d a n y r e visi o ns t o t hese d oc u me nts will be pr o vi de d t o t he I R B /I E C b y t he 
I n v esti gat or. 
T he I n vesti gat or is o bli gate d t o kee p t he I R B/I E C i nf or me d of a n y u na ntici pate d pr o ble ms. T his 
ma y i ncl u d e n otificati o n t o t he I R B/I E C of I n v esti gati o nal N e w Dr u g Safet y Re p orts.  
Fe deral  re g ulati o ns  a n d  I C H  r e q uire  t hat  a p pr o val  be  o btai ne d  fr o m  a n  I R B /I E C pri or  t o  
partici pati o n of s u bjects  i n researc h st u dies. Pri or t o st u d y o ns et, t he pr ot oc ol, a n y pr ot oc ol  
a me n d me nts, I C Fs, a d v ertise me nts t o be use d f or s u bject recr uit me nt, a n d a n y ot h er writte n 
i nf or mati o n re gar di n g t his st u d y t o be pr o vi de d t o a s u bject or s u bject’s l e gal g u ar dia n m ust be 
a p pr o ve d b y t he I R B /I E C. 
N o dr u g will be release d t o t he site f or d osi n g u ntil writte n I R B /I E C a ut h orizati o n has bee n 
receiv e d b y t he S p o ns or. 
It is t he r es p o nsi bilit y of t he S p o ns or or t heir desi g nee t o o btai n t he a p pr o val of t he res p o nsi ble 
et hics c o m mittees acc or di n g t o t he nati o nal re g ulati o ns.  
T he st u d y will o nl y start i n t he res pecti ve sites o n ce t he res pecti ve c o m mitte e’s writte n a p pr o v al 
has bee n gi ve n. 
1 2. 3  
Pr ot oc ol A me n d me nts  
A n y a me n d me nts t o t he st u d y pr ot o c ol will be c o m m u nicate d t o t he I n v esti gat ors b y t h e S p o ns or  
or desi g n ee . All pr ot oc ol a me n d me nts will u n der g o t he sa me re vie w a n d a p pr o val pr ocess as t he 
ori gi nal pr ot oc ol. A pr ot oc ol a me n d me nt ma y be i m ple me nte d after it has bee n a p pr o ve d b y t h e 
I R B/I E C,  u nless  i m me diate  i m ple me ntati o n  of  t he  c ha n ge  is  necessar y  f or  s u bject  safet y.  
S u bsta ntial a me n d me nt s m ust be a p pr o ve d as per l ocal re g ulati o ns  pri or t o e nr olli n g s u bjects. I n 
t his case, t he sit uati o n m ust be d oc u me nte d a n d re p orte d t o t he I R B/I E C wit hi n 5 w or ki n g da ys. 
1 2. 4  
I nf or me d C o nse nt 
T he I C F a n d a n y c h a n ges t o t he I C F m a de d uri n g t he c o urs e of t h e st u d y m ust be a gree d t o b y t h e 
S p o ns or or desi g nee a n d t he I R B /I E C pri or t o its use a n d m ust be i n c o m plia nce wit h all I C H G C P, 
l ocal re g ulat or y re q uir e me nts, a n d le gal re q uire me nts.   


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T he I n vesti gat or m ust e ns ure t hat eac h st u d y s u bject is f ull y i nf or me d a b o ut t he nat ure a n d 
o bjecti ves of t he  st u d y a n d p ossi ble ris ks ass ociate d wit h partici pati o n a n d m ust e ns ure t hat t he 
su bject  has  bee n  i nf or m e d  of  his/ her  ri g hts  t o  pri vac y.  T he  I n v esti gat or will  o btai n  writte n  
i nf or me d c o ns e nt fr o m eac h s u bject bef ore a n y st u d y-s pecific acti vit y is perf or me d a n d s h o ul d 
d oc u me nt i n t he s o urce d oc u me ntati o n t hat c o nse nt was o btai ne d pri or t o e nr oll me nt i n t he st u d y. 
T he ori gi nal si g ne d c o p y of t he I C F m ust be m ai ntai ne d b y t he I n vesti gat or a n d is s u bject t o 
i ns pecti o n b y a re prese nt ati ve of t he S p o ns or, t heir re prese ntati ves, a u dit ors, t he I R B/I E C, a n d/ or 
re g ulat or y a ge ncies. A c o p y of t he si g n e d I C F will be gi v e n t o t he s u bject.  
1 2. 5  
St u d y M o nit ori n g Re q uire me nts  
It is t he res p o nsi bilit y of t he I n v esti gat or t o e ns ure t hat t he st u d y is c o n d uct e d i n acc or d a nce wit h 
t he pr ot oc ol, D eclarati o n of Helsi n ki, I C H G C P, Directi ve 2 0 0 1/ 2 0/ E C, a n d a p plica ble  re g ulat or y 
re q uire me nts, a n d t h at vali d data are e ntere d i nt o t he e C R Fs.  
T o ac hie ve t his o bjecti ve, t he C R A ’s d uties are t o ai d t he I n vesti gat or a n d, at t he sa me ti me, t he 
S p o ns or, i n t he mai nte na nce of c o m plete, le gi ble, well or ga nize d, a n d easil y retrie va bl e data. 
Bef ore t he e nr oll me nt of a n y s u bject i n t his st u d y, t he S p o ns or or t heir desi g nee will re vie w wit h 
t he I n vesti gat or a n d site pers o n nel t he f oll o wi n g d oc u me nts: pr ot oc ol, I n vesti gat or’s Br oc h ure, 
e C R Fs a n d pr oce d ures f or t heir c o m pleti o n, i nf or me d c o nse nt pr ocess, a n d t he pr oce d ure f or 
re p orti n g S A Es. 
T he I n v esti gat or will per mit t he S p o ns or or t heir desi g nee t o m o nit or t he st u d y as fre q ue ntl y as 
dee me d necessar y t o  deter mi ne t hat data rec or di n g a n d pr ot oc ol a d here nce are satisfact or y. D uri n g 
t he m o nit ori n g  visits,  i nf or mati o n  rec or de d  o n  t he  e C R Fs  will  be  verifie d  a gai nst  s o urce  
d oc u me nts a n d re q uests f or clarificati o n or c orrecti o n ma y be m a de. After t he e C R F d ata is e ntere d 
b y t he site, t he C R A will re vie w t he data f or safet y i nf or mati o n, c o m pl ete ness, acc urac y, a n d 
l o gical c o nsiste nc y. C o m p uter pr o gr a ms t hat i d e ntif y data i nc o nsiste nci es ma y b e us e d t o h el p 
m o nit or t he cli nical st u d y. If necessar y, re q uests f or cl arificati o n or c orrecti o n will be se nt t o 
In v esti gat ors. T he I n vesti gat or a n d his/ her staff will be e x pecte d t o c o o p erate wit h t he C R A  a n d 
pr o vi de a n y missi n g i nf or mati o n, w he ne ver p ossi ble. 
All m o nit ori n g acti vities will be re p orte d a n d arc hi ve d. I n a d dit i o n, m o nit ori n g visits will be 
d oc u me nte d at t he i n vesti gati o nal site b y si g nat ure a n d date o n t h e st u d y- s pecific m o nit ori n g l o g. 
1 2. 6  
Discl os ure of D at a  
Data  ge nerate d  b y  t his  st u d y  m ust  be  a vaila ble  f or  i ns pecti o n  b y  t he  F o o d  a n d  Dr u g  
A d mi nistrati o n ,  t he  S p o ns or  or  t heir  desi g nee,  a p plica ble  f orei g n  h ealt h  a ut h orities,  a n d  t h e  
I R B/I E C as  ap pr o priate.  S u bjects  or  t h eir  le gal  re prese ntati ves  m a y  re q uest  t heir  me dical  
i nf or mati o n  be  gi ve n  t o  t heir  pers o nal  p h ysicia n  or  ot her  a p pr o priat e  me dical  pers o n nel  
res p o nsible f or t heir welf are.  
S u bject ’s me dical i nf or mati o n o btai ne d d uri n g t he st u d y is c o nfi de ntial a n d discl os ure t o t hir d 
parties ot her t ha n t h ose n ote d a b o ve is pr o hi bite d. 
1 2. 7  
Rete nti o n of Rec or ds  
T o e na ble e val uati o ns a n d/ or a u dits fr o m re g ulat or y a ut h orities or t he S p o ns or, t he In v esti gat or 
will kee p r ec or ds, i ncl u di n g t h e i de ntit y of all partici pati n g s u bjects (s uffici e nt i nf or mati o n t o li n k 
rec or ds, e g, eC R Fs a n d h os pital rec or ds), all ori gi n al si g ne d I C Fs, c o pi es of all eC R Fs, S A E  f or ms, 


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s o urce d oc u me nts, a n d d etaile d rec or ds of treat m e nt dis p ositi o n. T he rec or ds s h o ul d be retai ne d 
b y t h e I n vesti gat or acc or di n g t o s pecificati o ns i n t he I C H g ui deli nes, l ocal re g ulati o ns, or as 
s pecifie d i n t he Cli nical St u d y A gree me nt, w hic he ver is l o n ger. T he I n v esti gat or m ust o btai n 
writte n  per missi o n  fr o m  t he  S p o ns or bef ore  dis p osi n g  of  a n y  rec or ds,  e ve n  if  ret e nti o n  
re q uire me nts ha v e bee n met. 
If t h e I n vesti gat or rel o cat es, retires, or f or a n y reas o n wit h dra ws fr o m t he st u d y, t he S p o ns or s h o ul d 
be pr os pecti vel y n otifie d. T he st u d y rec or ds m ust be tra nsferre d t o a n ac ce pta ble desi g nee, s uc h 
as a n ot her I nv esti gat or , a n ot her i nstit uti o n, or t o t he S p o ns or.   
1 2. 8  
P u blic ati o n P olic y  
F oll o wi n g c o m pleti o n of t he st u d y, t h e data m a y be c o nsi dere d f or p u blicati o n i n a scie ntifi c 
j o ur nal  or  f or  r e p orti n g  at  a  scie ntific  meeti n g.  Eac h I n vesti gat or is  o bli gate d  t o  kee p  data 
pertai ni n g t o t he st u d y c o nfi de ntial. T he I n v esti gat or m ust c o ns ult wit h t he S p o ns or bef ore a n y 
st u d y data ar e s u b mitte d f or p u blicati o n. T he S p o ns or reser ves t he ri g ht t o de n y p u blicati o n ri g hts 
u ntil m ut ual a gree me nt o n t he c o nte nt, f or mat, i nter pretati o n of data i n t he ma n uscri pt, a n d j o ur nal 
selecte d f or p u blicati o n are ac hi e ve d. 
1 2. 9  
Fi n a nci al Discl os ure  
I n v esti gat ors are re q uire d t o pr o vi de fi n a ncial discl os ure i nf or mati o n t o t h e S p o ns or t o per mit t he 
S p o ns or t o f u lfill its o bli gati o ns u n d er 2 1 C F R Pa rt 5 4. I n a d diti o n, In vesti gat ors m ust c o m mit t o 
pr o m ptl y u p dati n g t his i nf or mati o n if a n y rel e va nt c ha n ges o cc ur d uri n g t he st u d y a n d f or a p eri o d 
of 1 year after t he c o m pl eti o n of t he st u d y. 
1 2. 1 0  
I ns ur a nce a n d I n de m nit y 
I n acc or da n ce wit h t he r ele va nt nati o na l re g ulati o ns, t he S p o ns or has ta k e n o ut s u bject lia bilit y 
i ns ura nce f or all s u bjects w h o ha ve gi ve n t heir c o nse nt t o t he cli nical st u d y. T his c o vera ge is 
desi g ne d f or t he e v e nt t hat a fatalit y, p h ysical i nj ur y, or d a ma ge t o healt h occ urs d uri n g t he cli nic al 
st u d y’s e x ec uti o n. 


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1 3  
R E F E R E N C E S  
1.  K uter DJ. Ma na gi n g t hr o m b oc yt o pe ni a ass o ciate d wit h ca ncer c h e m ot hera p y. O nc ol o g y 
( Willist o n Par k). 2 0 1 5 A pr; 2 9( 4): 2 8 2- 9 4. 
2.  Hassa n B A, Y us off Z B, Hassali M A, Bi n Ot h ma n S. Treat me nt patter ns a n d o utc o mes i n 
ma na ge me nt of s ol i d ca n cer p atie nts s ufferi n g fr o m t hr o m b oc yt o p e nia i n P e na n g h os pital. 
Asia n Pac J Ca ncer Pre v. 2 0 1 1; 1 2( 1 1): 2 8 4 1- 5. 
3.  A vatr o m b o pa g maleate Gl o bal I n vesti gat or’s Br o c h ure, v 1 4, J a n uar y 2 0 1 9. 
4.  Ha yes S, M u d d P N Jr, O uellet D,  J o h ns o n B M, Willia ms D, Gi bia ns k y E.  P o p ulati o n 
P K/ P D  m o deli n g  of  eltr o m b o pa g  i n  s u bjects  wit h  a d v a nce d  s oli d  t u m ors  wit h  
c he m ot hera p y-i n d uce d
 t hr o m b oc yt o p e nia.  Ca ncer  C he m ot her  P har mac ol.  2 0 1 3
 
J u n; 7 1( 6): 1 5 0 7- 2 0. 
5.  B o na d o n n a  G,  V ala g ussa  P,  M oliter ni  A,  Za m b etti  M,  Bra m billa  C.   A dj u va nt 
c ycl o ph os p ha mi de,  met h otre x ate,  a n d  fl u or o uracil  i n  n o de -p ositi ve  breast  ca ncer:  t he  
res ults of 2 0 years of f oll o w- u p. N E n gl J Me d. 1 9 9 5 A pr 6; 3 3 2( 1 4): 9 0 1- 6. 
6.  B osl y A, Br o n D, V a n H o of A, De B oc k R, Ber n e m a n  Z, Ferra nt A, Ka uf m a n L, D a u we  M, 
Ver h oef G. Ac hie ve m e nt of o pti mal a vera ge relati ve d ose i nte nsit y a n d c orrelati o n wit h 
s ur vi val i n diff use lar ge B-cell l y m p h o ma patie nts treate d wit h C H O P. A n n He mat ol. 2 0 0 8 
A pr; 8 7( 4): 2 7 7- 8 3. 
7.  C hiri vella I, Ber mej o B, I nsa A, Pérez -Fi dal g o  A, Ma gr o A, R osell o S, García -Garre E, 
Martí n P, B osc h A, Ll u c h A. O pti mal deli ver y of a nt hrac ycli ne -base d c he m ot hera p y i n t he 
a dj u va nt setti n g i m pr o ves o utc o me of breast ca ncer patie nts. Breast Ca ncer R es Treat. 2 0 0 9 
A pr; 1 1 4( 3): 4 7 9- 8 4. 
8.  Ha vriles k y LJ, et al. J Cli n O nc ol. 2 0 1 1: 2 9(s u p pl). A bstract 5 0 8 4. 
9.  We yc k er  D,  Barr o n  R,  E dels ber g  J,  Kartas h o v  A,  L y ma n  G H.  I n ci de n ce  of  re d uce d  
c he m ot hera p y rel ati ve d ose i nte nsit y a m o n g w o me n wit h earl y sta ge breast ca n cer i n U S 
cli nical practice. Breast Ca ncer Res Treat.  2 0 1 2 Ma y; 1 3 3( 1): 3 0 1 - 1 0. 
1 0.  F o ote M. T he  I m p orta nce of Pla n ne d D ose of C he m ot hera p y o n Ti me: D o We Nee d t o 
C ha n ge O ur Cli nical Practice? O nc ol o gist. 1 9 9 8; 3( 5): 3 6 5- 3 6 8. 
1 1.  L y m a n G H. I m p act of c he m ot hera p y d ose i nte nsit y o n ca ncer patie nt o utc o mes. J Natl 
C o m pr Ca nc Net w. 2 0 0 9 J a n; 7( 1): 9 9- 1 0 8. 
1 2.  Hr y ni u k W M. T he i m p orta nce of d ose i nte nsit y i n t he o utc o me of c he m ot hera p y. I m p orta nt 
A d v O nc ol. 1 9 8 8: 1 2 1- 4 1. 
1 3.  Li n k B K, B u d d G T, Sc ott S, Dic k ma n E, Pa ul D, La wless G, Lee M W, Fri d ma n M, F or d 
J,  Carter  W B;  O nc ol o g y Practice  Patter n  St u d y W or ki n g Gr o u p.  D eli veri n g  a dj u va nt  
c he m ot hera p y  t o  w o me n  wit h  earl y-st a ge  breast  carci n o ma:  c urre nt  patter ns  of  care.  
Ca ncer. 2 0 0 1 Se p 1 5; 9 2( 6): 1 3 5 4- 6 7. 
1 4.  L y m a n G H, D ale D C, Cra wf or d J. I nci de n ce a n d pre dict ors of l o w d ose -i nte nsit y i n  
a dj u va nt breast ca n cer c he m ot hera p y: a nati o n w i de st u d y of c o m m u nit y practices. J Cli n 
O nc ol. 2 0 0 3 Dec 1 5; 2 1( 2 4): 4 5 2 4- 3 1. 


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1 5.  L y m a n G H, D ale D C, Fri e d ber g J, Cra wf or d J, Fis her RI. I nci de nce a n d pre dict ors of l o w 
c he m ot hera p y d ose-i nte nsit y i n a g gressi ve n o n- H o d g ki n's l y m p h o ma: a nati o n wi de st u d y. 
J Cli n O nc ol. 2 0 0 4 N o v 1; 2 2( 2 1): 4 3 0 2- 1 1. 
1 6.  N ort o n L. T h e oretical c o nce pts a n d t he e m er gi n g r ole of ta x a nes i n a dj u va nt t hera p y. 
O nc ol o gist. 2 0 0 1; 6 S u p pl 3: 3 0- 5. 
1 7.  Pic ozzi VJ, P o hl ma n B L, M orris o n V A, La wless G D, Lee M W, Kerr R O, F or d J M, 
Del ga d o DJ, Fri d ma n M, Carter  W B. Patter ns of c he m ot hera p y a d mi nistrati o n i n patie nts 
wit h  i nter me diate -gra d e  n o n -H o d g ki n's  l y m p h o ma.  O nc ol o g y  ( Willist o n  Par k).  2 0 0 1  
Oct; 1 5( 1 0): 1 2 9 6- 3 0 6; disc ussi o n 1 3 1 0- 1, 1 3 1 4. 
1 8.  Citr o n M L, Berr y D A, Cirri nci o ne C, H u dis C, Wi ner E P, Gra dis h ar WJ, Da vi ds o n N E, 
Marti n o S, Li vi n gst o n R, I n gle J N, Perez E A, Car pe nter J, H ur d D, H olla n d J F, S mit h B L, 
Sart or CI, Le u n g E H, A bra ms J, Sc hils k y R L, M uss H B, N ort o n L. Ra n d o mize d trial of 
d ose- de nse vers us c o n ve nti o nall y s c he d ule d a n d s e q ue ntial vers us c o nc urre nt c o m bi nati o n 
c he m ot hera p y as p ost o perati ve a dj u va nt treat me nt of n o de -p ositi ve pri mar y breast ca ncer: 
first re p ort of I nter gr o u p Trial C 9 7 4 1/ Ca ncer a n d Le u k e mia Gr o u p B Trial 9 7 4 1. J Cli n 
O nc ol. 2 0 0 3 A pr 1 5; 2 1( 8): 1 4 3 1- 9. 
1 9.  K wa k L W, H al per n J, Ols he n  R A, H or ni n g SJ. Pr o g n ostic si g nifi ca nce of act ual d ose 
i nte nsit y i n diff use lar ge-cell l y m p h o ma: res ults of a tree -str uct ure d s ur vi val a nal ysis. 
J Cli n O nc ol. 1 9 9 0 J u n; 8( 6): 9 6 3- 7 7. 
2 0.  B o na d o n n a G, M oliter ni A, Za m betti M, Dai d o ne M G, Pil otti  S, Gia n ni L, Vala g uss a P. 
3 0 years' f oll o w u p of r a n d o mise d st u dies of a dj u va nt C M F i n o pera ble breast ca ncer: 
c o h ort st u d y. B MJ. 2 0 0 5 J a n 2 9; 3 3 0( 7 4 8 5): 2 1 7. 
2 1.  See bac h er V, Rei nt haller A, K o el bl H, C o n ci n N, Ne h o da R, P oltera uer S. T he I m pact of 
t he D urati o n of A dj u v a nt C he m ot hera p y o n S ur vi val i n Patie nts wit h E pit helial O vari a n 
Ca ncer - A Retr os pecti ve St u d y. P L o S O ne. 2 0 1 7 J a n 6; 1 2( 1):e 0 1 6 9 2 7 2. 
 


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A P P E N DI X A:  S C H E D U L E O F P R O C E D U R E S  
T a ble 1. 
Sc he d ule of Pr oce d ures  ( D o u ble-Bli n d Tre at me nt Peri o d)  
Da y  
C he m o t her ap y  C ycle X a 
C he m o t her a p y C ycle X + 1  
Scree ni n g  
D -2 8  t o D -1  
B aseli ne  
Pre -C he m o I P 
Tre at me nt ( 5 D)  
C he m o D a y 
( D 1 u p t o D 3)  
P ost -C he m o  
I P Tre at me nt ( 5 D) 
D 1 1 ( ± 1 D), D 1 5 
(± 1 D), a n d D 1 8 ( ± 1 D)  
Visit  
1 b  
2  
3 c 
4 d  
5 e 
6, 7, 8  
S u bj ect i nf or me d c o nse nt  
X  
 
 
 
 
 
I/E criteria  
X  
X  
 
 
 
 
Ra n d o mizati o n  
 
X f 
 
 
 
 
De m o gra p hics  (i ncl. race) 
X  
 
 
 
 
 
Me dical hist or y
g  
X  
 
 
 
 
 
E C O G perf or ma nce stat us  
X  
 
 
 
 
 
C o nc o mita nt me dicati o ns h  
X  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
X  
P h ysical e xa mi nati o n  
X  
X i 
 
X i 
 
 
Vital si g ns j 
X  
X  
 
X  
 
 
P K k 
 
 
X  
 
X  
 
He mat ol o g y (i ncl. platelet c o u nts)  l 
X b  
X  
X  
X  
X  
X  
C oa g ulati o n pa nel  (ce ntral la b) 
 
X  
 
 
X  
 
Ser u m c he mistr y m  
X b  
X  
 
X  
X  
 
Pre g na nc y testi n g n 
X b 
X o 
 
 
 
 
Blee di n g assess me nt (I S T H)  
 
←−−−−−−−−−−−− c o nti n u o us  −−−−−−−−−−−−−→
p 
 
C o ntact I R T  
X  
X  
X  
 
X  
 
I P d osi n gq 
 
X  
X r 
 
X r 
 
Dis pe nse I P  a n d d osi n g diar y 
 
X  
 
X s 
 
 
C ollect d osi n g diar y a n d I P pac ka ge  
 
 
X  
 
X  
 
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p; I/ E  = i n cl usi o n/e xcl usi o n; i n cl. = i n cl u di n g; I P = i n vesti gati o nal pr o d uct; I R T = I nteracti ve 
Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y  o n T hr o m b osis a n d Hae m ostasis; P K =  p h ar ma c o ki n etic.  
N ote : Pri or t o c o n d u cti n g a n y st u d y -relat e d acti vities, writte n inf or me d c o nse nt m ust b e si g n e d a n d d ate d b y t h e s u bject. T hr o u g h o ut t he d o u ble -bli n d treat me nt peri o d, all s u bjects 
will be assess e d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose re d u cti o ns or d ela ys.  
a. 
T he q ualif yi n g c h e m o c ycle is d efi n e d as C ycle X.  
b.  
Scr ee ni n g Visit ma y o cc ur o n t h e sa me d a y as t h e Baseli n e Visit , if o n e d a y pri or t o I P treat me nt. If t h ese b s o cc ur o n t he sa me da y, o nl y t he Baseli ne ( Visit 2) la b orat or y 
sa mples s h o ul d b e se nt t o t h e ce ntral la b.  L o cal platelet c o u nts ma y b e re p eate d as n e e d e d. 
c. 
Visit 3 will o cc ur o n t h e last d a y of t h e 5 -d a y pre -c h e m o I P treat me nt. 


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d.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n (e g, if c h e m ot h era p y is gi ve n o n Da y 1 a n d Da y 2, s u bjects will recei ve 
a vatr o m b o p a g or place b o o n Da y 3). A vatr o m b o p a g or place b o will n ot b e a d mi nistere d c o n c urre ntl y wit h c h e m ot h era p y o n C he m ot hera p y Da y.  All assess me nts will occ ur 
o n t he first d a y of c h e m ot h era p y  pri or t o c h e m ot h era p y d osi n g.  
e. 
Visit 5 will o cc ur o n t h e last d a y of t h e  5-d a y p ost -c h e m o I P treat me nt.  
f. 
Ra n d o mizati o n m ust o cc ur pri or t o I P d osi n g.  
g.  
Me dical hist or y t o i n cl u d e t u m or t y p e, d ate of ca n cer dia g n osis, a n d pri or c h e m ot h era p e utic re gi me ns ( n u m b e rs of c ycles, dates). 
h.  
C o nc o mita nt me dicati o ns t o i n cl u d e d etails of c h e m ot h era p e utic re gi me n ( d ose s, sc h e d ule) 
i. 
S y m pt o m -directe d p h ysical e xa mi n ati o n; f ull p h ysical e x a mi n ati o n o nl y re q uire d at Scree ni n g.  
j. 
I ncl u des hei g ht (at t h e Scree ni n g Visit o nl y), wei g ht  ( Scree ni n g a n d Baseli n e Visits o nl y), b o d y te m p erat ure ( Scree ni n g a n d Baseli ne Visits o nl y), bl o o d press ure, a n d p ulse 
rate, a n d will b e meas ure d after resti n g f or 5 mi n utes.  O nl y scree ni n g vital si g ns will b e rec or d e d if scree ni n g a n d b aseli ne visits occ ur t he sa me da y.   
k.  
Bl o o d sa m ples f or P K a n al ysis will b e c ollecte d at t h e f oll o wi n g ti me p oi nts: pre -d ose a n d 0. 5 -2, 2 -4, a n d 4 -6 h o urs p ost -d ose. A pre -d ose P K sa m ple will be c ollecte d wit hi n 
3 0 mi n utes of I P d osi n g. Eac h P K sa m ple m ust  b e se p arate d b y at l east o n e  h o ur fr o m a djace nt  sa m ples. P h ar mac o ki netic sa m ples d o n ot nee d t o be collecte d at i de ntical 
ti mes f or pre- a n d p ost -c h e m o visits.  
l. 
He mat ol o g y sa m ples s h o ul d b e se nt t o t h e ce ntral la b i n a d diti o n t o l o cal la b platelet c o u nts at Visits 1, 2, 3, 4, a n d 5. Platelet c o u nts at Baseli ne ( Visit 2) ma y be perf or me d 
pri or ( -1 da y) t o ra n d o mizati o n. O nl y l o cal la b platelet c o u nts will b e assesse d at Visits 6, 7, a n d 8.  
m.   Scree ni n g c h e mistries ca n  b e p erf or me d l o call y t o d eter mi n e eli gi bil it y. C h e mistr y s a m ples will  b e se nt t o t h e ce ntral la b at Visits  1,  2, 4, a n d 5.  
n.  
F or fe males of c hil d b eari n g p ote ntial o nl y. A ser u m  or uri n e  pre g n a n c y test will b e p erf or me d at t h e Scree ni n g Visit. At t he Baseli ne Visit, t he pre g na nc y test will be 
perf or m e d pri or t o I P a d mi nistrati o n.  
o.  
U ri ne or ser u m pre g n a n c y test will b e p erf or me d at t h e Baseli n e Visit . 
p.  
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
q.  
F oll o wi n g ra n d o mizati o n, I P will b e dis p e nse d i n a d o u ble -bli n d ma n n er. S u bjects will recei ve eit h er a vatr o m b o p a g or place b o o nce dail y f or 5 da ys pri or t o C he m ot hera p y 
Da y i n C ycle X + 1. S u bjects will als o recei ve a v atr o m b o p a g or place b o o n ce d ail y f or 5 d a ys f oll o wi n g last d a y of c he m ot hera p y treat me nt. T he first d ose o f I P ma y be 
a d mi nistere d at t h e site if t h e Baseli n e visit o cc urs o n t h e first d a y of t h e 5 -d a y I P tr eat me nt, or self-d ose d if t h e Baseli ne visit occ urs t he da y pri or t o t he first da y of I P 
treat me nt. At sc h e d ule d st u d y visits, I P ma y b e a d mi nistere d at t h e site or t h e s u bject ma y self-d ose  e xce pt f or Visits 3 a n d 5  w he n s u bjects will be d ose d at t he site  a n d serial 
P K sa m ples will b e c ollecte d pre - a n d p ost-d ose of I P . S u bjects will self-d ose at all ot h er ti mes. S u bjects will b e i nstr ucte d t o ta ke I P wit h f o o d. T he I n vesti gat or or desi g nee 
will pr o vi de s u bjects wit h s uffi cie nt I P t o c o m plete t h e re gi me n.  
r. 
S u bjects will recei ve t h e last d ose of I P at t h e site.  
s. 
T hese pr oce d ures will b e p erf or me d p ost c h e m ot h era p y d osi n g o n t h e last C h e m ot h era p y Da y of C ycle X  + 1.  
 


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Versi o n 2. 0, 0 4 A pril 2 0 1 9  
6 6  
T a ble 2. 
Sc he d ule of Pr oce d ures ( O bser v ati o n al Peri o d)  
D a y  
C he m o t her ap y  C ycle X + 2 a 
C he m o D a y  
( D 1 u p t o D 3) 
D 1 1  
(± 1 D)  
D 1 5  
(± 1 D)  
D 1 8  
(± 1 D)  
F oll o w -U p  
Pri or t o C he m o D a y (-3 D) 
i n C ycle X + 3 
Visit  
9 b  
1 0  
1 1  
1 2 c 
1 7 / Earl y T er mi n ati o n d  
E C O G perf or ma nce stat us  
X  
 
 
 
X  
C o nc o mita nt me dicati o n  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
F ull p h ysical e xa mi nati o n  
 
 
 
 
X  
Vital si g ns e 
 
 
 
 
X  
He mat ol o g y (i ncl. platelet c o u nts) f 
X  
X  
X  
X  
X  
C oa g ulati o n  (ce ntral la b) 
X  
 
 
 
X  
Ser u m c he mistr y  (ce ntral la b) 
X  
 
 
 
X  
Pre g na nc y testi n g g 
 
 
 
 
X  
Blee di n g assess me nt (I S T H) h 
X  
 
 
 
X  
C o ntact I R T  
 
 
 
 
X  
C o llect u n use d I P, if a p plica ble 
 
 
 
 
X i 
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p;  i n cl. = i n cl u di n g; I P = i n vesti gati o n al 
pr o d uct; I R T = I nteracti ve Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y o n Thr o m b osis a n d Hae m o stasis; O L E = O pe n-
La bel E xte nsi o n . 
N ote : T hr o u g h o ut t h e o bser vati o nal  p eri o d, all s u bjects will b e assesse d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose 
re d ucti o ns or dela ys. 
a. 
C ycle X + 2 will b e a n O bser vati o n al P eri o d.  
b.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n . All assess me nts will o cc ur o n t he 
first da y of c h e m ot h era p y pri or t o c h e m ot h era p y d osi n g.  
c. 
O nl y f or s u bjects recei vi n g a 2 8 -da y c ycle w h o are n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d.  
d.  
O nl y f or s u bjects  n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d. F or s u bjects n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d, a 
F oll o w- U p Visit will o cc ur pri or t o ( wit hi n 3 d a ys) C h e m ot h era p y Da y i n C ycle X + 3. If C ycle X + 2 is t h e s u bject’s last 
c he m ot hera p y c ycle, a F oll o w-U p Visit will o cc ur at 3 0 d a ys ( ± 3 d a ys) after C h e m ot h era p y Da y i n C ycle X + 2. F or 
s u bjects c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d, Visit 13 will o cc ur 5 d a ys pri or t o C h e m ot h era p y Da y i n C ycle X + 3.  
e. 
I ncl u des bl o o d press ure a n d p ulse rate, a n d will b e meas ure d after r esti n g f or 5  mi n utes.  
f. 
He mat ol o g y sa m ples will  b e se nt t o t h e ce ntral la b i n a d diti o n t o l ocal la b platelet c o u nts at Visits 9 a n d 1 7. O nl y l o cal la b 
platelet c o u nts will b e assesse d at Visits 1 0, 1 1, a n d 1 2.  
g.  
Uri ne pre g n a n c y test ma y  b e p er f or me d f or fe mal es of c hil d b eari n g p ote ntial o nl y. 
h.  
Assess me nt of blee di n g will b e perf or me d if a s u b ject h as a n u nsc h e d ule d st u d y visit. 
i. 
O nl y f or a n E arl y T er mi n ati o n  Visit.  
 


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T a ble 3. 
Sc he d ule of Pr oce d ures ( O pti o n al O pe n -L a bel E xt e nsi o n Peri o d)  
Da y  
 
C he m ot her a p y C ycle X + 3 & O n  
 
Pre -C he m o 
A v atr o m b o p a g 
Tre at me nt ( 5 D)  
C he m o D a y  
( D1  u p t o D 3 ) 
P ost -C he m o 
A v atr o m b o p a g  
Tre at me nt ( 5 D)  
D 1 5 (± 1 D)  
F oll o w -U p  
3 0 D ( ± 3 D)  After L ast 
A v atr o m b o p a g  D ose  
Visit  
1 3 a 
1 4 b  
1 5 c 
1 6 d  
1 7 / Earl y T er mi n ati o n e 
I/ E criteria 
X  
 
 
 
 
E C O G perf or ma nce stat us  
X  
 
 
 
X  
C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
F ull p h ysical e xa mi nati o n  
 
 
 
 
X  
S y m pt o m -directe d p h ysical e xa mi nati o n  
 
X  
 
 
 
Vital si g ns f 
X  
X  
 
 
X  
He mat ol o g y  (i ncl. platelet c o u nts)g 
X h 
X  
X  
X  
X  
C oa g ulati o n pa nel  (ce ntral la b) 
X  
 
X  
 
X  
Ser u m c he mistr y  (ce ntral la b) 
X  
 
X  
 
X  
Pre g na nc y testi n g i 
X  
 
 
 
X  
Blee di n g assess me nt (I S T H)  
←−−−−−−−−−−−− c o nti n u o us  −−−−−−−−−−−−−→
j 
C o ntact I R T  
X  
 
X  
 
X  
A vatr o m b o pa g d osi n g k 
X  
 
X  
 
 
Dis pe nse a vatr o m b o pa g  
X  
X l 
 
 
 
C ollect u n use d a vatr o m b o pa g, if a p plica ble  
 
X  
X  
 
X m  
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p; I/ E = i n cl usi o n/e xcl usi o n; i n cl.  = i n cl u di n g; I R T = I nteracti ve Res p o nse Tec h n ol o g y; I S T H = 
I nter nati o nal S o ciety o n T hr o m b os is a n d Hae m ostasis. 
N ote : T hr o u g h o ut t h e o p e n -la b el e xte nsi o n p eri o d, all s u bjects will b e assesse d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose re d ucti o ns or dela ys.  
a. 
Visit 1 3 will o cc ur o n t h e first d a y of t h e pre -c h e m ot h era p y a vatr o m b o p ag treat me nt. F or C ycle X + 4, t his visit will be de n ote d Visit 1 3. 1 a n d f or C ycle X + 5, t his visit will 
be de n ote d Visit 1 3. 2. T his n u m b eri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycl es. 
b.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n (e g, if c h e m ot h era p y is gi ve n o n Da y 1 an d Da y 2, t he sec o n d r o u n d of 
a vatr o m b o p a g will start o n Da y 3). A vatr o m b o p a g will n ot b e a d mi nistere d c o n c urre ntl y wit h c h e m ot h era p y o n C h e m ot hera p y Da y.  All assess me nts will occ ur  o n t he first 
da y of c he m ot h era p y pri or t o c h e m ot h era p y d osi n g. F or C ycle X  + 4, t his visit will b e d e n ote d Visit 1 4. 1 a n d f or C ycle X + 5, t his visit will be de n ote d Visit 1 4. 2. T his 
n u m beri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycles. 
c. 
Visit 1 5  will o cc ur o n t h e last d a y of t h e 5 -d a y p ost -c h e m o a v atr o m b o p a g treat me nt. F or C ycle X + 4, t his visit will b e de n ote d Visit 1 5. 1 a n d f or C ycle X + 5, t his visit will 
be de n ote d Visit 1 5. 2. T his n u m b eri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr o lle d o p e n-la b el c ycl es. 
d.  
F or C ycle X + 4, t his visit will b e d e n ote d Visit 1 6. 1 a n d f or C ycle X + 5, t his visit will b e d e n ote d Visit 1 6. 2. T his n u m beri n g sc he me will c o nti n ue f or s u bse q ue nt e nr olle d 
o pe n -la bel c ycl es. 
e. 
S u bjects will h a ve a F oll o w -U p V isit at 3 0 d a ys (± 3 d a ys) after t h e last d ose of a vatr o m b o p a g treat me nt of t h e s u bject’s last c he m ot hera p y c ycle. 
f. 
I ncl u des bl o o d press ure a n d p ulse rate  a n d will b e meas ure d after resti n g f or 5  mi n utes.  
g.  
He mat ol o g y sa m ples will  b e se nt t o t h e ce ntral la b i n a d diti o n t o l ocal la b platelet c o u nts f or Visits 1 3, 1 4, 1 5, a n d 1 7. O nl y l ocal la b platelet c o u nts will be assesse d at Visit 
1 6.  
h.  
Bl o o d sa m ple f or platelet c o u nts will b e c ollecte d pri or t o a vatr o m b o p a g d osi n g.  Platelet c o u nts ma y b e p erf or me d pri or ( -1 da y) t o  a vatr o m b o pa g d osi n g . 


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i. 
F or fe males of c hil d b eari n g p ote ntial o nl y. A ser u m or uri n e pre g n a n c y test ma y  b e p erf or me d at Visit  1 3 . 
j. 
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
k.  
All s u bjects will recei ve a v atr o m b o p a g o n c e d ail y f or 5 d a ys pri or t o C h e m ot h era p y Da y i n C ycle X + 3. S u bjects will  als o recei ve a vatr o m b o pa g o nce dail y f or 5  da ys 
f oll o wi n g t h e last d a y of c h e m ot h era p y treat me nt. At sc h e d ule d st u d y visits, a v atr o m b o p a g ma y b e a d mi nistere d at t h e site or t he s u bj ect ma y s elf-d ose. S u bjects will 
self-d ose at all ot h er ti mes. S u bjects will b e i nstr u cte d t o ta ke a vatr o m b o p a g  wit h f o o d. T h e I n vesti gat or or d esi g n ee will pr o vi de s u bjects wit h s ufficie nt a vatr o m b o pa g  t o 
c o m plete t h e re gi me n.  
l. 
T hese pr oce d ures will b e p er f or me d p ost-c h e m ot h era p y d osi n g o n t h e last C h e m ot h era p y Da y of t h e c ycle.  
m.  O nl y f or a n E arl y T er mi n ati o n  Visit.  


A P P E N DI X B:  C LI NI C A L L A B O R A T O R Y A N A L Y T E S 
S af et y C he mist r y P a nel  
Ala ni ne a mi n otra nsf eras e  
As partate a mi n otra nsferase  
Al kali ne p h os p hatase  
Dire ct bilir u bi n  
T otal car b o n di o xi de ( Bi car b o nat e ) 
Urea ( Bl o o d urea nitr o ge n ) 
Calci u m  
C hl ori de  
I n or ga nic p h os p h or us 
Creati ni ne  
P otassi u m  
Gl uc ose  
T otal bilir u bi n  
S o di u m  
 
He m at ol o g y  
He mat ocrit  
He m o gl o bi n  
Platelets  
Re d bl o o d cell c o u nt  
W hite bl o o d cell c o u nt a n d differe ntial  
 
 
C o a g ul ati o n  
Pr ot hr o m bi n ti me  
Acti vate d partial t hr o m b o plasti n ti me  
I nter nati o nal n or malize d rati o 
 
 
Pre g n a nc y Test  
Beta -h u ma n c h ori o nic g o na d otr o pi n  
 
 
Cre ati ni ne Cle ar a nce usi n g t he C oc kcr oft -G a ult f or m ul a  


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A P P E N DI X C:  C Y T O C H R O M E P 4 5 0 I N D U C E R S  
T a ble 4 
C yt oc hr o me P 4 5 0 I n d ucers  
 
Str o n g  
M o der ate  
C Y P 2 C 9 i n d ucers  
N A  
A pre pita nt, car ba maze pi ne, 
e nzal uta mi de, f osa pre pita nt, rifa m pi n, 
rit o na vir 
C Y P 3 A 4 i n d ucers  
Car ba maze pi ne, e nzal uta mi de, mit ota ne, 
p he n yt oi n, r ifa m pi n, St.  J o h n’s w ort 
B ose nta n, efa vire nz, etra viri ne, m o dafi nil  
C Y P = c yt oc hr o me P 4 5 0; N A = n ot a p plica ble.  
S o urce:  
htt ps:// w w w.f d a. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr o cess/ De v el o p me nt Res o urces/ Dr u gI nteracti o ns La b eli n g/ u c m 0 9 3 6 6 4. ht m
#i n Vi v o  
 


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A P P E N DI X D:  I N T E R N A TI O N A L S O CI E T Y O N T H R O M B O SI S A N D 
H A E M O S T A SI S B L E E DI N G  D E FI NI TI O N S  
T a ble 5.  I nter n ati o n al S ociet y o n T hr o m b osis a n d H ae m ost asis Blee di n g Defi niti o ns 
Maj or blee di n g  
Defi ne d as o vert blee di n g wit h 1 or m ore of t he f oll o wi n g:  
• 
Ass ociate d wit h a fall i n he m o gl o bi n le vel of 2 0 g/ L ( 1. 2 4 m m ol/ L) or m ore;  
• 
Lea ds t o a tra nsf usi o n of 2 or m ore u nits of pac ke d re d bl o o d cells or w h ole bl o o d;  
• 
Occ urs i n a critical site: i ntracra nial, i ntras pi nal, i ntra oc ular, pericar dial, i ntra -artic ular, 
i ntra m usc ular wit h c o m part me nt s y n dr o me, retr o perit o neal; a n d/ or 
• 
C o ntri b utes t o deat h.  
N o n -maj or 
cli nicall y rele va nt 
blee di n g  
 
Defi ne d as o vert blee di n g n ot meeti n g t he criteria f or maj or blee di n g, b ut ass ociate d wit h 
me dical i nter ve nti o n, u nsc he d ule d c o nt act wit h a p h ysicia n ( visit or tele p h o ne call), 
(te m p orar y) cessati o n of st u d y treat me nt, or ass ociate d wit h a n y ot her disc o mf ort, s uc h as 
pai n or i m pair me nt of dail y acti vities. E xa m ples of s uc h blee di n g i ncl u de:  
• 
A n y blee di n g c o m pr o misi n g he m o d y na mics;  
• 
A n y blee di n g lea di n g t o h os pitalizati o n;  
• 
E pista xis if it lasts f or > 5 mi n utes, if it is re petiti ve (ie, ≥2 e pis o des of tr ue blee di n g [ie, 
n ot s p ots o n a ha n d kerc hief] wit hi n 2 4  h o urs), or if it lea ds t o a n i nter ve nti o n ( pac ki n g, 
electr oc oa g ulati o n, etc.);  
• 
Gi n gi val blee di n g if it occ urs s p o nta ne o usl y (ie, u nrelate d t o t o ot h br us hi n g or eati n g) 
or lasts > 5 mi n ut es;  
• 
He mat uria if it is macr osc o pic a n d eit her s p o nta ne o us or lasts > 2 4 h o urs after 
i nstr u me ntati o n (e g, cat heter place me nt or s ur ger y) of t he ur o ge nital tract; 
• 
Macr osc o pic gastr oi ntesti nal he m orr ha ge (at least 1 e pis o de of mele na/ he mate mesis, if 
cli nicall y a p pare nt, a n d he m oc c ult p ositi ve rectal bl o o d l oss, if m ore t ha n a fe w s p ots o n 
t oilet pa per); 
• 
He m o pt ysis, if m ore t ha n a fe w s pec kles i n t he s p ut u m a n d n ot occ urri n g wit hi n t he 
c o nte xt of a p ul m o nar y e m b olis m;  
• 
I ntra m usc ular he mat o ma;  
• 
S u bc uta ne o us (s ki n) he mat o ma if t he size is > 2 5 c m 2 or > 1 0 0 c m 2 if pr o v o ke d; a n d/ or 
• 
A n y ot her blee di n g t y pe t hat is c o nsi dere d t o ha ve cli nical c o nse q ue nces f or a s u bj ect.  
Mi n or blee di n g  
Defi ne d as all ot her o vert blee di n g e pis o des n ot meeti n g t he criteria f or maj or or cli nicall y 
rele va nt n o n-maj or blee di n g.  
S o urces: Sc h ul ma n S, A n geras D, Ber g q vist B, et al. Defi niti o n of maj or blee di n g i n cli nical i n vesti gati o ns of a nti h e m ostatic 
me dici nal pr o d u cts i n s ur gical p atie nts. J T hr o m b Hae m ost. 2 0 1 0; 8: 2 0 2 -2 0 4 a n d Ta n gel d er M, N wac h u k u C, Jaff M, et al. A 
re vie w of a ntit hr o m b otic t h era p y a n d t h e rati o n ale a n d d esi g n of t he ra n d o mize d e d o xa b a n i n p atie nts wit h p eri p h eral arter y 
di sease (e P A D) trial a d di n g e d o xa b a n or cl o pi d o grel t o as piri n after fe m or o p o pliteal e n d o vasc ular i nter ve nti o n. J E n d o vasc 
T her. 2 0 1 5; 2 2( 2) 2 6 1 -2 6 8.   
 
 
 


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A P P E N DI X E :  Pr ot oc ol A me n d me nts  
A me n d me nt # 1 – 0 4 A pril  2 0 1 9 
 
Rati o nale f or A me n d me nt  
A me n d me nt 1 has bee n i ntr o d uce d t o i ncl u de a n a d diti o nal t u m or t y pe, clarif y t he ti me peri o d f or 
assess me nt  of  t he  efficac y  e n d p oi nts,  a n d  clarif y  certai n  i ncl usi o n  a n d  e x cl usi o n  criteria.  
A d diti o nall y, t he Scree ni n g a n d Baseli ne Visits ma y n o w be c o m bi ne d a n d perf or me d o n  t he sa me 
da y a n d t he wi n d o w f or a se parat e Scree ni n g Visit has bee n i ncreas e d t o 2 8 da ys. 
A d diti o nal T u m or T y pe: D ue t o t he si milarities i n c he m ot hera p y a ge nts us e d i n t he treat me nt of 
s mall cell l u n g ca ncer c o m pare d t o n o n-s mall cell l u n g ca ncer, s u bj ects wit h s mall cell l u n g ca n cer 
are eli gi ble f or e nr oll me nt .  
Ti me  Peri o d  f or  Assess me nt  of  E n d p oi nts:  T he  ti me  peri o d  f or  effi cac y  assess me nts  f or  
c he m ot hera p y d ela ys a n d d ose re d ucti o ns has b ee n clarifie d t o ‘t he peri o d aft er p ost -c h e m ot hera p y 
I P treat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y Da y  of C ycl e X + 2 ’. If a s u bject has decrease d 
or dela ye d d oses of a c he m ot hera pe utic a ge nt d ue t o t hr o m b oc yt o p e nia d uri n g t he mi d dle of C ycl e 
X + 1 ( e g, D a y 1 5 ge mcita bi ne), t his c o ul d affect w het her or n ot t h ere is a nee d f or a dela y or d ose 
re d ucti o n at t he be gi n ni n g of C ycle X + 2 d ue t o t hr o m b oc yt o p e nia.  As a res ult, t his ti me peri o d 
clarificati o n was w arr a nte d t o e ns ur e acc urate dat a c ollecti o n f or t he assess me nt of t he efficac y 
e n d p oi nts. 
I n cl usi o n/ E x cl usi o n Criteria Clarificati o n:  I n cl usi o n  C riteri o n # 5 pre vi o usl y re q uire d t hat  t he 
s u bject w o ul d be a ble t o recei v e t he sa me d os e a n d sc he d ule of c he m ot hera p y i n C ycl e X + 1 as 
t he y recei ve d i n C ycle X. T his criteri o n has n o w bee n clarifie d t o “ S u bject is pla n ne d t o recei ve 
the sa me c he m ot her a p y r e gi me n a n d t h e sa me d os e(s) o n C he m ot he ra p y D a y ( D a ys 1-3) of C ycl e 
X + 1 as was gi ve n i n t he q ualif yi n g c he m ot hera p y C ycle X ” t o ali g n wit h t he clarificati o n i n t he 
ti mi n g of t he efficac y e n d p oi nt clarificati o n descri be d a b o ve.  
E x cl us i o n Criteri o n # 9 has bee n m o difie d t o e x cl u de patie nts wit h a rece nt hist or y ( 3 m o nt hs pri or 
t o Scree ni n g) of si g nifica nt car diac disease. T here is n o e vi de n ce t hat w o ul d precl u d e use of 
a vatr o m b o pa g i n s u bjects wit h sta ble car diac disease.  
D ue t o c o m merc ial a vaila bilit y of r ec o m bi na nt h u ma n T P O i n s o me c o u ntries, E x cl usi o n C riteri o n 
# 1 4 has bee n clarifie d t o e x cl u de rec o m bi na nt h u ma n t hr o m b o p oieti n i n a d diti o n t o t he T P O -
rece pt or a g o nists i n t he 3 m o nt hs pri or t o Scree ni n g.  
C o m bi ne d Scree ni n g a n d Baseli n e: T he Bas eli ne Visit ma y n o w be c o n d u cte d o ne da y pri or t o I P 
treat me nt, a n d ma y be c o m bi ne d wit h t he Scree ni n g Visit. As platelet c o u nts fr o m sta n dar d of care 
la b orat or y  assess me nts  ma y  b e  use d  f or  eli gi bilit y,  t his  c h a n ge  s h o ul d  all o w  f or  l o gistical  
efficie n cies a n d r e d uce t he re q uire d n u m ber of visits f or a p ote ntial s u bject. T he wi n d o w f or a 
se parat e  Scree ni n g  Visit  has  bee n  i ncrease d  t o  2 8  da ys,  fr o m  1 4  da ys,  t o  all o w  f or  earlier  
c o nse nti n g of s u bjects i n or der t o scr ee n f or t hr o m b oc yt o p e nia i n C ycl e X.  
 
 


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S u m mar y of Si g nifica nt C ha n ges i n A m e n d me nt 1 
•  Patie nts wit h s mall cell l u n g ca ncer are eli gi ble t o be e nr olle d  
•  T he ti mefra me f or efficac y assess me nts f or d ose re d ucti o ns a n d dela ys i n c he m ot hera p y 
has bee n clarifie d t o i ncl u de t he peri o d after p ost -c he m ot hera p y I P treat me nt i n C ycle X + 1 
•  E x cl usi o n  C riterio n # 9  h as bee n  clarifie d  t o  e xcl u de  o nl y  t h ose  patie nts  wit h  rece nt  
hist ories of  si g nifica nt  car diac diseas e i n t he 3 m o nt hs pri or t o Scree ni n g; Ex cl usi o n 
C riterio n  # 1 4  n o w e x cl u des rec o m bi na nt h u ma n T P O, i n a d diti o n t o eltr o m b o pa g a n d 
r o mi pl osti m 
•  T he Baseli ne Vi sit ma y b e perf or me d o ne d a y pri or t o I P treat me nt, a n d ma y b e c o m bi ne d 
wit h t he Scree ni n g Visit . T he visit wi n d o w f or t h e Scree ni n g Visit has bee n i ncrease d t o 
2 8 da ys. 
 
T he f oll o wi n g pr ese nts c ha n ges ma d e b y t his a m e n d me nt . Ne w/revise d te xt is prese nte d i n b ol d 
it alics; delete d te xt is i de ntifie d b y stri ket hr o u g h. T y p o gra p hic c orrecti o ns, i ncl u di n g gra m matical 
a n d p u nct uati o n err ors, are n ot s h o w n. 
 
S Y N O P SI S  
3. 1. 1 Scree ni n g/ Q ualif yi n g C he m ot her a p y Re gi me n ( C ycle X)  
T o be eli gi ble f or t he st u d y, s u bjects m ust ha ve e x perie nce d t hr o m b oc yt o pe nia d uri n g t heir c urre nt 
c he m ot hera p y  r e gi me n  as  descri be d  i n  t he  i ncl usi o n  criteria  i n  Secti o n  4. 1.  T he  q ualif yi n g  
c he m ot hera p y c ycle is defi ne d as “ C ycle X”. S u bjects m ust be scree ne d ≤1 4  2 8  da ys pri or t o t he 
Baseli ne Visit, u nless Scree ni n g a n d B aseli ne Visits are perf or m e d o n t he s a m e d ay , a n d be gi n 
treat me nt d uri n g C ycle X. 
3. 1. 2 D o u ble- Bli n d Tr eat me nt Peri o d  
At  t he  Baseli ne  Visit,  eli gi ble  s u bjects  will  be  r a n d o mize d  i n  a  2: 1  ra ti o  t o  recei ve  eit her  
a vatr o m b o pa g  or  pl ace b o  i n  a  d o u ble -bli n d  ma n ner  pri or  t o  a n d  d uri n g  t he  s u bs e q ue nt  
c he m ot hera p y c ycle, C ycle X + 1. Ra n d o mizati o n will be stratifie d b y t he n u m ber of c h e m ot hera p y 
a ge nts t he s u bject is r ecei vi n g ( 1  or  ≥2  per missi ble  c he m ot hera p y a ge nts [ n ucle osi de a nal o g, 
i ncl u di n g  ge mcita bi ne  a n d  fl u or o uracil;  car b o pl ati n  or  cis plati n;  a nt hrac ycli ne;  or  al k ylati n g  
a ge nt]). S u bjects will recei ve eit her a v atr o m b o p a g or place b o o n ce dail y f or 5 da ys pri or t o 
C he m ot he ra p y Da y i n C ycle X + 1. S u bjects will als o recei v e a vatr o m b o pa g or place b o o n ce d ail y 
f or 5 da ys i m me diatel y f oll o wi n g C he m ot hera p y Da y. C he m ot hera p y D a y is defi ne d per pr ot oc ol 
as Da y 1 t o 3 of t h e s u bject’s c h e m ot hera p y re gi me n (e g, if c he m ot hera p y is g i ve n o n D a y 1 a n d 
Da y  2, t he sec o n d r o u n d of a v atr o m b o pa g or place b o will start o n D a y 3). A v atr o m b o pa g or 
place b o  will  n ot  be  a d mi nistere d  c o nc urre ntl y  wit h  c he m ot hera p y  o n  C he m ot hera p y  Da y.  
C he m ot hera p y r e gi me ns re q uiri n g d osi n g be y o n d C he m ot hera p y D a y wit hi n t he 2 1 -da y or 2 8- da y 
c ycle ( e g, ge m cita bi ne o n Da y 8) ar e all o we d. T hese mi d -cycle c he m ot her a py d oses, after I P 
tre at m e nt,  will  be  p art  of  t he  assess m e nt  of  t he  c o m p osite  pri m ary  e n d p oi nt  f or  d os e  
m o dific ati o ns or del ays. 


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3. 1. 3 O bser vati o nal Peri o d  
C ycle X + 2 will be a n  O bser vati o nal Peri o d. T he O bser v ati o nal Peri o d is desi g n e d t o e n a ble 
assess me nt of w h et her t he s u bjects meet t he c h e m ot hera p y d os e m o dificati o ns or d ose dela y 
c o m p o ne nts  of  t he  c o m p osite  pri mar y  e n d p oi nt  o n  t he  C he m ot her a py  D ay  w hile re d uci n g 
decisi o n ma k i n g bias f or c he m ot hera p y d os e m o dificati o ns or dela ys. S u bjects i n t he O bser vati o nal 
Peri o d will n ot recei ve a n y I P pr e- or p ost- C he m ot hera p y Da y i n C ycl e X + 2.  
4. 1 I ncl usi o n Criteri a f or All S u bjects  
2.  S u bject wit h a dia g n osis  wit h o v aria n ca ncer , n o n s mall cell l u n g ca ncer (s m all cell or n o n-
s m all cell), or bla d der ca ncer, r e q uiri n g s yste mic c he m ot hera p y;  
4.  S u bject  e x perie nce d  se v ere  t hr o m b oc yt o pe ni a,  defi ne d  as  2  platelet  c o u nts  < 5 0  ×   1 09/ L 
meas ure d at least 2 4  h o urs a part, d uri n g t he q ualif yi n g c he m ot hera p y c ycle ( C ycle X), of t heir 
c urre nt c he m ot hera p y re gi me n . Pl atel et c o u nts o bt ai ne d per st a n d ar d of c are d uri n g Cycle X 
pri or t o c o nse nt m ay be use d;  
5.  S u bject is a ble pl a n ne d  t o receive t he s a m e c he m ot her a py re gi m e n a n d t he s a m e d ose(s) o n 
C he m ot her a py D ay ( D ays 1 -3) of Cycle X + 1  c o nti n ue t o recei ve t he c urre nt c he m ot hera p y 
re gi me n at t he sa me d ose a n d sc he d ule as w as gi ve n i n t he q ualif yi n g c h e m ot hera p y C ycle X;  
4. 2 E xcl usi o n Criteri a f or All S u bjects  
4.  S u bject w h o recei v e d > 2 pre vi o us lines of c he m ot hera p y ( a dj uv a nt/ ne o a dj uv a nt t her a py is 
c o nsi dere d a previ o us li ne; i m m u n ot her a py al o ne is n ot c o nsi dere d a previ o us li ne)  or is 
recei vi n g w h ole brai n r a diati o n d uri n g t he st u d y treat me nt peri o d; 
6.  S u bject h as a k n o w n me dic al hist ory of  is k n o w n t o be h u ma n i m m u n o deficie nc y vir us 
p ositi ve; 
9.  S u bject has a rece nt  hist or y ( wit hi n 3 m o nt hs of Scree ni n g) of si g nifica nt car di o vas c ular 
disease (e g, c o n gesti ve heart fail ure Ne w Y or k Heart Ass ociati o n Gra d e 3/ 4  e x a cer b ati o n , 
arr h yt h mia  k n o w n  t o  i n creas e  t h e  ris k  of  t hr o m b oe m b olic  e ve nts  [e g,  atrial  fi brillati o n],  
c or o nar y arter y ste nt place me nt, a n gi o plast y, or c or o nar y arter y b y p ass graft);  
1 4.  S u bject  has  pre vi o usl y recei v e d  a  t hr o m b o p oieti n  rece pt or  a g o nist  (e g,  eltr o m b o pa g or 
r o mi pl osti m) or  rec o m bi n a nt  h u m a n  t hr o m b o p oieti n  f or  t he  treat me nt  of  CI T wit hi n  3 
m o nt hs of Scree ni n g ; 
1 5.  S u bject recei v e d a platel et tra nsf usi o n wit hi n 3 da ys 7 2 h o urs  of ra n d o mizati o n; 
1 8.  Fe male  s u bjects  w h o  are  lactati n g  or  pre g n a nt  at  Scree ni n g  or  t he  B aseli ne  Visit  (as 
d oc u me nte d b y a p ositi ve ser u m  or uri ne  beta -h u m a n c h ori o nic g o n a d otr o pi n [ β -h C G] test)  or 
t he Bas eli ne Visit ( uri ne); 
4. 5 Wit h dr a w al Criteri a 
If a s u bject wit h dra ws pr e mat urel y fr o m t he st u d y d u e t o t he a b o ve criteria or a n y ot her reas o n, 
st u d y staff s h o ul d ma k e e ver y eff ort t o c o m plet e t he f ull pa nel of ass ess me nts sc he d ule d f or 
Visit  1 3 (f or s u bjects n ot i n t he o pti o nal O L E Peri o d) or Visit  1 7 (f or s u bjects partici pati n g i n  t he 
o pti o nal O L E Peri o d). All s u bjects s h o ul d c o nti n ue i nt o t he  L o n g -Ter m F oll o w -U p Peri o d u nless 
c o nse nt h as bee n wit h dr a w n.  T he reas o n f or s u bject wit h dra w al m ust b e d oc u me nte d i n t he 
electr o nic case re p ort f or m (e C R F).  


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5. 3 R a n d o miz ati o n a n d Bli n di n g 
T his is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y. F or t he D o u bl e -Bli n d Treat me nt 
Peri o d, s u bjects w h o c o m plete t he Scree ni n g Visit a n d  meet t he i ncl usi o n criteria a n d e x cl usi o n 
criteria will be ra n d o mize d t o recei ve eit her a vatr o m b o pa g 6 0 m g or  place b o i n a 2: 1 rati o at 
t he Bas eli ne Visit. 
5. 6. 1 E x cl u de d Me dicati o ns a n d/ or Pr oce d ures 
T he f oll o wi n g m e dicati o ns a n d/ or pr oce d ures are e x cl u de d: 
•  Use of t hr o m b o p oieti n rece pt or a g o nists or rec o m bi n a nt h u m a n t hr o m b o p oieti n; 
6. 2. 1 Scree ni n g ( Visit 1, Da y  - 1 4 2 8 t o Da y - 1) 
T he Scree ni n g Visit m ay be c o m bi ne d wit h t he B aseli ne Visit o n t he d ay pri or t o I P tre at m e nt 
( D ay -1).  
T he f oll o wi n g pr oce d ures will be perf or me d at t he Scree ni n g Visit:  
•  Perf or m pre g n a nc y test ( ser u m or uri ne ) f or fe male s u bjects of c hil d beari n g p ote ntial o nl y; 
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts  (if Scree ni n g Visit occ urs o n t he s a me 
d ay as t he B aseli ne Visit, o nly t he B aseli ne l a b or at ory assess m e nts s h o ul d be perf or m e d):  
o  He mat ol o g y (i ncl u di n g platelet c o u nts) . L oc al pl a t elet c o u nts m ay be re pe ate d as nee de d; 
a n d 
6. 2. 2 Bas eli ne Visit ( Visit 2 , First  D a y [ or -1 D ay]  of t he 5-da y I n vesti gati o nal Pr o d uct Treat me nt)  
T he B aseli ne Visit m ay occ ur o ne d ay pri or t o I P tre at m e nt, a n d m ay be c o m bi ne d wit h t he 
Scree ni n g Visit.  
Eli gi ble s u bjects will recei ve eit her a v atr o m b o p a g or place b o o nce dail y f or 5 da ys pri or t o 
C he m ot hera p y  D a y i n C ycl e X + 1. T h e f oll o wi n g pr oce d ures will be perf or me d at t he Bas eli ne 
Visit pri or t o I P d osi n g: 
•  Rec or d vital si g ns (i ncl u des wei g ht, b o d y te m perat ure, bl o o d press ure, a n d p ulse rate) . 
O nly Scree ni n g vit al si g ns will be rec or de d if c o m bi ne d wit h t he Scree ni n g Visit ; 
•  Perf or m pre g n a nc y test ( s er u m or uri ne) f or fe m ale s u bjects of c hil d beari n g p ote ntial o nl y;  
•  A d mi nister or self -d ose I P  wit h f o o d , if t he B aseli ne Visit occ urs o n t he first d ay of t he 
5- d ay I P tre at m e nt.  
6. 3. 2  P ost- C he m ot hera p y I n vesti ga ti o nal Pr o d uct Treat me nt ( Visit 5) , Last Da y of t he 5-da y 
I n v esti gati o nal Pr o d uct Treat me nt) 
6. 4 O bser v ati o n al Peri o d ( C ycle X + 2) 
If C he m ot her a py D ay i n Cycle X + 2 is del aye d, r ec or d t he re as o n f or del ay i n t he e C R F. If t he 
del ay is d ue t o l a b or at ory res u lts, rec or d t he relev a nt res ults i n t he e C R F. 
7 E F FI C A C Y A S S E S S M E N T S   


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T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all of t he f oll o wi n g criteria  
d uri n g t he peri o d after p ost -c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py 
D ay of Cycl e X + 2 : 
•  N ot re q uiri n g a platelet tra nsf usi o n  d uri n g C ycl e X + 1 t hr o u g h i m me di atel y pri or t o 
C ycle  X + 2; 
•  N ot  re q uiri n g  a  c he m ot hera p y  d os e  re d ucti o n  b y  ≥1 5 % i n  C ycle  X  +  2 d ue  t o  
t hr o m b oc yt o pe ni a i n C ycle X + 1; a n d  
•  N ot re q uiri n g a c he m ot h er a p y dela y b y ≥4 da ys i n C ycle X + 2 d ue t o t hr o m b oc yt o pe ni a  
i n C ycle X + 1. 
T he ke y sec o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  D urati o n of se ver e t hr o m b oc yt o pe ni a defi ne d as a platelet c o u nt < 5 0 ×  1 0 9/ L d uri n g t he 
peri o d after p ost -c he m ot her a py I P  tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay 
of Cycle X + 2  C ycle  X + 1 t hr o u g h i m me diatel y pri or t o C ycle X + 2; 
•  C ha n ge i n platel et c o u nt fr o m baseli ne ( q u alif yi n g c he m ot hera p y c ycle [ C ycle X]) ( n a dir) 
t o C ycle X + 1 ( na dir); 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve maj or or n o n -maj or cli nicall y rel e va nt blee di n g 
d uri n g t he peri o d  after  p ost -c he m ot her a py  I P  tre at m e nt  i n  Cycle  X + 1  t hr o u g h  
C he m ot her a py D ay of Cycle X + 2  C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycle  X + 2; 
a n d 
•  Pr o p orti o n of s u bjects w h o d o n o t recei ve a platelet tra nsf usi o n d uri n g t he peri o d after 
p ost- c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2 
C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycl e X + 2.  
T he ot her effi cac y e n d p oi nts i ncl u de t he f oll o wi n g  d uri n g t he p eri o d after p ost -c he m ot her a py I P 
tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycl e X + 2: 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c h e m ot hera p y d os e re d u cti o n t hat is ≥1 5 % i n 
C ycle  X + 2  d ue t o t hr o m b oc yt o p e nia i n C ycl e X + 1; 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c he m ot hera p y dela y t hat is ≥4 da ys i n C ycl e X 
+ 2 d ue t o t hr o m b oc yt o p e nia i n C ycl e X + 1; 
•  Pr o p orti o n of s u bjects wit h a pre -d efi ne d p ost -bas eli ne na dir platelet c o u nt  d uri n g C ycle 
X +  1 a n d t hr o u g h i m me diatel y pri or t o C ycl e X + 2; a n d 
•  Pr o p orti o n of s u bjects ac hie vi n g a pre -d efi ne d p ost -baseli ne ma xi m u m platelet c o u nt  
d uri n g C ycle X + 1 a n d t hr o u g h i m me diatel y pri or t o C ycle X + 2. 
9. 1 A d verse E ve nts 
A d verse  e v e nts,  w hic h  i ncl u de  cli nical  la b orat or y  test  varia bles,  will  be  m o nit ore d  a n d  
d oc u me nte d fr o m t he ti me of i nf or me d c o ns e nt u ntil t he F oll o w -U p Vi sit occ urri n g pri or t o ( wit hi n 
3 da ys)  C he m ot hera p y Da y i n C ycle X + 3 (f or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E 
Peri o d) a n d t he F oll o w -U p Visit occ urri n g 3 0 da ys aft er last d ose of I P (f or s u bjects c o nti n ui n g 
i nt o t he o pti o nal O L E Peri o d). S u bjects s h o ul d b e i nstr ucte d t o re p ort a n y a d verse e ve nt t h at t he y 
e x perie nce t o t he I n vesti gat or. Be gi n ni n g wit h t he Scree ni n g Visit, I n vesti gat ors s h o ul d ma ke a n 


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assess me nt f or a d verse e ve nts at eac h visit a n d rec or d t he e ve nt o n t he a p pr o priate a d verse e ve nt  
e C R F. E ve nts ass o ciate d wit h disease pr o gressi o n s h o ul d n ot be re p orte d as a d verse e ve nts /S A E s. 
T he e ve nts will be ca pt ure d as a n o utc o me o n a se parate f or m f or deat hs d ue t o disease pr o gress i o n. 
H o we ver, if i n t he I n vesti gat or’s o pi ni o n t he disease pr o gressi o n is ma nifesti n g i n a n u n us ual or 
u nc haracteristic ma n n er, t he ass ociate d e ve nts s h o ul d be re p orte d as a d verse e v e nts/ S A Es, as 
a p pr o priate. 
1 0. 2. 1. 1 Pri mar y efficac y a nal ysis  
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all o f t he f oll o wi n g criteria 
d uri n g t he peri o d after p ost -c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py 
D ay of Cycl e X + 2 : 
•  N ot re q uiri n g a platelet tra nsf usi o n  d uri n g C ycl e X + 1 t hr o u g h i m me di atel y pri or t o 
C ycle  X + 2; 
•  N ot  re q uiri n g  a  c he m ot hera p y  d os e  re d ucti o n  b y  ≥1 5 % i n  C ycle  X  +  2 d ue  t o  
t hr o m b oc yt o pe ni ai n C ycl e X + 1; a n d  
•  N ot re q uiri n g a c he m ot h era p y dela y b y ≥4 da ys i n C ycle X + 2 d ue t o t hr o m b oc yt o pe ni a  
i n C ycle X + 1. 
1 0. 2. 1. 2 Ke y sec o n d ar y efficac y a nal ysis  
T he ke y sec o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  D urati o n of se ver e t hr o m b oc yt o pe ni a defi ne d as a platelet c o u nt < 5 0 ×  1 0 9/ L d uri n g t he 
peri o d after p ost -c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay 
of Cycle X + 2  C ycle  X + 1 t hr o u g h i m me diatel y pri or t o C ycle X + 2; 
•  C ha n ge i n platel et c o u nt fr o m baseli ne ( q u alif yi n g c he m ot hera p y c ycle [ C ycle X]) ( n a dir) 
t o C ycle X + 1 ( na dir); 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve maj or or n o n -maj o r cli nicall y rel e va nt blee di n g 
d uri n g t he  peri o d  after  p ost-c he m ot her a py  I P  tre at m e nt  i n  Cycle  X + 1  t hr o u g h  
C he m ot her a py D ay of Cycle X + 2  C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycle  X + 2; 
a n d 
•  Pr o p orti o n of s u bjects w h o d o n ot recei ve platelet tra nsf usi o n d uri n g t he peri o d after p ost -
c he m ot her a py I P tre at m e nt i n Cycle  X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2  
C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycl e X + 2.   
If t he test of t he treat me nt effect o n t he pri mar y efficac y e n d p oi nt is statisticall y si g nifica nt, t he 
a nal ysis of t he ke y s ec o n dar y efficac y e n d p oi nts will pr ocee d usi n g ste p-d o w n cl ose d testi n g 
pr oce d ur e i n t he f oll o wi n g or der t o mai ntai n t he fa mil y-wise T y pe I err or rate at si g nifica nce le vel 
al p ha = 0. 0 5 ( 2-si de d): 
•  Ste p  1:  Test  t he  treat me nt  effect  at  a si g nifica nt  le vel  of  0. 0 5 o n  d urati o n of se v ere  
t hr o m boc yt o pe ni a defi ne d as a platelet c o u nt < 5 0 ×  1 09/ L d uri n g t he peri o d after p ost -
c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2  
d uri n g C ycle X + 1 t hr o u g h i m me diatel y pri or t o  C ycle X + 2 ; if s uccessf ul, pr ocee d t o 
Ste p 2; ot her wise st o p at Ste p 1.  


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•  Ste p 2: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n c ha n ge i n platelet c o u nt 
fr o m bas eli ne ( q u alif yi n g c he m ot hera p y c ycle [ C ycle X]) ( na dir) t o C ycle X + 1 ( n a dir); if 
s uccessf ul, pr o cee d t o Ste p 3; ot her wise st o p at Ste p 2. 
•  Ste p 3: Test t he treat me nt effect at a si g nifi ca nt le v el of 0. 0 5 o n pr o p orti o n of s u bjects w h o 
d o n ot ha ve maj or or n o n -maj or cli nicall y rel e va nt blee di n g d uri n g t he peri o d after p ost -
c he m ot her a py  I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2 
d uri n g C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycle X + 2 ; if s uccessf ul, pr ocee d t o 
Ste p 4; ot her wise st o p at Ste p 3. 
•  Ste p 4: Test t he treat me nt effect at a si g nifi ca nt le v el of 0. 0 5 o n pr o p orti o n of s u bjects w h o 
d o  n ot  recei v e  platelet  tra nsf usi o n d uri n g  t he  peri o d  after  p ost -c h e m ot her a py  I P  
tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2 d uri n g C ycle X + 1 
t hr o u g h i m me diatel y pri or t o C ycle X + 2. 
1 0. 2. 1. 3 Ot her efficac y a nal ysis  
T he ot her effi cac y e n d p oi nts i ncl u de t he f oll o w i n g d uri n g t he peri o d after p ost -c he m ot her a py I P 
tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycl e X + 2: 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c he m ot hera p y d ose re d ucti o n t hat is ≥1 5 % i n 
C ycle  X + 2 d ue t o t hr o m b oc yt o p e nia i n C ycl e X + 1; 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c he m ot hera p y del a y t h at is ≥4 da ys i n C ycle X + 
2 d ue t o t hr o m b oc yt o p e nia i n C ycle X + 1; 
•  Pr o p orti o n of s u bjects wit h a pre -defi n e d p ost -bas eli ne na dir pl atelet c o u nt d uri n g C ycl e X 
+ 1 a n d t hr o u g h i m me diatel y pri or t o C ycle X + 2; a n d  
•  Pr o p orti o n  of  s u bjects  ac hie vi n g  a  pre -defi n e d  p ost -baseli ne  ma xi m u m  platelet  c o u nt   
d uri n g C ycle X + 1 a n d t hr o u g h i m me diatel y pri or t o C ycle X + 2. 
 
1 3 R E F E R E N C E S  
3. A vatr o m b o pa g maleate Gl o bal I n vesti gat or’s Br oc h ure, v 1 2 v 1 4, A pril 2 0 1 6 J a n u ary 2 0 1 9 . 


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A P P E N DI X A:  S C H E D U L E O F P R O C E D U R E S  
T a ble 1 
Sc he d ule of Pr oce d ures  ( D o u ble-Bli n d Tre at me nt Peri o d)  
Da y  
C he m o t her a p y C ycle X a 
C he m o t her a p y C ycle X + 1  
Scree ni n g  
D -1 4 2 8  t o D 
-1  
B aseli ne  
Pre -C he m o I P 
Tre at me nt ( 5 D)  
C he m o D a y 
( D 1 u p t o D 3)  
P ost -C he m o  
I P Tre at me nt ( 5 D) 
D 1 1 ( ± 1 D), D 1 5 
(± 1 D), a n d D 1 8 ( ± 1 D)  
Visit  
1 b  
2  
3 c 
4 d  
5 e 
6, 7, 8  
S u bj ect i nf or me d c o nse nt  
X  
 
 
 
 
 
I/ E criteria 
X  
X  
 
 
 
 
Ra n d o mizati o n  
 
X f 
 
 
 
 
De m o gra p hics  (i ncl. race) 
X  
 
 
 
 
 
Me dical hist or y
g  
X  
 
 
 
 
 
E C O G perf or ma nce stat us  
X  
 
 
 
 
 
C o nc o mita nt me dicati o ns h  
X  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
X  
P h ysical e xa mi nati o n  
X  
X i 
 
X i 
 
 
Vital si g ns j 
X  
X  
 
X  
 
 
P K k 
 
 
X  
 
X  
 
He mat ol o g y (i ncl. platelet c o u nts)  l 
X b  
X l 
X  
X  
X  
X  
C oa g ulat i o n pa nel (ce ntr al l a b) 
 
X  
 
 
X  
 
Ser u m c he mistr y m  
X b  
X  
 
X  
X  
 
Pre g na nc y testi n g n 
X b  
X o 
 
 
 
 
Blee di n g assess me nt (I S T H)  
 
←−−−−−−−−−−−− c o nti n u o us  −−−−−−−−−−−−−→
p 
 
C o ntact I R T  
X  
X  
X  
 
X  
 
I P d osi n gq 
 
X  
X r 
 
X r 
 
Dis pe nse I P  a n d d osi n g diar y 
 
X  
 
X s 
 
 
C ollect d osi n g diar y a n d I P pac ka ge  
 
 
X  
 
X  
 
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p; I/ E  = i n cl usi o n/e xcl usi o n; i n cl. = i n cl u di n g; I P = i n vesti gati o nal pr o d uct; I R T = I nteracti ve 
Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y o n T hr o m b osis a n d Hae m ostasis; P K = p h ar ma c o ki n etic.  
N ote : Pri or t o c o n d u cti n g a n y st u d y-relat e d acti vities, writte n inf or me d c o nse nt m ust b e si g n e d a n d d ate d b y t h e s u bject. T hr o u g h o ut t he d o u ble -bli n d treat me nt peri o d, all s u bjects 
will be assess e d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose re d u cti o ns or d ela ys.  
a. 
T he q ualif yi n g c h e m o c ycle is d efi n e d as C ycle X.  
b.  
Scr ee ni n g Visit will o cc ur at t h e disc o ver y of se vere t hr o m b o c yt o p e nia  m a y o cc ur o n t he s a m e d a y as t he B aseli ne Visit,  if o ne d ay pri or t o I P tre at m e nt. If t hese visits 
occ ur o n t he s a m e d a y, o nly t he B aseli ne ( Visit 2) l a b or at ory s a m ples s h o ul d b e se nt t o t he ce ntr al l a b. L o c al pl atelet c o u nts m ay be re pe ate d as nee de d.  
c. 
Visit 3 will o cc ur o n t h e last d a y of t h e 5 -d a y pre -c h e m o I P treat me nt. 


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d.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n (e g, if c h e m ot h era p y is gi ve n o n Da y 1 a n d Da y 2, s u bjects will recei ve 
a vatr o m b o p a g or place b o o n Da y 3). A vatr o m b o p a g or place b o will n ot b e a d mi nistere d c o n c urre ntl y wit h c h e m ot h era p y o n C he m ot hera p y Da y.  All assess me nts will occ ur 
o n t he first d a y of c h e m ot h era p y pri or t o c h e m ot h era p y d osi n g.  
e. 
Visit 5 will o cc ur o n t h e last d a y of t h e  5-d a y p ost -c h e m o I P treat me nt.  
f. 
Ra n d o mizati o n m ust o cc ur pri or t o I P  d osi n g.  
g.  
Me dical hist or y t o i n cl u d e t u m or t y p e, d ate of ca n cer dia g n osis, a n d pri or c h e m ot h era p e utic re gi me ns ( d oses  n u m b ers of cycles , dates). 
h.  
C o nc o mita nt me dicati o ns t o i n cl u d e d etails of c h e m ot h era p e utic re gi me n ( d oses, sc h e d ule)  
i. 
S y m pt o m -directe d p h ysic al e xa mi n ati o n; f ull p h ysical e x a mi n ati o n o nl y re q uire d at Scree ni n g.  
j. 
I ncl u des hei g ht (at t h e Scree ni n g Visit o nl y), wei g ht ( Scree ni n g a n d Baseli n e Visits o nl y) , b o d y te m p erat ure ( Scree ni n g a n d Baseli ne Visits o nl y), bl o o d press ure, a n d p ulse 
rate, a n d will b e meas ure d after resti n g f or 5 mi n utes.  O nly scree ni n g vit al si g ns will b e rec or d e d if scree ni n g a n d b aseli ne visits occ ur t he s a m e d ay.    
k.  
Bl o o d sa m ples f or P K a n al ysis will b e c ollecte d at t h e f oll o wi n g ti me p oi nts: pre -d ose a n d 0. 5 -2, 2 -4, a n d 4- 6 h o urs p ost -d ose. A pre -d ose P K sa m ple will be c ollecte d wit hi n 
3 0 mi n utes of I P d osi n g. Eac h P K sa m ple m ust  b e se p arate d b y at l east o n e  h o ur f r o m a djace nt  sa m ples. P h ar mac o ki netic sa m ples d o n ot nee d t o be c ollecte d at i de ntical 
ti mes f or pre- a n d p ost-c h e m o visits.  
l. 
He m at ol o g y s a m ples s h o ul d b e se nt t o t he ce ntr al l a b i n a d diti o n t o l o c al l a b pl atelet c o u nts  at Visits 1, 2, 3, 4, a n d 5. Platelet  c o u nts at B aseli ne ( Visit 2)  ma y be 
perf or me d pri or ( -1 d a y) t o ra n d o miz ati o n. O nl y l o c al l a b pl atelet c o u nts will b e assesse d at Visits 6, 7, a n d 8. 
m.  O nl y platelet c o u nts will b e assesse d at Visits 6, 7, a n d 8.  Scree ni n g c he mistries c a n b e p erf or m e d l o c al ly t o d eter mi ne eli gi bility. C he mistry s a m ples will be se nt t o t he 
ce ntr al l a b at Visits 1, 2, 4, a n d 5.  
n.  
F or fe males of c hil d b eari n g p ote ntial o nl y. A ser u m or uri ne  pre g na n c y test will b e p erf or me d at t h e Scree ni n g Visit. At t he Baseli ne Visit, t he pre g na nc y test will be 
perf or me d pri or t o I P a d mi nistrati o n.  
o.  
U ri ne or ser u m  pre g n a n c y test will b e p erf or me d at t h e  Baseli n e Visit . 
p.  
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
q.  
F oll o wi n g ra n d o mizati o n, I P will b e dis p e nse d i n a d o u ble -bli n d ma n n er. S u bjects will recei ve eit h er a vatr o m b o p a g or place b o o nce dail y f or 5 da ys pri or t o C he m ot hera p y 
Da y i n C ycle X + 1. S u bjects will als o recei ve a v atr o m b o p a g or place b o o n ce d ail y f or 5 d a ys f oll o wi n g last d a y of c h e m ot hera p y tre at me nt. T he first d ose of I P m ay be 
a d mi nistere d at t he site if t he B aseli ne visit o cc urs o n t he first d ay of  t he 5-d a y I P tre at m e nt, or self -d ose d if t he B aseli ne visit occ urs t he d ay pri or t o t he first d ay of I P 
tre at m e nt. At sc h e d ule d st u d y visits, I P m a y b e a d mi nistere d at t h e site or t h e s u bject ma y self -d ose  e xce pt f or Visits 3 a n d 5  w he n s u bjects will be d ose d at t he site a n d serial 
P K sa m ples will b e c ollecte d pre - a n d p ost-d ose of I P . S u bjects will self-d ose at all ot h er ti mes. S u bjects will b e i ns tr ucte d t o ta ke I P wit h f o o d. T he I n vesti gat or or desi g nee 
will pr o vi de s u bjects wit h s uffi cie nt I P t o c o m ple te t h e re gi me n.  
r. 
S u bjects will recei ve t h e last d ose of I P at t h e site.  
s. 
T hese pr oce d ures will b e p erf or me d p ost c h e m ot h era p y d osi n g o n t h e last C h e m ot h era p y Da y of C ycle X + 1.  
 


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C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
8 1  
T a ble 2 
Sc he d ule of Pr oce d ures ( O bser v ati o n al Peri o d)  
D a y  
C he m o t her a p y C ycle X + 2 a 
C he m o D a y  
( D 1 u p t o D 3) 
D 1 1  
(± 1 D)  
D 1 5  
(± 1 D)  
D 1 8  
(± 1 D)  
F oll o w -U p  
Pri or t o C he m o D a y (-3 D) 
i n C ycle X + 3 
Visit  
9 b  
1 0  
1 1  
1 2 c 
1 7 / Earl y T er min ati o n d  
E C O G perf or ma nce stat us  
X  
 
 
 
X  
C o nc o mita nt me dicati o n  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
F ull p h ysical e xa mi nati o n  
 
 
 
 
X  
Vital si g ns e 
 
 
 
 
X  
He mat ol o g y (i ncl. platelet c o u nts) f 
X  
X f 
X f 
X f 
X  
C oa g ulati o n  (ce ntr al l a b) 
X  
 
 
 
X  
Ser u m c he mistr y  (ce ntr al l a b) 
X  
 
 
 
X  
Pre g na nc y testi n g g 
 
 
 
 
X  
Blee di n g assess me nt (I S T H) h 
X  
 
 
 
X  
C o ntact I R T  
 
 
 
 
X  
C ollect u n use d I P, if a p plica ble  
 
 
 
 
X i 
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p;  i n cl. = i n cl u di n g; I P = i n vesti gati o nal 
pr o d uct; I R T = I nteracti ve Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y o n T hr o m b osis a n d Hae m ostasis; O L E = O pe n-
La bel E xte nsi o n . 
N ote : T hr o u g h o ut t h e o bser vati o nal  p eri o d, all s u bjects will b e assesse d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose 
re d ucti o ns or dela ys. 
a. 
C ycle X + 2 will b e a n O bser vati o n al P eri o d.  
b.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n . All assess me nts will o cc ur o n t he 
first da y of c h e m ot h era p y pri or t o c h e m ot h era p y d osi n g.  
c. 
O nl y f or s u bjects receivi n g a 2 8-d a y cycle w h o are  n ot c o nti n ui n g i n t o t h e o pti o n al O L E P eri o d. 
d.  
O nl y f or s u bjects n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d. F or s u bjects n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d, a 
F oll o w- U p Visit will o cc ur pri or t o ( wit hi n 3 d a ys) C h e m ot h era p y Da y i n C ycle X + 3. If C ycle X + 2 is t h e s u bject’s last 
c he m ot hera p y c ycle, a F oll o w-U p Visit will o cc ur at 3 0 d a ys ( ± 3 d a ys) after C h e m ot h era p y Da y i n C ycle X + 2. F or 
s u bjects c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d, Visit 13 will o cc u r 5 d a ys pri or t o C h e m ot h era p y Da y i n C ycle X + 3. 
e. 
I ncl u des bl o o d press ure a n d p ulse rate, a n d will b e meas ure d after r esti n g f or 5  mi n utes.  
f. 
He m at ol o g y s a m ples will b e se nt t o t he ce ntr al l a b  i n a d diti o n t o l o c al l a b pl atelet c o u nts at Visits 9 a n d 1 7.  O nl y l oc al 
l a b platelet c o u nts will b e assesse d at Visits 1 0,  1 1, a n d 1 2.  
g.  
Uri ne or ser u m  pre g n a n c y test ma y  b e p erf or me d f or fe males of c hil d b eari n g p ote ntial o nl y.  
h.  
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
i. 
O nl y f o r a n Earl y T er mi n ati o n  Visit.  
 


D o va P har mace uticals  
Cli nical St u d y Pr ot oc ol A V A -CI T -3 3 0  
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T a ble 3 
Sc he d ule of Pr oce d ures ( O pti o n al O pe n -L a bel E xte nsi o n Peri o d)  
Da y  
 
C he m ot her a p y C ycle X + 3 & O n  
 
Pre -C he m o I P 
Av atr o m b o p a g  
Tre at me nt ( 5 D)  
C he m o D a y  
( D1  u p t o D 3 ) 
P ost -C he m o 
Av atr o m b o p a g  
I P Tre at me nt 
( 5D)  
D 1 5 (± 1 D)  
F oll o w -U p  
3 0 D ( ± 3 D)  After L ast 
Av atr o m b o p a g  I P D ose  
Visit  
1 3 a 
1 4 b  
1 5 c 
1 6 d  
1 7 / Earl y T er mi n ati o n e 
I/ E criteria 
X  
 
 
 
 
E C O G perf or ma nce stat us  
X  
 
 
 
X  
C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
F ull p h ysical e xa mi nati o n  
 
 
 
 
X  
S y m pt o m -directe d p h ysical e xa mi nati o n  
 
X  
 
 
 
Vital si g ns f 
X  
X  
 
 
X  
He mat ol o g y  (i ncl. platelet c o u nts)g 
X g h  
X  
X  
X h 
X  
C oa g ulati o n pa nel  (ce ntr al l a b) 
X  
 
X  
 
X  
Ser u m c he mistr y  (ce ntr al l a b) 
X  
 
X  
 
X  
Pre g na nc y testi n g i 
X  
 
 
 
X  
Blee di n g assess me nt (I S T H)  
←−−−−−−−−−−−− c o nti n u o us  −−−−−−−−−−−−−→
j 
C o ntact I R T  
X  
 
X  
 
X  
A vatr o m b o pa g d osi n g k 
X  
 
X  
 
 
Dis pe nse a vatr o m b o pa g  
X  
X l 
 
 
 
C ollect u n use d a vatr o m b o pa g, if a p plica ble  
 
X  
X  
 
X m  
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p; I/ E = i n cl usi o n/e xcl usi o n; i n cl.  = i n cl u di n g; I P = i n vesti gati o nal pr o d uct; I R T = I nteracti ve 
Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y o n T hr o m b osis a n d Hae m ostasis . 
N ote : T hr o u g h o ut t h e o p e n -la b el e xte nsi o n p eri o d, all s u bjects will b e assesse d f or platelet t ra nsf usi o ns a n d c h e m ot h era p y d ose re d ucti o ns or dela ys. 
a. 
Visit 1 3 will o cc ur o n t h e first d a y of t h e pre -c h e m ot h era p y a v atr o m b o p a g  I P treat me nt. F or C ycle X + 4, t his visit will be de n ote d Visit 1 3. 1 a n d f or C ycle X + 5, t his visit 
will be de n ote d Visit 1 3. 2. T his n u m b eri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycles. 
b.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n (e g, if c h e m ot h era p y is gi ve n o n Da y 1 a n d Da y 2, t he sec o n d r o u n d of 
a vatr o m b o p a g will st art o n Da y 3). A vatr o m b o p a g will n ot b e a d mi nistere d c o n c urre ntl y wit h c h e m ot h era p y o n C h e m ot hera p y Da y.  All assess me nts will occ ur o n t he first 
da y of c he m ot h era p y pri or t o c h e m ot h era p y d osi n g. F or C ycle X + 4, t his visit will b e d e n ote d Visit 1 4. 1 a n d f o r C ycle X + 5, t his visit will be de n ote d Visit 1 4. 2. T his 
n u m beri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycles. 
c. 
Visit 1 5  will o cc ur o n t h e last d a y of t h e 5 -d a y p ost -c h e m o a v atr o m b o p a g  I P treat me nt. F or C ycle X + 4, t his visit will be de n ote d Visit 1 5. 1 a n d f or C ycle X + 5, t his visit 
will be de n ote d Visit 1 5. 2. T his n u m b eri n g sc he me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycles. 
d.  
F or C ycle X + 4, t his visit will b e d e n ote d Visit 1 6. 1 a n d f or C ycle X + 5, t his visit will b e d e n ote d Visit 1 6. 2. T his n u m beri n g sc he me will c o nti n ue f or s u bse q ue nt e nr olle d 
o pe n -la bel c ycl es. 
e. 
S u bjects will h a ve a F oll o w -U p V isit at 3 0 d a ys (± 3 d a ys) after t h e last d ose of a v a tr o m b o p a g I P treat me nt of t h e s u bject’s last c he m ot hera p y c ycle. 
f. 
I ncl u des bl o o d press ure a n d p ulse rate  a n d will b e meas ure d after resti n g f or 5  mi n utes.  
g.  
He m at ol o g y s a m ples will b e se nt t o t he ce ntr al l a b i n a d diti o n t o l o c al l a b pl atelet c o u nts  f or Visits 1 3, 1 4, 1 5, a n d 1 7.  O nly l oc al l a b pl atelet c o u nts will be assesse d at 
Visi t 1 6. 


D o va P har mace uticals  
Cli nical St u d y Pr ot oc ol A V A -CI T -3 3 0  
C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
8 3  
h.  
Bl o o d sa m ple f or platelet c o u nts will b e c ollecte d pri or t o a v atr o m b o p a g  I P d osi n g.  Platelet c o u nts ma y b e p erf or me d pri or ( -1 da y) t o  av atr o m b o p a g  I P d osi n g . 
i. 
O nl y platelet c o u nts will b e assesse d at Visit 1 6.  
i. 
F or fe males of c hil d b eari n g p ote ntial o n l y. A ser u m or uri n e pre g n a n c y test ma y  b e p erf or me d at Visit  1 3 . 
j. 
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
k.  
All s u bjects will recei ve a v atr o m b o p a g o n ce dail y f or 5 d a ys pri or t o C h e m ot h era p y Da y i n C ycle X + 3. S u bjects will als o recei ve a vatr o m b o pa g o nce dail y f or 5  da ys 
f oll o wi n g t h e last d a y of c h e m ot h era p y treat me nt. At sc h e d ule d st u d y visits, a v atr o m b o p a g  I P ma y b e a d mi nistere d at t he  site or t he s u bject ma y self-d ose. S u bjects will 
self-d ose at all ot h er ti mes. S u bjects will b e i nstr u cte d t o ta ke a v atr o m b o p a g  I P wit h f o o d. T h e I n vesti gat or or d esi g n ee will pr o vi de s u bjects wit h s ufficie nt av atr o m b o p a g  I P 
t o c o m plete t h e re gi me n. 
l. 
T hese pr oce d ures will b e p erf or me d p ost -c h e m ot h era p y d osi n g o n t h e last C h e m ot h er a p y Da y of t h e c ycle.  
m.  O nl y f or a n E arl y T er mi n ati o n  Visit.  
 
 
 


D o va P har mace uticals  
Cli nical St u d y Pr ot oc ol A V A -CI T -3 3 0  
C o nfi de ntial & Pr o prietar y  
 
Versi o n 2. 0, 0 4 A pril 2 0 1 9  
8 4  
A P P E N DI X C:  C Y T O C H R O M E P 4 5 0 I N D U C E R S  
T a ble 4 
C yt oc hr o me P 4 5 0 I n d ucers  
 
Str o n g  
M o der ate  
C Y P 2 C 9 i n d ucers  
N A  
A pre pita nt, car ba maze pi ne, 
e nzal uta mi de, f os a pre pit a nt, rifa m pi n, 
rit o na vir 
C Y P 3 A 4 i n d ucers  
Car ba maze pi ne, e nzal uta mi de, mit ota ne, 
p he n yt oi n, rifa m pi n, St.  J o h n’s w ort 
B ose nta n, efa vire nz, etra viri ne, m o dafi nil  
C Y P = c yt oc hr o me P 4 5 0; N A = n ot a p plica ble.  
S o urce:  
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