Clinical trial NCT03303339
Conditions: Acute Myeloid Leukemia
Keywords: PLK1 PLK Inhibitor Onvansertib
Sponsor: Cardiff Oncology
Start date: 2017-11-17; Completion date: 2021-11-17
Enrollment: 72 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the phase 1b/2 study is to determine whether Onvansertib given orally daily for 5 consecutive days every 28 days is safe and tolerable in adult patients who have relapsed/refractory Acute Myeloid Leukemia (AML), or are ineligible for intensive induction therapy, and to determine the maximum tolerated dose and recommended phase 2 dose of Onvansertib in combination with decitabine or Onvansertib in combination with low-dose cytarabine. In the phase 2 portion of the study, Onvansertib in combination with decitabine will be studied to provide further data on the safety profile of the combination and to preliminarily assess the activity of the chosen combination in patients with untreated AML who are not candidates for aggressive induction therapy, or who have received one prior treatment for their AML.

Detailed description:

Arms: arm 1: Onvansertib, administered in escalating doses orally Day 1 through Day 5 every 28 days (1 cycle) in combination with cytarabine, which will be administered in all cohorts as 20 mg/m\^2 subcutaneously, once daily on Day 1 through Day 10 every 28 days (1 cycle). Onvansertib administration, in combination with cytarabine, will be initiated at a starting dose of 12 mg/m\^2 orally, daily for 5 days. Onvansertib dose will be escalated in successive cohorts until the recommended phase 2 dose is achieved. arm 2: Onvansertib will be administered in escalating doses orally, Day 1 through Day 5 every 28 days (1 cycle) in combination with decitabine, administered consistently in all cohorts as 20 mg/m\^2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle). Onvansertib administration, in combination with decitabine, will be initiated at a starting dose of 12 mg/m\^2 orally, daily for 5 days (Day 1 through Day 5). Onvansertib dose will be escalated in successive cohorts until the recommended phase 2 dose is achieved. arm 3: Onvansertib recommended phase 2 dose, orally Day 1 through Day 5 every 28 days (1 cycle) and decitabine, administered consistently as 20 mg/m\^2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle), with treatment modifications or delays based on return of hematopoietic function to baseline or Grade ≤1 toxicity for optimal subject management.
Interventions: intervention 1: Onvansertib intervention 2: Cytarabine intervention 3: Decitabine
Intervention descriptions: intervention 1: Onvansertib orally intervention 2: subcutaneously intervention 3: intravenously

Protocol documents:
Prot_000.pdf: 
Protocol Number: TROV-052 
Official Title: A Phase 1b/2 Study of Onvansertib (PCM-075) in
Combination with Either Low-dose Cytarabine or Decitabine
in Subjects with Acute Myeloid Leukemia (AML)
NCT Number: NCT03303339 
Document Date:  07 Aug 2019 


TROV-052 
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07 Aug 2019 
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1 CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 1b/2 Study of Onvansertib (PCM-075) in 
Combination with Either Low-dose Cytarabine or Decitabine 
in Subjects with Acute Myeloid Leukemia (AML) 
Protocol Number: 
TROV-052 
Study Phase: 
1b/2 
Product Name: 
Onvansertib (PCM-075) 
IND Number: 
135237 
Sponsor: 
Trovagene, Inc. 
11055 Flintkote Avenue 
San Diego, CA 92121 
 
 
Issue Date: 
07 Aug 2019 
Amendment Number: 
Amendment 2 
Protocol Version: 
Version 6.0 
Prior Protocol Version: 
Version 5.0, dated 16 May 2018 
This study will be performed in compliance with Good Clinical Practice (GCP), the 
Declaration of Helsinki (with amendments), and local legal and regulatory requirements. 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Trovagene, Inc. 
(hereinafter referred to as Trovagene). Any unauthorized copying or use of this 
document is prohibited. 


 
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2 TABLE OF CONTENTS 
 
1 
CLINICAL STUDY PROTOCOL .......................................................................................1 
2 
TABLE OF CONTENTS ......................................................................................................2 
3 
SYNOPSIS ............................................................................................................................8 
4 
LIST OF ABBREVIATIONS .............................................................................................20 
5 
ADMINISTRATIVE STRUCTURE ..................................................................................23 
6 
INTRODUCTION ..............................................................................................................24 
6.1 
Background ......................................................................................................................24 
6.1.1 
Acute Myeloid Leukemia ...................................................................................24 
6.1.2 
Polo-like Kinase 1 ...............................................................................................25 
6.1.3 
Onvansertib (PCM-075) .....................................................................................25 
6.2 
Study and Dose Rationale ................................................................................................29 
6.3 
Risks and Benefits for Subjects ........................................................................................29 
7 
STUDY OBJECTIVES .......................................................................................................30 
7.1 
Primary Objectives ...........................................................................................................30 
7.2 
Secondary Objectives .......................................................................................................30 
7.3 
Exploratory Objectives .....................................................................................................30 
8 
INVESTIGATIONAL PLAN .............................................................................................31 
8.1 
Overall Study Design and Plan ........................................................................................31 
8.1.1 
Phase 1b ..............................................................................................................31 
8.1.1.1 
Combination Treatment Arms ........................................................................... 31 
8.1.1.2 
Dose Escalation.................................................................................................. 32 
8.1.1.3 
Preliminary Safety and Efficacy Assessment .................................................... 33 
8.1.2 
Phase 2 ................................................................................................................34 
8.1.3 
Study Endpoints ..................................................................................................34 
8.2 
Study Duration .................................................................................................................35 
8.3 
Eligibility Criteria .............................................................................................................35 
8.3.1 
Inclusion Criteria ................................................................................................36 
8.3.2 
Exclusion Criteria ...............................................................................................37 
8.3.3 
Removal of Subjects from Therapy or Assessment ............................................38 


 
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8.4 
STUDY DRUG TREATMENT .......................................................................................38 
8.4.1 
Description of Study Treatments ........................................................................38 
8.4.1.1 
Onvansertib (PCM-075) .................................................................................... 38 
8.4.1.2 
Cytarabine .......................................................................................................... 40 
8.4.1.3 
Decitabine .......................................................................................................... 40 
8.4.2 
Dosing Schedule .................................................................................................40 
8.4.3 
Study Drug Inventory and Accountability ..........................................................41 
8.4.4 
Treatment Compliance ........................................................................................41 
8.4.5 
Concomitant Medications and Treatments .........................................................41 
9 
ASSESSMENTS .................................................................................................................43 
9.1 
Schedule of Assessments ..................................................................................................43 
9.2 
Study Visits ......................................................................................................................54 
9.2.1 
Phase 1b ..............................................................................................................54 
9.2.1.1 
Pretreatment Evaluations (Screening and Baseline) .......................................... 54 
9.2.1.2 
Evaluations During Treatment ........................................................................... 55 
9.2.1.3 
Post-Treatment Evaluations (Follow-up/End of Study) .................................... 56 
9.2.2 
Phase 2 ................................................................................................................56 
9.2.2.1 
Pretreatment Evaluations (Screening and Baseline) .......................................... 56 
9.2.2.2 
Evaluations During Treatment ........................................................................... 57 
9.2.2.3 
Post-treatment Evaluations (Follow-up/End of Study) ...................................... 58 
9.3 
Efficacy Assessments .......................................................................................................59 
9.3.1 
Efficacy Variables...............................................................................................59 
9.3.1.1 
Morphologic Leukemia-free State ..................................................................... 59 
9.3.1.2 
Complete Response............................................................................................ 59 
9.3.1.3 
Complete Response with Incomplete Blood Count Recovery........................... 59 
9.3.1.4 
Partial Response ................................................................................................. 59 
9.3.1.5 
Duration of Response......................................................................................... 60 
9.3.1.6 
Event-free Survival ............................................................................................ 60 
9.3.1.7 
Overall Survival ................................................................................................. 60 
9.4 
Safety Assessments ..........................................................................................................60 
9.5 
Pharmacokinetic Assessments ..........................................................................................60 


 
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9.6 
Pharmacodynamic and Biomarker Evaluation .................................................................61 
10 
ADVERSE EVENT REPORTING.....................................................................................61 
10.1 Definitions ........................................................................................................................61 
10.1.1 
Adverse Event .....................................................................................................61 
10.1.2 
Unexpected Adverse Events ...............................................................................61 
10.1.3 
Serious Adverse Event ........................................................................................61 
10.1.4 
Definition of Dose-limiting Toxicities ...............................................................62 
10.1.5 
Determination of the Maximum Tolerated Dose ................................................63 
10.2 Severity of Adverse Events ..............................................................................................63 
10.3 Relationship of Adverse Events to the Study Drug ..........................................................63 
10.4 Monitoring of Adverse Events .........................................................................................64 
10.5 Reporting Procedures .......................................................................................................64 
10.5.1 
Routine Reporting of Adverse Events ................................................................64 
10.5.2 
Reporting of Serious Adverse Events, Including Death .....................................65 
10.5.3 
Other Events Requiring Immediate Reporting ...................................................66 
10.5.3.1 Overdose ............................................................................................................ 66 
10.5.3.2 Pregnancy........................................................................................................... 66 
11 
SUBJECT DISCONTINUATION AND TRIAL DISCONTINUATION .........................68 
11.1 Subject Discontinuation ...................................................................................................68 
11.2 Study Discontinuation ......................................................................................................68 
12 
STATISTICAL METHODS ...............................................................................................69 
12.1 Dosing Algorithm and Determination of Sample Size .....................................................69 
12.2 Statistical Analysis of Safety Data ...................................................................................69 
12.3 Statistical Analysis of Efficacy Data ................................................................................70 
13 
ACCESS TO SOURCE DOCUMENTS AND RETENTION OF RECORDS ..................71 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ..................................................72 
14.1 Data Collection .................................................................................................................72 
14.2 Study Monitoring .............................................................................................................72 
14.3 Data Management .............................................................................................................73 
14.4 Sponsor Audits .................................................................................................................73 
14.5 Inspection by Regulatory Authorities ...............................................................................73 


 
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15 
ETHICS...............................................................................................................................74 
15.1 Declaration of Helsinki ....................................................................................................74 
15.2 Good Clinical Practice and Regulatory Compliance ........................................................74 
15.3 Institutional Review Board/Independent Ethics Committee ............................................74 
15.4 Informed Consent .............................................................................................................74 
15.5 Emergency Departure from Protocol ...............................................................................75 
16 
PUBLICATION POLICY ..................................................................................................76 
17 
PROTOCOL AMENDMENTS AND MODIFICATIONS ................................................77 
18 
REFERENCES ...................................................................................................................78 
19 
APPENDICES: ...................................................................................................................80 
19.1 Appendix 1: National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 .........................................................................................81 
19.2 Appendix 2: New York Heart Association Functional Classification .............................81 
19.3 Appendix 3: ECOG Performance Status ..........................................................................82 
19.4 Appendix 4: Package Insert for Cytarabine and Dacogen™ (Decitabine).......................82 
19.5 Appendix 5: Clinical Study Report PLKA-937-001 ........................................................82 
19.6 Appendix 6: Torsades de Pointes Risk QT Interval Normogram ....................................83 
 
LIST OF TABLES 
Table 6-1: Drug-related Treatment-emergent AEs ....................................................................... 28 
Table 8-1: Onvansertib (PCM-075) Dose and Dosing Levels ...................................................... 33 
Table 9-1: Schedule of Events: Phase 1b Cycle 1 ........................................................................ 44 
Table 9-2: Schedule of Events: Phase 1b Cycle ≥2 ...................................................................... 47 
Table 9-3: Schedule of Events: Phase 2 (all cycles) ..................................................................... 50 
 
 
 


DocuSign Envelope ID: A731D39D-A6AA-467E-9971-3FA6F4C76176 
®o •trovagene
ONCOlOCY 
Onvansertib (PCM-075) 
TROV-052 
Clinical Study Protocol 
Amendment 2, Version 6.0 
07 Aug 2019 
A Phase lb/2 Study of Onvansertib (PCM-075) in Combination with Either Low-dose 
Cytarabine or Decitabine in Subjects with Acute Myeloid Leukemia (AML) 
 
 
 
Signature 
CONFIDENTIAL 
PROTOCOL APPROVAL IGNATURES 
Trovagene, Inc. 
Chief Executive Officer 
Title 
8/12/2019 
Date 
Chief Scientific Officer 
Title 
8/12/2019 
Date 
Vice President, Scientific Services 
PRA Health Sciences 
Title 
-
Date
Page 6 of 83 


 
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INVESTIGATOR SIGNATURE PAGE 
 
Protocol No: TROV-052 
Protocol Version: Amendment 2, Version 6.0 
Protocol Date: 07 Aug 2019 
Protocol Title: 
A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with Either Low-dose 
Cytarabine or Decitabine in Subjects with Acute Myeloid Leukemia (AML) 
I have read the attached protocol and hereby agree that it contains all the necessary details for 
performing the Product Study.  
I will provide copies of the protocol to the Investigational Review Board and all members of the 
Study team responsible to me who participate in the Study. I will discuss this material with them 
to ensure that all participating personnel at the Study site are fully informed regarding the 
investigational device and the conduct of the protocol.  
Once the Investigational Review Board approves the protocol, I will not modify this protocol 
without obtaining the prior approval of both the Sponsor and the Investigational Review Board. 
I will submit the protocol modifications and/or any informed consent modifications to the 
Sponsor and the Investigational Review Board, as applicable, and approval will be obtained 
before any modifications are implemented.  
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Investigator’s Printed Name 
 
 
 
 
 
Study Site Name 
 
 
 
 
 
Address 
 
 
 
City, State, Zip Code, Country 
 


 
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3  SYNOPSIS 
 
Protocol Title: 
A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with Either 
Low-dose Cytarabine or Decitabine in Subjects with Acute Myeloid 
Leukemia (AML) 
Protocol Number: 
TROV-052 
IND Number: 
135237 
Number of Study Sites:  This study is being conducted at 8 study centers.  
Phase: 
1b/2 
Objectives: 
Primary Objectives 
Phase 1b: 
• 
To evaluate the dose limiting toxicities (DLTs) and maximum 
tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of 
onvansertib (PCM-075) in combination with either low-dose 
cytarabine or decitabine in subjects with AML 
Phase 2: 
• 
To assess the safety and tolerability of the combination of either 
onvansertib (PCM-075) at the MTD (or RP2D) and low-dose 
cytarabine or the combination of onvansertib (PCM-075) at the MTD 
(or RP2D) and decitabine in subjects with AML 
• 
To evaluate the preliminary anti-leukemic activity of the combination 
of either onvansertib (PCM-075) at the MTD (or RP2D) and low-dose 
cytarabine or the combination of onvansertib (PCM-075) at the MTD 
(or RP2D) and decitabine in subjects with AML 
Secondary Objectives 
Phase 1b: 
• 
To assess the incidence and severity of adverse events (AEs) 
according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) (version 4.03) of onvansertib 
(PCM-075) in combination with either low-dose cytarabine or 
decitabine in subjects with AML 
• 
To analyze the pharmacokinetics (PK) of onvansertib (PCM-075) 
when given in combination with either low-dose cytarabine or 
decitabine in subjects with AML 


 
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Phase 2: 
• 
To assess the incidence and severity of AEs according to the 
NCI-CTCAE version 4.03 of onvansertib (PCM-075) in combination 
with either low-dose cytarabine or decitabine in subjects with AML 
• 
To analyze the PK of onvansertib (PCM-075) when given in 
combination with either low-dose cytarabine or decitabine in subjects 
with AML 
Exploratory Objectives 
Phase 1b and Phase 2: 
• 
To explore additional analyses evaluating potential pharmacodynamic 
(PD) and diagnostic biomarkers of onvansertib (PCM-075) in subjects 
with AML 
Study Design: 
This is a Phase 1b/2, open-label study of the safety and anti-leukemic 
activity of onvansertib in combination with either low-dose cytarabine or 
decitabine in subjects with AML.  
In Phase 1b, subjects will have relapsed or refractory disease and must have 
received no more than 3 prior regimens for the treatment of their AML. 
Subjects may be treatment naïve as long as they are not candidates for or 
have refused intensive induction therapy. 
In Phase 2, subjects must have received no more than 1 prior regimen for the 
treatment of their AML. Subjects may be treatment naïve as long as they are 
not candidates for or have refused intensive induction therapy.   
In both phases, prior treatment with either low-dose cytarabine or decitabine 
for myelodysplastic syndromes (MDS) will not be considered a prior 
regimen. For subjects who have undergone hematopoietic stem cell 
transplantation, the preparative (conditioning) regimen and transplant will 
be considered to be a single line of prior therapy. 
Phase 1b: 
Subjects in Phase 1b will receive either a combination of onvansertib and 
low-dose cytarabine, or a combination of onvansertib and decitabine in 
2 separate arms using a standard 3+3 design in each arm. 
In Arm A, onvansertib will be administered in escalating doses orally (p.o.) 
Day 1 through Day 5 every 21 to 28 days in combination with cytarabine, 
which will be administered in all cohorts as 20 mg/m2 subcutaneously (SC) 
once daily on Day 1 through Day 10 every 28 days. Onvansertib 
administration, in combination with cytarabine, will be initiated at a starting 
dose of 12 mg/m2 p.o. daily for 5 days (Dose Level 0). On days where both 
agents are administered (Days 1-5), cytarabine will be administered first 
followed by onvansertib. Investigator assessment of subjects may allow them, 


 
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at their discretion, to treat more frequently than every 21 to 28 days; however, 
in no case may a cycle length be less than 21 days. 
In Arm B, onvansertib will be administered in escalating doses p.o. Day 1 
through Day 5 every 21 to 28 days in combination with decitabine, which will 
be administered consistently in all cohorts as 20 mg/m2 intravenously (IV) 
over 1 hour on Day 1 through Day 5 every 28 days. Onvansertib 
administration, in combination with decitabine, will be initiated at a starting 
dose of 12 mg/m2 p.o. daily for 5 days (Dose Level 0). The daily dose of 
decitabine will be administered first followed by onvansertib. Investigator 
assessment of subjects may allow them, at their discretion, to treat more 
frequently than every 21 to 28 days; however, in no case may a cycle length 
be less than 21 days. 
The first 3 subjects will be allocated to Arm A (Cohort A1). If Cohort A1 is 
expanded to 6 subjects prior to the first subject being enrolled in Arm B, then 
enrollment in Cohort A1 will be completed before enrollment begins in 
Arm B. After all subjects are enrolled in Cohorts A1 and B1, subjects will 
enroll in subsequent dose escalation cohorts based on the following decision 
rules: 
• 
If Arm A is open for enrollment, subjects will enroll in the open Arm A 
cohort regardless of dose level 
• 
If Arm A is closed to enrollment, subjects will enroll in the open Arm B 
cohort regardless of dose level 
Dosing in Arms A and B will proceed independently. Each arm will follow a 
standard 3+3 dose-escalation design in which the onvansertib dose will be 
escalated by 50% increments in successive cohorts of 3 subjects. If none of 
the 3 subjects enrolled at any dose level experience a DLT, the dose of 
onvansertib will be escalated by 1 dose level in each successive cohort. If 
1 subject in the first 3 experiences a DLT, up to 3 additional subjects will be 
enrolled at that dose level. If there are no additional DLTs (ie, ≤1 of 
6 subjects with DLT), then dose escalation will again proceed. If there are 
2 subjects who experience DLTs among the first 3 subjects enrolled, or there 
is a second DLT in up to 6 subjects enrolled at any dose level, the MTD will 
be judged to have been exceeded, and no additional subjects will be started at 
that dose. The MTD will then be established at a prior dose level or an 
additional cohort may be enrolled at an intermediate dose level upon 
agreement with the Sponsor, Medical Monitor, and Principal Investigator.  
The RP2D can be determined based on the assessment of safety, PK, PD, and 
preliminary efficacy of subjects treated at a dose level that has been cleared 
for safety, regardless of whether or not an MTD has been reached. In this 
case, no further dose escalation will be done to determine an MTD.  
Each cohort will be evaluated for toxicity, recovery of blood counts, and PK. 
DLTs will be evaluated for the first 28 days after initiation of therapy. In the 
case of pancytopenia present at Day 28 in the absence of other toxicity that 


 
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constitutes a DLT, the duration for DLT evaluation will be extended to 
42 days (unless the pancytopenia resolves between Days 28 and 42, or is 
determined to be due to persistent leukemic involvement of the bone marrow 
or another cause unrelated to study therapy). Pancytopenia, related to 
onvansertib in the absence of another cause unrelated to study therapy that 
persists beyond Day 42, will be considered a DLT. If an Investigator elects to 
re-treat a subject prior to 28 days (allowed no sooner than on Day 22), the 
DLT evaluation period will end at the time of initiation of the second cycle of 
therapy. 
Dose modifications and delays for safety will be performed as described in 
the protocol. After the first cycle, additional cycles can be administered to 
individual subjects based on Investigator judgment, if hematopoietic recovery 
is documented, and may incorporate delays or supportive care until 
hematopoietic function returns to baseline or Grade ≤1, as long as the subject 
is receiving clinical benefit without safety or tolerability issues. In the case 
that failure to achieve hematopoietic recovery is judged to be related to 
persistent leukemic involvement in the bone marrow, Investigators may re-
initiate therapy according to their clinical judgment upon discussion with the 
Medical Monitor.  
Investigators will also have the option for intra-subject dose escalation in 
later cycles if safety and tolerability have been demonstrated at higher doses 
of onvansertib. 
At any time during Phase 1b, the Sponsor, in consultation with the Safety 
Review Committee (SRC), may elect to discontinue enrollment into either 
arm of the study based on safety, efficacy, PK, and PD considerations. In this 
case, enrollment in the other arm will continue as described.  
Following assessment of safety and preliminary efficacy in the first 5 dose 
level escalation cohorts (0: 12 mg/m2; +1: 18 mg/m2; +2: 27 mg/m2; 
+3: 40 mg/m2; +4: 60 mg/m2) in both Arm A (onvansertib in combination 
with low-dose cytarabine) and Arm B (onvansertib in combination with 
decitabine), the decision was made to discontinue Arm A from further dose 
escalation and subject enrollment.  
Arm B will continue forward with dose escalation as outlined in the protocol, 
or until such time as the RP2D is determined at a dose level previously 
cleared for safety.  
Phase 2: 
In Phase 2, a total of 32 subjects will be enrolled at the RP2D to further 
evaluate safety and preliminary efficacy. Onvansertib will be administered 
p.o. on Day 1 through Day 5 every 21 to 28 days, in combination with 
decitabine, administered consistently as 20 mg/m2 IV over 1 hour on Day 1 
through Day 5 every 28 days, with treatment modifications or delays based 
on return of hematopoietic function to baseline or Grade ≤1 toxicity for 
optimal subject management. The daily dose of decitabine will be 


 
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administered first followed by onvansertib. Investigator assessment of 
subjects may allow them, at their discretion, to treat more frequently than 
every 28 days; however, in no case may a cycle length be less than 21 days. 
Subjects may continue treatment in the study at any dose until clinically 
significant disease progression or death, unacceptable toxicity, withdrawal of 
consent, or discontinuation based on Investigator discretion. Any subject 
becoming pregnant while on the study should be withdrawn from treatment 
but will remain in the study. After obtaining the subject’s consent (or subject 
and pregnant partner’s consent in the case of a male participant), monitoring 
of the pregnancy should continue until conclusion of the pregnancy. Each 
subject will be followed for survival for up to 1 year after enrollment. 
AEs and concomitant medication use will be queried, monitored, and 
recorded throughout the study. Safety evaluations will include: physical 
examinations, performance status, vital signs, electrocardiograms (ECGs), 
hematology, and serum chemistry laboratory tests and urinalysis. 
Sample Size: 
Phase 1b: up to 84 subjects (42 in each arm), dependent on the number of 
dose escalation cohorts required to determine the MTD or RP2D   
Phase 2: 32 subjects at the RP2D 
Total: up to 116 subjects 
Endpoints: 
Primary safety endpoints:  
1. 
Characterization of DLTs; characterization of Aes by type, incidence, 
severity (graded by NCI-CTCAE version 4.03), seriousness, and 
relationship to treatment effects on vital signs and laboratory parameters; 
and changes from baseline in ECGs, physical examinations, weight, and 
ECOG performance status 
Primary efficacy endpoint: 
1. 
Rate of complete response (CR + Cri) in Phase 2, defined as a 
morphologic leukemia-free state (MLF; see below) plus: 
For CR: 
a. Subject is independent of transfusions  
b. Absolute neutrophil count (ANC) of >1000/mm3 
c. Platelets of ≥100,000/mm3 
For Cri: 
1. Meets all criteria for CR except for either neutropenia (ANC 
<1000/mm3) or thrombocytopenia (<100,000/mm3) but must 
include transfusion independence 
Secondary endpoints: 


 
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1. 
Rate of achievement of a MLF in Phase 2, defined as: 
a. Bone marrow (BM) <5% blasts in an aspirate with spicules (a BM 
biopsy should be performed if spicules are absent) 
b. No blasts with Auer rods or persistence of extramedullary disease 
2. Rate of partial response (PR) in Phase 2: All of the hematologic values 
for a CR but with a decrease of at least 50% in the percentage of blasts to 
5% to 25% in the bone marrow aspirate and a normalization of blood 
counts as noted above 
3. Duration of response (DOR) in Phase 2: Time from documentation of 
response until documentation of recurrence of or progression of disease 
4. Event-free survival (EFS) in Phase 2: Time from enrollment until disease 
progression or death from any cause 
5. Overall survival (OS) in Phase 2: Time from enrollment until death from 
any cause 
6. Concentrations of onvansertib in plasma samples collected at pre-
specified time points before and after administration of onvansertib, 
including maximum plasma concentration (Cmax), trough plasma 
concentration (Cmin), time to maximum plasma concentration (Tmax), area 
under the plasma concentration versus time curve (AUC), and plasma 
terminal elimination half-life (t1/2) 
Exploratory endpoints: 
1. Blood samples for PD and diagnostic biomarker evaluation 
2. Evaluation of the rate of complete response (CR + CRi), MLF, PR, DOR, 
EFS and OS in all enrolled subjects (Phases 1b and 2) 
Indication: 
Acute myeloid leukemia (AML) 
Diagnosis and Main 
Eligibility Criteria: 
Subjects who meet all of the following inclusion criteria and none of the 
exclusion criteria will be eligible to be enrolled in the study. 
Inclusion Criteria: 
1. Disease Status and Prior Therapy: 
a. Histologically confirmed diagnosis of AML  
b. Phase 1b:  
i. Subjects with relapsed or refractory AML who have received no 
more than 3 prior treatment regimens for AML. Subjects who have 
received prior treatment with cytarabine or decitabine are not 
excluded. Prior treatment with either low-dose cytarabine or 
decitabine given for MDS will not be considered a prior regimen. 
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transplantation, the preparative (conditioning) regimen and 
transplant will be considered to be a single line of prior therapy. 
OR 
ii. Subjects who are treatment naïve and are not candidates for or have 
refused intensive induction therapy. 
c. Phase 2:  
i. Subjects with relapsed or refractory AML who have received no 
more than one prior treatment regimen for AML. Subjects who have 
received prior treatment with decitabine are not excluded. Prior 
treatment with decitabine given for MDS will not be considered a 
prior regimen.   
OR 
ii. Subjects who are treatment naïve and are not candidates for or have 
refused intensive induction therapy.  
2. Age ≥18 years  
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 
(Appendix19.3) 
4. Subjects must be willing and able to review, understand, and provide 
written consent before starting any study-specific procedures or therapy 
5. All men and women must agree to practice effective contraception during 
the entire study period and after discontinuing study drug, unless 
documentation of infertility exists, as follows: 
a. Sexually active, fertile women must use 2 effective forms of 
contraception (abstinence, intrauterine device, oral contraceptive, or 
double barrier device) from the time of informed consent and until at 
least 6 months after discontinuing study drug 
b. Sexually active men and their sexual partners must use effective 
contraceptive methods from the time of subject informed consent and 
until at least 3 months after discontinuing study drug 
Exclusion Criteria: 
1. Treatment-related AML or acute promyelocytic leukemia (APL) 
2. Active malignancies within the last 12 months with the exception of those 
with a negligible risk of metastasis or death 
3. Clinical evidence of active central nervous system leukemia at the time 
of screening 
4. Alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) ≥2.5 x upper limit of normal (ULN). 


 
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5. Total bilirubin >2.0 mg/dL (or >3.0 mg/dL in subjects with documented 
Gilbert syndrome) 
6. Serum creatinine ≥2.0 mg/dL 
7. New York Heart Association (NYHA) Class III or IV heart disease 
(Appendix 19.2), active ischemia or any other uncontrolled cardiac 
condition, or hypertensive or metabolic condition 
8. Myocardial infarction in the previous 12 weeks (from the start of 
treatment) 
9. Resting left ventricular ejection fraction <50% at the time of screening 
10. QT interval with Fridericia’s correction [QTcF] [16] >450 milliseconds 
for men, or >470 milliseconds for women. The QTcF should be 
calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the 
case of potentially correctible causes of QT prolongation (eg, 
medications, hypokalemia), the triplicate ECG may be repeated once 
during screening and that result may be used to determine eligibility. 
11. Pregnant or breast feeding 
12. Active and uncontrolled disease (other than AML) or infection as 
judged by the treating physician 
13. Treatment with systemic therapy for the primary disease within 14 days 
of first dose (except for hydroxyurea or isolated doses of cytarabine or 
decitabine for white blood cell control) 
 
14. Grade 2 or greater toxicities from prior therapy, except for Grade 2 
toxicities that are not expected to resolve and that in the judgment of the 
Investigator do not pose a significant safety risk to subject participation.  
15. Subjects with any other medical condition, including mental illness or 
substance abuse, deemed by the Investigator to be likely to interfere with 
the subject’s ability to sign the informed consent form or his/her ability to 
cooperate and participate in the study, or to interfere with the 
interpretation of the results. 
Test Product, Dose, 
and Mode of 
Administration: 
Onvansertib (PCM-075): The Phase 1b onvansertib starting dose is 
12 mg/m2 (Dose Level 0) administered p.o. on Day 1 through Day 5 every 28 
days. Dose escalation is discussed in detail in the protocol. In Phase 2, 
onvansertib will be administered at the MTD (or RP2D) p.o. on Day 1 
through Day 5 every 21 to 28 days. Investigator assessment of subjects may 
allow them, at their discretion, to treat more frequently than every 28 days; 
however, in no case may a cycle length be less than 21 days. Day 1 of 
onvansertib therapy should always be Day 1 of either cytarabine or decitabine 
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Cytarabine: 20 mg/m2 SC once daily on Day 1 through Day 10 every 
28 days in Phase 1b. On days where both agents are administered (Days 1-5), 
cytarabine will be administered first followed by onvansertib. 
Decitabine: 20 mg/m2 IV over 1 hour on Day 1 through Day 5 every 21 to 
28 days in Phase 1b. Based on the RP2D combination determined in 
Phase 1b, decitabine will be given in combination with onvansertib in 
Phase 2. The daily dose of decitabine will be administered first followed by 
onvansertib. 
Efficacy Evaluation: 
Efficacy Assessments 
All subjects evaluable for anti-leukemic activity will be assessed for 
response to treatment using the recommendations of the International 
Working Group (IWG) for standardization of response criteria, treatment 
outcomes, and reporting for therapeutic trials. [17] The primary efficacy 
variable is leukemia responses, evaluated by the Investigator based on bone 
marrow aspirate and peripheral blood examination.  
Efficacy Endpoints [18]: 
1. Morphologic leukemia-free state 
a. BM <5% blasts in an aspirate with spicules (a BM biopsy should be 
performed if spicules are absent) 
b. No blasts with Auer rods or persistence of extramedullary disease  
2. Complete response (CR): 
a. Morphologic leukemia-free state plus: 
i. Subject is independent of transfusions  
ii. Absolute neutrophil count (ANC) of >1000/mm3 
iii. Platelets of ≥100,000/mm3 
3. Complete response with incomplete blood count recovery (CRi) meets 
all criteria for CR except for either neutropenia (ANC <1000/mm3) or 
thrombocytopenia (<100,000/mm3) but must include transfusion 
independence 
4. Partial response (PR): All of the hematologic values for a CR but with a 
decrease of at least 50% in the percentage of blasts to 5% to 25% in the 
bone marrow aspirate and a normalization of blood counts as noted 
above 
5. Duration of response (DOR): Time from documentation of response 
until documentation of recurrence of or progression of disease  
6. Event-free survival (EFS): Time from enrollment until disease 
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7. Overall survival (OS): Time from enrollment until death from any cause 
Safety Evaluation: 
Toxicity will be graded using the NCI-CTCAE version 4.03  
1. Safety analyses will be conducted on all subjects who have received at 
least 1 dose of study drug, and will include the frequency of all AEs and 
laboratory abnormalities as well as the frequency of dose interruptions, 
dose reductions, and treatment discontinuations. All AEs must be 
attributed to study drugs unless there is a reasonably acceptable 
alternate cause for the AEs. 
2. In each phase of the study, DLTs will be considered to be any non-
hematologic Grade 3 abnormalities that persist >7 days without 
decreasing in severity despite standards of care, are clinically significant, 
or that are Grade 4 and symptomatic. Exceptions and additional 
parameters for assessment of non-hematologic DLT are provided in the 
protocol. For hematologic toxicities, only persistent pancytopenia 
resistant to current standards of care that continues for ≥42 days and is 
not related to leukemic infiltration or another cause judged to be 
unrelated to study therapy will be considered as a DLT, since marrow 
aplasia is an expected consequence of AML therapy. 
3. Additional safety assessments will include physical examination; 
medical history; ECG; ECOG performance status; weight; vital signs 
measurements; clinical laboratory testing (hematology, clinical 
chemistry, and urinalysis) and multigated acquisition (MUGA) or 
echocardiography (ECHO) scans 
Safety Monitoring: 
The SRC consisting of the Principal Investigators and Medical Monitor, will 
monitor subjects for safety and evaluate the efficacy of onvansertib doses to 
minimize exposure of subjects to a non-efficacious dose level.  
Pharmacokinetic 
Evaluation: 
Blood samples for PK analysis of onvansertib will be collected pre-dose, and 
0.5, 1, 2, 3, 4, 8, (±10 minutes) and 24 hours (±1 hour) after administration of 
onvansertib on Day 1 and Day 5, as well as once each on Days 8, 15, and 22 
(Cycle 1 only). For Cycle 2, blood samples for PK analysis should be 
collected, if feasible, pre-dose, 3 hours, and 24 hours (all ±10 minutes) after 
administration of onvansertib on Days 1 and 5, and once each on Days 8, 15, 
and 22. 
Pharmacodynamic and 
Diagnostic Biomarker 
Evaluation: 
Pharmacodynamic and diagnostic biomarker analysis will be obtained, if 
feasible, pre-dose, 3 hours (±10 minutes), and 24 hours (±1 hour) after 
administration of onvansertib on Days 1 and 5, and once each on Days 8, 15, 
and 22 (Cycles 1-3). For Cycle 4 and beyond, samples will be collected on 
Days 1 (pre-dose) and 15. The schedule for obtaining these may be amended 
based on results of prior evaluations. 
Statistical Methods: 
Safety Analysis: 


 
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Safety assessment data for all subjects who receive at least one dose of study 
drug will be listed and summarized and will include data from AEs and 
concomitant medication queries, physical examination findings, ECOG 
performance status, weight and vital signs measurements, ECG 
measurements, and clinical laboratory testing (hematology, clinical 
chemistry, and urinalysis) values. Descriptive statistics will be generated as 
appropriate (eg, mean, median, range, and SD for continuous data; and 
frequency for categorical data). 
Efficacy Analysis: 
Data from all subjects who receive at least 1 dose of onvansertib in 
combination therapy will be included in the intention-to-treat (ITT) efficacy 
analysis. Subjects completing at least 1 cycle of treatment will be included in 
the per protocol efficacy analysis. 
Descriptive statistics will be generated as appropriate (ie, mean, median, 
range, and SD). Median survival statistics will be estimated using the 
Kaplan-Meier method. 
The primary efficacy endpoint is the rate of CR + CRi in the Phase 2 portion 
of the study. Based on a population CR + CRi rate of 20% for either the 
combination of cytarabine plus onvansertib or decitabine plus onvansertib, 
with 32 evaluable patients in the primary analysis the 90% CI for the 
CR + CRi rate from the study will have an estimated precision of 
approximately 58% and width 0.23, and a 95% CI would have an estimated 
precision of approximately 70% and width 0.28. 
Pharmacokinetic Analysis: 
PK parameters of the population defined in the Statistical Analysis Plan will 
include maximum concentration (Cmax), time of maximum concentration 
(Tmax), area under the curve over the first 24 hours (AUC0-24), and drug 
elimination half-life (t1∕2), which will be estimated from plasma concentration 
data. The geometric mean and 95% CIs will be reported for all evaluable 
subjects. 
Sample Size Rationale: 
Exposure of any subject at the starting dose, based on prior experience with 
this drug in patients with solid tumors (Section 6.1.3) with exclusively 
hematologic toxicities that are required in the treatment of patients with 
AML, is reasonable in Phase 1b for a dose that has the potential for efficacy 
based on preclinical modeling. The 3+3 design will allow a dose with a ≥50% 
probability of causing a DLT to have at most a 12.5% chance of satisfying the 
conditions for dose escalation after the first 3 subjects and a ≥50% chance of 
stopping at 3. With 6 subjects, there is at most a 17.2% chance of satisfying 
the conditions for dose escalation after 6 subjects. 
Phase 2 will proceed with a total of 32 subjects at the identified RP2D; 
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a DLT-level AE (as per protocol), accrual will stop and the RP2D will be 
reassessed in additional cohorts. 


 
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4 LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
APC/C 
Anaphase-promoting Complex/Cyclosome 
APL 
Acute Promyelocytic Leukemia 
ASCO 
American Society of Clinical Oncology 
ASH 
American Society of Hematology 
AST 
Aspartate Aminotransferase 
AUC 
Area under the plasma concentration vs time curve 
BM 
Bone Marrow 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
Cmin 
Trough plasma concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CRi 
Complete Response with Incomplete Blood Count Recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting Toxicity 
DOR  
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic CRF 
EFS 
Event-free Survival 
EOS 
End of Study 
FDA 
Food and Drug Administration 


 
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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
HI 
Hematologic Improvement 
HIPAA 
Health Insurance Portability and Accountability Act 
HMA 
Hypomethylating Agent 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat 
IV 
Intravenous(ly) 
IWG 
International working group 
LDAC 
Low-dose Ara-C 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDS 
Myelodysplastic Syndromes 
MLF 
Morphologic Leukemia-Free State 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition Scan 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PD 
Pharmacodynamics 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PLK1 
Polo-Like Kinase 1 
p.o. 
Orally or By Mouth 
PR 
Partial Response 
RP2D 
Recommended Phase 2 Dose 


 
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Abbreviation 
Definition 
QT 
Interval from the beginning of the QRS complex to the end of the T wave on an 
electrocardiogram 
QTcF 
QT interval with Fridericia’s correction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
SCT 
Stem Cell Transplant 
SEER 
Surveillance, Epidemiology, and End Results 
SRC 
Safety Review Committee 
t1/2 
Half-life 
Tmax 
Time to maximum plasma concentration 
TdP 
Torsade de pointes 
ULN 
Upper Limit of Normal 
 
 


 
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5 ADMINISTRATIVE STRUCTURE 
Coordinating Investigator: 
 
Contract Research Organization (CRO): 
PRA Health Sciences 
Medical Monitor: 
 
 
 


 
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6 INTRODUCTION 
6.1 Background 
6.1.1 Acute Myeloid Leukemia 
Acute myeloid leukemia (AML) is a hematologic malignancy in which myeloid lineage cells of 
the bone marrow cease to differentiate appropriately, resulting in a marked increase in the 
number of circulating immature blast cells. As a consequence, the counts of mature red blood 
cells, platelets, and normal white blood cells decline, causing fatigue, shortness of breath, 
bleeding, and increased susceptibility to infection.[1] The Surveillance, Epidemiology, and 
End Results (SEER) program estimates the annual incidence rate of AML in the US to be 
approximately 21,000 cases in 2017.[2] Rates of new AML cases have been rising an average 
of 3.1% each year over the last 10 years. The median age of AML diagnosis is 68 years of age, 
and approximately 45% of new diagnoses are among patients age 70 years or older. [3] 
Treatment options for AML patients are limited and vary depending on the age and fitness of 
the patient.[4] Typically, patients 60 to 65 years of age or younger undergo induction 
chemotherapy using a combination of the nucleoside analog cytarabine and an anthracycline 
(either daunorubicin or idarubicin), a regimen commonly referred to as “7+3” because the 
administration of the therapies consists of 7 consecutive days of cytarabine intravenous (IV) 
infusion followed by 3 consecutive days of anthracycline IV bolus; each cycle of 7+3 therapy 
is 28 days in duration and can be repeated. Complete remission is defined as <5% blast cells in 
the bone marrow, with recovery of neutrophils to ≥109/L and platelets to ≥100 x109/L within 
1 to 2 cycles of induction chemotherapy. Patients then have follow-up consolidation therapy 
with high-dose cytarabine for 3 to 4 cycles and, when feasible, either an autologous or 
allogeneic stem cell transplant (SCT). Because of the intensity of this approach, induction 
therapy as a means to transplant is less frequently adopted for patients over 60 to 65 years of 
age, although patients over 60 to 65 years of age can be considered for transplant (usually with 
reduced intensity conditioning regimens) based on other factors suggesting that they will 
survive the treatment regimen. Thus, despite 7+3 having been the standard first-line treatment 
for AML for over 30 years, better therapies for all patients are urgently needed, and this need is 
particularly critical for elderly or frailer patients. [5] 
As an alternative to the standard cytotoxic chemotherapy, older patients are most frequently 
treated with lower-intensity options including hypomethylating agents (HMAs), such as 
5’-azacitidine (Vidaza®) and decitabine (DacogenTM) or antimetabolites such as cytosine 
arabinoside (also referred to as cytarabine or Ara-C) given at a low-dose commonly known as 
low-dose Ara-C (LDAC). These agents have demonstrated a survival benefit compared to best 
supportive care in elderly AML patients. However, when these drugs are used as single-agents, 
AML relapses are inevitable and generally occur within 12 months. 
Clearly, new and better therapeutic options are urgently required for AML, supporting the 
current study exploring onvansertib (PCM-075), a polo-like kinase 1 (PLK1) inhibitor, in 
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6.1.2 Polo-like Kinase 1 
Polo-like kinase 1 is the most well characterized member of the 5 members of the family of 
serine/threonine protein kinases and strongly promotes the progression of cells through mitosis. 
PLK1 performs several important functions throughout mitotic (M) phase of the cell cycle, 
including the regulation of centrosome maturation and spindle assembly, the removal of 
cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome 
(APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. [6] It plays a key role in 
centrosome functions and the assembly of bipolar spindles. It also acts as a negative regulator 
of p53 family members leading to ubiquitination and subsequent degradation of p53/TP53, 
inhibition of the p73/TP73 mediated pro-apoptotic functions and phosphorylation/degradation 
of bora, a cofactor of Aurora kinase A. During the various stages of mitosis, PLK1 localizes to 
the centrosomes, kinetochores, and central spindle. PLK1 is aberrantly overexpressed in a 
variety of human cancers including AML and is correlated with cellular proliferation and poor 
prognosis. [7] The first PLK1 inhibitor, BI 2536, showed interesting clinical activity in patients 
with relapsed and treatment refractory AML in an early clinical study, and its successor 
volasertib (also known as BI 6727) demonstrated a more favorable toxicity profile, as well as 
potent anti-leukemic activity as monotherapy and in combination with LDAC in heavily 
pretreated AML patients. [8, 9, 10] In 2013, volasertib received a Breakthrough Therapy 
designation from the Food and Drug Administration (FDA) for its potential as a treatment for 
patients with untreated AML who are ineligible for intensive remission induction therapy. 
6.1.3 Onvansertib (PCM-075) 
Onvansertib (also known as PCM-075 and NMS-1286937) is the first PLK1-specific ATP 
competitive inhibitor administered by oral route to enter clinical trials with proven antitumor 
activity in different preclinical models. [11, 12, 13, 14, 15] The compound shows high potency 
in proliferation assays having low nanomolar activity on a large number of cell lines, both from 
solid as well as hematologic tumors. Onvansertib potently causes a mitotic cell-cycle arrest 
followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with a clear 
PLK1-related mechanism of action at well tolerated doses in mice after oral administration. In 
addition, onvansertib shows activity in combination therapy with approved cytotoxic drugs, 
such as irinotecan, in which there is enhanced tumor regression in HT29 human colon 
adenocarcinoma xenografts compared to each agent alone, and shows prolonged survival of 
animals in a disseminated model of AML in combination therapy with cytarabine. Onvansertib 
has favorable pharmacologic parameters and good oral bioavailability in rodent and nonrodent 
species, as well as proven antitumor activity in different nonclinical models using a variety of 
dosing regimens, which may potentially provide a high degree of flexibility in dosing 
schedules, warranting investigation in clinical settings. Onvansertib has several advantages 
over volasertib, including a higher degree of potency and specificity for the PLK1 isozyme, 
and oral bioavailability. 
To date, a single Phase 1 dose-escalation safety study with onvansertib has been completed in 
adult subjects with advanced/metastatic solid tumors at a single study site in the US. The 


 
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primary objective of that study was to determine first-cycle dose-limiting toxicities (DLT) and 
maximum tolerated dose (MTD) of onvansertib administered p.o. for 5 consecutive days every 
3 weeks (ie, 21-day treatment cycle) in adult subjects with advanced/metastatic solid tumors. 
Secondary objectives of the study were to define the safety profile of onvansertib, determine 
the pharmacokinetics (PK) of onvansertib in plasma (at the MTD), and document any 
antitumor activity.  
A total of 21 subjects were enrolled in the Phase 1 study, and 19 subjects were treated. Four 
dose levels were explored: 6 mg/m2/day (4 subjects enrolled, 3 treated), 12 mg/m2/day 
(3 subjects treated), 24 mg/m2/day (6 subjects treated), 48 mg/m2/day (4 subjects enrolled, 
3 subjects treated), and 36 mg/m2/day (4 subjects treated). 
The PK parameters of onvansertib showed that the systemic exposure to onvansertib was 
generally higher on Day 5 than after the first administration on Day 1, with a terminal half-life 
ranging between 20 to 30 hours. Following the second cycle of treatment, the systemic 
exposure appeared to be similar to that in the first cycle, suggesting comparable exposure to 
the onvansertib in the 2 treatment cycles.  
In onvansertib subjects with ≥1 on-treatment safety assessment (as of the cut-off date of 
18 Dec 2013), no DLT occurred at the first 3 dose levels of 6, 12, and 24 mg/m2/day. No 
patients experienced myelosuppression of any grade, defined as thrombocytopenia, leukopenia, 
neutropenia, or thrombocytopenia, at the 6 mg/m2 or 12 mg/m2 dose levels, and a single patient 
(1/6) developed thrombocytopenia at the 24 mg/m2 dose level. At the subsequent dose level of 
48 mg/m2/day, 2 of the 3 subjects treated developed a first-cycle DLT: in 1 subject, a decrease 
in platelets to Grade 4 and an absolute neutrophil count (ANC) to Grade 4 lasted >7 days, and 
both events were considered by the Investigator to be not related to onvansertib; in the second 
subject, who was also receiving opiates, Grade 3 constipation was judged by the Investigator to 
be possibly related to onvansertib. At the 48 mg/m2/day dose level, the MTD was considered to 
have been exceeded and an intermediate dose level of 36 mg/m2/day was investigated. 
Four subjects were treated at the 36 mg/m2/day dose level. Two of the 4 subjects had DLT 
following 5 days of treatment with onvansertib: 
• One subject had DLT of thrombocytopenia Grade 4 (platelet count <25,000/mm3) and 
neutropenia Grade 4 (ANC <500/mm3 for >7 days). Vitamin K and platelet transfusions 
were given to treat thrombocytopenia, and granulocyte colony-stimulating factor was 
administered for neutropenia. The subject demonstrated complete recovery of 
neutrophil and platelet counts to within normal limits within 10 days. 
• In a second subject, a DLT of thrombocytopenia Grade 4 (platelet count <25,000/mm3) 
was observed. Following platelet transfusion, the subject’s platelet level recovered to 
Grade 1. 
Treatment-emergent abnormalities in hematology tests included lymphopenia (84.2%, 36.8%; 
Grade 3-4), neutropenia (52.6%, 21%; Grade 3-4), anemia (36.8%, 10.5%; Grade 3-4), 
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Treatment-emergent abnormalities were dose-dependent and mostly mild to moderate in 
severity except for 4 cases of neutropenia and leukopenia Grade 4, 3 cases of 
thrombocytopenia Grade 4, and 4 cases of lymphopenia Grade 4. At baseline all of these 
patients had Grade 1 to 2 hematological toxicities with the exception of 2 patients with 
lymphopenia Grade 3. During Cycle 1, median time to anemia, thrombocytopenia, leukopenia, 
neutropenia, and lymphocytopenia nadir was 10, 14.5, 15, 15, and 13 days, respectively. 
Median time to recovery from nadir was 3.5 days for hemoglobin, 7 days for platelets, 7 days 
for white blood cells, 6.5 days for neutrophils, and 7.5 days for lymphocytes. Some of the 
hematological abnormalities detected were also reported as adverse events (AEs) related to 
study medication, in particular: thrombocytopenia (4 patients, 21.1%, Grade 4 in 3 cases), 
neutropenia (3 patients, 15.8% all Grade 4), anemia and leukopenia (2 patients each, 10.5%, 
Grade 3 in both cases).  
Treatment-emergent abnormalities of blood chemistry parameters were mostly of Grade ≤2 
severity. Grade 3 abnormalities included: 2 cases of hypoalbuminemia in patients with renal 
metastases and a Grade 1 or Grade 2 value at baseline; 2 cases of increase in alkaline 
phosphatase (ALP) in 2 patients who already had a Grade 2 value at baseline; 1 case of 
hyponatremia in one patient with a borderline Grade 3 value (129 mmol/L); 1 case of increase 
in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), 1 case of increase in 
lipase and 1 case of hypophosphatemia in one patient each. Only 1 case of increase in ALP 
Grade 4 was recorded in 1 patient, who had already presented with a Grade 3 value at baseline, 
likely tumor-related. Only ALT Grade 3 and AST Grade 3, recorded in 1 patient treated at 
12 mg/m2, were judged drug related by the Investigator. 
Hematological toxicity was dose-limiting at doses of 48 mg/m2/day for 5 consecutive days 
every 3 weeks. At the 48 mg/m2/day dose level, serious adverse events (SAEs) of 
thrombocytopenia Grade 4 and leukopenia Grade 4 occurred in 1 subject and at 36 mg/m2/day, 
thrombocytopenia Grade 4 and neutropenia Grade 4 occurred in 1 subject. No other relevant 
toxicities were observed during the study. Recovery for both platelets and ANC (even without 
colony-stimulating factors support) was prompt, being generally achieved in 1 to 2 weeks. 
A summary of Drug-related Treatment-emergent AEs by dose level is provided in  
Table 6-1 below. 
 
 
 
 
 
 


 
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Table 6-1: Drug-related Treatment-emergent AEs 
MS-1286937H PO,  
Days 1-5, q 3 weeks 
Assigned Dose Level (mg/m2/day) 
Any Dose 
Level (N=19) 
6 (N=3) 
12 
(N=3) 
24 
(N=6) 
36 
(N=4) 
48 (n=3) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Preferred Term 
CTC Grade 
  
Any Term 
1–4 
11 
57.9 
2 
66.7 
2 
66.7 
2 
33.3 
3 
75.0 
2 
66.7 
3–4 
7 
36.8 
  
  
1 
33.3 
1 
16.7 
3 
75.0 
2 
66.7 
Thrombocytopenia 
1–4 
4 
21.1 
  
  
  
  
1 
16.7 
2 
50.0 
1 
33.3 
3–4 
3 
15.8 
  
  
  
  
  
  
2 
50.0 
1 
33.3 
Hypokalemia 
1–4 
3 
15.8 
1 
33.3 
1 
33.3 
  
  
  
  
1 
33.3 
Neutropenia 
1–4 
3 
15.8 
  
  
  
  
  
  
2 
50.0 
1 
33.3 
3–4 
3 
15.8 
  
  
  
  
  
  
2 
50.0 
1 
33.3 
Anemia NOS 
1–4 
2 
10.5 
  
  
  
  
  
  
1 
25.0 
1 
33.3 
3–4 
2 
10.5 
  
  
  
  
  
  
1 
25.0 
1 
33.3 
MS-1286937H PO, Days 1-5  
q 3 weeks 
Assigned Dose Level (mg/m2/day) 
Any Dose 
Level (N=19) 
6 (N=3) 
12 
(N=3) 
24 
(N=6) 
36 
(N=4) 
48 (n=3) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Preferred Term 
CTC Grade 
 
Aspartate 
aminotransferase 
elevation 
1–4 
2 
10.5 
1 
33.3 
1 
33.3 
  
  
  
  
  
  
3–4 
1 
5.3 
  
  
1 
33.3 
  
  
  
  
  
  
Hypocalcemia 
1–4 
2 
10.5 
1 
33.3 
  
  
  
  
  
  
1 
33.3 
Hypophosphataemia 
1–4 
2 
10.5 
  
  
1 
33.3 
1 
16.7 
  
  
  
  
3–4 
1 
5.3 
  
  
  
  
1 
16.7 
  
  
  
  
Leukopenia NOS 
1–4 
2 
10.5 
  
  
  
  
  
  
1 
25.0 
1 
33.3 
3–4 
2 
10.5 
  
  
  
  
  
  
1 
25.0 
1 
33.3 
Nausea 
1–4 
2 
10.5 
1 
33.3 
  
  
  
  
  
  
1 
33.3 
Alanine 
aminotransferase 
elevation 
1–4 
1 
5.3 
  
  
1 
33.3 
  
  
  
  
  
  
3–4 
1 
5.3 
  
  
1 
33.3 
  
  
  
  
  
  
Cholecystitis NOS 
1–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
3–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
Constipation 
1–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
3–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
Hyponatremia 
1–4 
1 
5.3 
1 
33.3 
  
  
  
  
  
  
  
  
Hypoxia 
1–4 
1 
5.3 
  
  
  
  
  
  
1 
25.0 
  
  
3–4 
1 
5.3 
  
  
  
  
  
  
1 
25.0 
  
  
Lymphocyte 
percentage elevation 
1–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
3–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
Pneumonia NOS 
1–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
3–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
White blood cell 
decrease 
1–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
3–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 


 
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White blood cell count 
elevation 
1–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
3–4 
1 
5.3 
  
  
  
  
  
  
  
  
1 
33.3 
Source: CSR PLKA-937-001 (Appendix 19.5) 
Further details regarding the nonclinical and clinical studies of onvansertib are provided in the 
onvansertib Investigator’s Brochure (IB). In addition, the current cytarabine and decitabine 
package inserts provide a description of the AEs that can be expected with their administration 
(Appendix 19.4). 
6.2 Study and Dose Rationale 
There is an urgent unmet medical need of subjects who have relapsed after or not responded to 
therapy for AML. Based on the body of data with therapies targeting PLK, there appears to be 
potential clinical benefit for subjects with AML. The aim of this study is to explore treatment 
with onvansertib in combination with either low-dose cytarabine or decitabine in subjects with 
AML. The onvansertib starting dose will be 12 mg/m2 based on results from the Phase 1 study 
PLKA-937-001. In that study, a dose of 12 mg/m2 p.o. daily for 5 days was evaluated during 
dose escalation, and was not associated with myelosuppression of any grade. 
6.3 Risks and Benefits for Subjects 
The current safety clinical profile of onvansertib in treated subjects indicates that 
hematological toxicity (thrombocytopenia and neutropenia) is the most relevant toxicity of 
treatment. Recovery from hematologic toxicity was prompt in all reported subject cases, 
occurring in 1 to 2 weeks from the onset, even without colony-stimulating factor support. 
Therefore, the toxicity of onvansertib appears to be manageable with conventional treatments. 
No other relevant toxicities were observed during the study 
Clinical data with a compound similar to onvansertib (ie, volasertib) in combination therapy 
produced promising results for subjects with AML. Onvansertib has several advantages over 
volasertib, including oral bioavailability and a higher degree of potency and specificity for the 
PLK1 isozyme. In a Phase 1 clinical study, onvansertib demonstrated a safety profile that was 
manageable, with transient AEs that were related to the drug’s mechanism of action.  


 
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7 STUDY OBJECTIVES 
7.1 Primary Objectives 
Phase 1b: 
• To evaluate the DLTs and MTD, or Recommended Phase 2 Dose (RP2D), of 
onvansertib (PCM-075) in combination with either low-dose cytarabine or decitabine in 
subjects with AML  
Phase 2: 
• To assess the safety and tolerability of the combination of onvansertib (PCM-075) at the 
MTD (or RP2D) and low-dose cytarabine, or the combination of onvansertib (PCM-075) 
at the MTD (or RP2D) and decitabine in subjects with AML 
 
• To evaluate the preliminary anti-leukemic activity of the combination of onvansertib 
(PCM-075) at the MTD (or RP2D) and low-dose cytarabine, or the combination of 
onvansertib (PCM-075) at the MTD (or RP2D) and decitabine in subjects with AML 
7.2 Secondary Objectives 
Phase 1b: 
• To assess the incidence and severity of AEs according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.03) of 
onvansertib (PCM-075) in combination with either low-dose cytarabine or decitabine in 
subjects with AML 
 
• To analyze the PK of onvansertib (PCM-075) when given in combination with either 
low-dose cytarabine or decitabine in subjects with AML 
 
Phase 2: 
• To assess the incidence and severity of AEs according to the NCI-CTCAE version 4.03 
of onvansertib (PCM-075) in combination with either low-dose cytarabine or decitabine 
in subjects with AML 
 
• To analyze the PK of onvansertib (PCM-075) when given in combination with either 
low-dose cytarabine or decitabine in subjects with AML 
7.3 Exploratory Objectives 
Phase 1b and Phase 2: 
• 
To explore additional analyses evaluating potential pharmacodynamic (PD) and 
diagnostic biomarkers of onvansertib (PCM-075) in subjects with AML  
 


 
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8 INVESTIGATIONAL PLAN 
8.1 Overall Study Design and Plan 
This is a Phase 1b/2, open-label study of the safety and anti-leukemic activity of onvansertib in 
combination with either low-dose cytarabine or decitabine in subjects with AML.  
In Phase 1b, subjects will have relapsed or refractory disease and must have received no more 
than 3 prior regimens for the treatment of their AML. Subjects may be treatment naïve as long 
as they are not candidates for or have refused intensive induction therapy. 
In Phase 2, subjects must have received no more than one prior regimen for the treatment of 
their AML. Subjects may be treatment naïve as long as they are not candidates for or have 
refused intensive induction therapy.   
In both phases, prior treatment with either low-dose cytarabine or decitabine for 
myelodysplastic syndromes (MDS) will not be considered a prior regimen. For subjects who 
have undergone hematopoietic stem cell transplantation, the preparative (conditioning) 
regimen and transplant will be considered to be a single line of prior therapy. 
8.1.1 Phase 1b 
Phase 1b will be conducted in 2 arms of subjects allocated to receive either a combination of 
onvansertib and low-dose cytarabine, or a combination of onvansertib and decitabine. 
8.1.1.1 Combination Treatment Arms 
In Arm A, onvansertib will be administered p.o. Day 1 through Day 5 every 21 to 28 days in 
combination with cytarabine which will be administered in all cohorts as 20 mg/m2 
subcutaneously (SC) once daily on Day 1 through Day 10 every 28 days. The starting dose of 
onvansertib in combination with cytarabine, will be 12 mg/m2 p.o. daily for 5 days (Dose Level 
0). On days where both agents are administered (Days 1-5), cytarabine will be administered 
first followed by onvansertib. Investigator assessment of subjects may allow them, at their 
discretion, to treat more frequently than every 28 days; however, in no case may a cycle length 
be less than 21 days. 
In Arm B, onvansertib will be administered orally (p.o.) Day 1 through Day 5 every 21 to 28 
days in combination with decitabine, which will be administered consistently in all cohorts as 
20 mg/m2 IV over 1 hour on Day 1 through Day 5 every 28 days. Onvansertib administration, 
in combination with decitabine, will be initiated at a starting dose of 12 mg/m2 (Dose Level 0). 
The daily dose of decitabine will be administered first followed by onvansertib. Investigator 
assessment of subjects may allow them, at their discretion, to treat more frequently than every 
28 days; however, in no case may a cycle length be less than 21 days. 
The first 3 subjects will be allocated to Arm A (Cohort A1). If Cohort A1 is expanded to 6 
subjects prior to the first subject being enrolled in Arm B, then enrollment in Cohort A1 will be 
completed before enrollment begins in Arm B.  


 
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After all subjects are enrolled in Cohorts A1 and B1, subjects will enroll in subsequent cohorts 
based on the following decision rules:  
• If Arm A is open for enrollment, subjects will enroll in the open Arm A cohort regardless 
of dose level 
• If Arm A is closed to enrollment, subjects will enroll in the open Arm B cohort regardless 
of dose level 
8.1.1.2 Dose Escalation 
Dosing in each arm will proceed independently. Each arm will follow a standard 3+3 dose-
escalation design in which the onvansertib dose will be escalated by 50% increments in 
successive cohorts of 3 subjects (Table 8-1). If none of the 3 subjects enrolled at any dose level 
experience a DLT, the dose of onvansertib will be escalated by 1 dose level in each successive 
cohort. If 1 subject in the first 3 experiences a DLT, up to 3 additional subjects will be enrolled 
at that dose level. If there are no additional DLTs (ie, ≤1 of 6 subjects with DLT), then dose 
escalation will again proceed. If there are 2 subjects who experience DLTs among the first 
3 subjects enrolled, or there is a second DLT in up to 6 subjects enrolled at any dose level, the 
MTD will be judged to have been exceeded and no additional subjects will be started at that 
dose. The MTD will then be established at a prior dose level or an additional cohort may be 
enrolled at an intermediate dose level upon agreement with the Sponsor, Medical Monitor, and 
Principal Investigator.  
The RP2D can be determined based on the assessment of safety, PK, PD, and preliminary 
efficacy of subjects treated at a dose level that has been cleared for safety, regardless of 
whether or not an MTD has been reached. In this case, no further dose escalation will be done 
to determine an MTD.  
Each cohort will be evaluated for toxicity, recovery of blood counts, and PK. DLTs will be 
evaluated for the first 28 days after initiation of therapy. In the case of pancytopenia present at 
Day 28 in the absence of other toxicity that constitutes a DLT, the duration for DLT evaluation 
will be extended to 42 days (unless the pancytopenia resolves between Days 28 and 42, or is 
determined to be due to persistent leukemic involvement of the bone marrow or another cause 
unrelated to study therapy). Pancytopenia in the absence of another cause unrelated to study 
therapy that persists beyond Day 42 will be considered a DLT. If an Investigator elects to 
re-treat a subject prior to 28 days (allowed no sooner than on Day 22), the DLT evaluation 
period will end at the time of initiation of the second cycle therapy. Dose modifications and 
delays for safety will be performed as described in the protocol. After the first cycle, additional 
cycles can be administered to individual subjects based on Investigator judgment if 
hematopoietic recovery is documented, and may incorporate delays or supportive care until 
hematopoietic function returns to baseline or Grade ≤1, as long as the subject is receiving 
clinical benefit without safety or tolerability issues. In the case that failure to achieve 
hematopoietic recovery is judged to be related to persistent leukemic involvement in the bone 
marrow, Investigators may re-initiate therapy according to their clinical judgment upon 
discussion with the Medical Monitor.  


 
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Investigators will also have the option for intra-subject dose escalation in later cycles if safety 
and tolerability have been demonstrated at higher doses of onvansertib. 
At any time during Phase 1b, the Sponsor, in consultation with the Safety Review Committee 
(SRC), may elect to discontinue enrollment into either arm of the study based on safety, 
efficacy, PK, and PD considerations. In this case, enrollment in the other arm will continue as 
described. 
Table 8-1: Onvansertib (PCM-075) Dose and Dosing Levels 
Dose Level 
Dose* 
-1 
6 mg/m2 
0 (Initial dose) 
12 mg/m2 
+1 
18 mg/m2 
+2 
27 mg/m2 
+3 
40 mg/m2 
+4 
60 mg/m2 
+5 
90 mg/m2 
+6  
135 mg/m2 
*Initial starting dose is Dose Level 0. If there are >1 DLTs at a dose level and the prior dose level was 
associated with 1 or fewer DLTs, an additional cohort may be enrolled at an intermediate dose level 
upon agreement with the Sponsor, Medical Monitor, and Principal Investigator. 
8.1.1.3 Preliminary Safety and Efficacy Assessment 
Following assessment of safety and preliminary efficacy in the first 5 dose level escalation 
cohorts (0: 12 mg/m2; +1: 18 mg/m2; +2: 27 mg/m2; +3: 40 mg/m2; +4: 60 mg/m2) in both 
Arm A (onvansertib plus low-dose cytarabine) and Arm B (onvansertib plus decitabine), the 
decision was made to discontinue Arm A from further dose escalation and subject enrollment.  
Arm B will continue forward with dose escalation as outlined in the protocol or until such time 
as the RP2D is determined at a dose level previously cleared for safety.  
The RP2D can be determined based on the assessment of safety, PK, PD, and preliminary 
efficacy of subjects treated at a dose level that has been cleared for safety. In this case, no 
further dose escalation will be done to determine an MTD. 


 
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8.1.2 Phase 2 
In Phase 2, a total of 32 subjects will be enrolled at the RP2D to further evaluate safety and 
preliminary efficacy. Onvansertib will be administered p.o. on Day 1 through Day 5 every 
21 to 28 days, in combination with decitabine, administered consistently as 20 mg/m2 IV over 
1 hour on Day 1 through Day 5 every 28 days, with treatment modifications or delays based on 
return of hematopoietic function to baseline or Grade ≤1 toxicity for optimal subject 
management. The daily dose of decitabine will be administered first followed by onvansertib. 
Investigator assessment of subjects may allow them, at their discretion, to treat more frequently 
than every 28 days; however, in no case may a cycle length be less than 21 days. 
Subjects may continue treatment in the study at any dose until clinically significant disease 
progression or death, unacceptable toxicity, withdrawal of consent, or discontinuation based on 
Investigator discretion. Subjects will be followed for survival for up to 1 year after enrollment. 
AEs and concomitant medication use will be queried, monitored, and recorded throughout the 
study. Safety evaluations will include: physical examinations, performance status, vital signs, 
electrocardiograms (ECGs), hematology and serum chemistry laboratory tests, and urinalysis. 
8.1.3 Study Endpoints 
Primary safety endpoints:  
1. Characterization of DLTs; characterization of AEs by type, incidence, severity (graded 
by NCI-CTCAE version 4.03), seriousness, and relationship to treatment; effects on 
vital signs and laboratory parameters; and changes from baseline in ECGs, physical 
examinations, weight, and ECOG performance 
 
Primary efficacy endpoint:  
1. Rate of complete response (CR + CRi) in Phase 2, defined as a morphologic leukemia-
free state (MLF; defined below) plus: 
For CR: 
a.       Subject is independent of transfusions  
b.       Absolute neutrophil count (ANC) of >1000/mm3 
c.       Platelets of ≥100,000/mm3 
For CRi: 
a.      Meets all criteria for CR except for either neutropenia (ANC <1000/mm3) or     
thrombocytopenia (<100,000/mm3) but must include transfusion independence  
 


 
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Secondary endpoints: 
1.   Rate of achievement of a MLF in Phase 2, defined as: 
a.      Bone marrow (BM) <5% blasts in an aspirate with spicules (a BM biopsy 
should be performed if spicules are absent) 
b.      No blasts with Auer rods or persistence of extramedullary disease 
2.   Rate of partial response (PR) in Phase 2: All of the hematologic values for a CR but 
with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone 
marrow aspirate and a normalization of blood counts as noted above 
3.   Duration of response (DOR) in Phase 2: Time from documentation of response until 
documentation of recurrence of or progression of disease 
4.   Event-free survival (EFS) in Phase 2: Time from enrollment until disease progression 
or death from any cause 
5.   Overall survival (OS) in Phase 2: Time from enrollment until death from any cause 
6.   Concentrations of onvansertib in plasma samples collected at pre-specified time points 
before and after administration of onvansertib, including maximum plasma 
concentration (Cmax), trough plasma concentration (Cmin), time to maximum plasma 
concentration (Tmax), area under the plasma concentration versus time curve (AUC), 
and plasma terminal elimination half-life (t1/2) 
Exploratory endpoints: 
1. Blood samples for PD and diagnostic biomarker evaluation 
2. Rate of complete response (CR+CRi), MLF, PR, DOR, EFS and OS in all enrolled 
subjects (Phases 1b and 2) 
8.2 Study Duration 
The screening period will be up to 28 days prior to enrollment. Onvansertib administration in 
both phases can continue for as long as the subject has documented hematopoietic recovery 
and for as long as the Investigator considers that the subject is receiving clinical benefit 
without safety or tolerability issues. In addition, subjects may be escalated or de-escalated to 
doses or schedules that are considered safe and well tolerated, and in the best interest of the 
subject. Subjects will be followed for survival for up to 1 year after enrollment. 
8.3 Eligibility Criteria 
Subjects who meet all of the following inclusion criteria and none of the exclusion criteria will 
be eligible to be enrolled in the study.  


 
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8.3.1 Inclusion Criteria 
1. Disease Status and Prior Therapy: 
a. Histologically confirmed diagnosis of AML  
b. Phase 1b:  
i. Subjects with relapsed or refractory AML who have received no more 
than 3 prior treatment regimens for AML. Subjects who have received 
prior treatment with cytarabine or decitabine are not excluded. Prior 
treatment with either low-dose cytarabine or decitabine given for MDS 
will not be considered a prior regimen. For subjects who have 
undergone hematopoietic stem cell transplantation, the preparative 
(conditioning) regimen and transplant will be considered to be a single 
line of prior therapy. 
OR 
ii. Subjects who are treatment naïve and are not candidates for or have 
refused intensive induction therapy. 
c. Phase 2:  
i. Subjects with relapsed or refractory AML who have received no more 
than 1 prior treatment regimen for AML. Subjects who have received 
prior treatment with cytarabine or decitabine are not excluded. Prior 
treatment with either low-dose cytarabine or decitabine given for MDS 
will not be considered a prior regimen.   
OR 
ii. Subjects who are treatment naïve and are not candidates for or have 
refused intensive induction therapy.  
2. Age ≥18 years  
3. ECOG performance status ≤2 (Appendix 19.3) 
4. Subjects must be willing and able to review, understand, and provide written consent 
before starting any study-specific procedures or therapy.  
5. All men and women must agree to practice effective contraception during the entire 
study period and after discontinuing study drug, unless documentation of infertility 
exists 
a. Sexually active, fertile women must use 2 effective forms of contraception 
(abstinence, intrauterine device, oral contraceptive, or double barrier device) from 
the time of informed consent and until at least 6 months after discontinuing study 
drug 


 
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b. Sexually active men and their sexual partners must use effective contraceptive 
methods from the time of subject informed consent and until at least 3 months 
after discontinuing study drug 
8.3.2 Exclusion Criteria  
Subjects must not meet any of the following exclusion criteria: 
1. Treatment-related AML or acute promyelocytic leukemia (APL) 
2. Active malignancies within 12 months with the exception of those with a negligible 
risk of metastasis or death 
3. Clinical evidence of active central nervous system leukemia at the time of screening 
4. ALT and/or AST ≥2.5 x upper limit of normal (ULN)  
5. Total bilirubin >2.0 mg/dL (or >3.0 mg/dL in subjects with documented Gilbert 
syndrome) 
6. Serum creatinine ≥2.0 mg/dL 
7. NYHA Class III or IV heart disease (Appendix 19.2), active ischemia or any other 
uncontrolled cardiac condition, or hypertensive or metabolic condition 
8. Myocardial infarction in the previous 12 weeks (from the start of treatment) 
9. Resting left ventricular ejection fraction <50% at the time of screening 
10. QT interval with Fridericia’s correction [QTcF] [16] >450 milliseconds for men, or 
>470 milliseconds for women. The QTcF should be calculated as the arithmetic mean 
of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT 
prolongation (eg, medications, hypokalemia), the triplicate ECG may be repeated once 
during screening and that result may be used to determine eligibility. 
11. Pregnant or breast feeding 
12. Active and uncontrolled disease (other than AML) or infection as judged by the 
treating physician 
13. Treatment with systemic therapy for the primary disease within 14 days of first dose 
(except for hydroxyurea or isolated doses of cytarabine or decitabine for WBC control) 
14. Grade 2 or greater toxicities from prior therapy, except for Grade 2 toxicities that are 
not expected to resolve and that in the judgment of the Investigator do not pose a 
significant safety risk to subject participation.  
15. Subjects with any other medical condition, including mental illness or substance abuse, 
deemed by the Investigator to be likely to interfere with the subject’s ability to sign the 
informed consent form (ICF) or his/her ability to cooperate and participate in the study, 
or to interfere with the interpretation of the results 


 
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8.3.3 Removal of Subjects from Therapy or Assessment 
Subjects will be discontinued from further study drug administration in the event of any of the 
following: 
• Intolerable toxicity as determined by the Investigator 
• Progression of disease requiring an alternate therapy, in the opinion of Investigator 
• Entry into another therapeutic clinical study or start of additional anticancer therapy 
• Significant deviation from the protocol or eligibility criteria, in the opinion of the 
Medical Monitor or Investigator 
• Noncompliance with study or follow-up procedures 
• Pregnancy 
• Subject withdrawal of consent and decision to discontinue participation 
• Termination of the study by the Sponsor 
• Any other reason that, in the opinion of the Investigator, would justify removal of the 
subject from the study. 
In the event that a subject is withdrawn from the study every effort will be made by the 
Investigator to document and report the reasons for withdrawal as thoroughly as possible. The 
reason(s) for withdrawal must be clearly reported on the appropriate page of the subject’s 
electronic case report form (eCRF). An eCRF must be completed for any subject who receives 
study drug. An End-of-Treatment reason must be recorded for any subject who receives study 
drug. The requirement for subject replacement is outlined in Section 11. 
If a subject is discontinued from the study for any reason, every effort must be made to 
perform all end of study (EOS) assessments (Section 9.1). In the event that the subject fails to 
return for the necessary visit(s), an effort must be made to contact the subject to determine the 
reason, and this information should be recorded in the appropriate source record and reported 
as a deviation. 
8.4 STUDY DRUG TREATMENT 
8.4.1 Description of Study Treatments 
8.4.1.1 Onvansertib (PCM-075) 
The chemical name of onvansertib is 1-(2-hydroxyethyl)-8-{[5-(4-methylpiperazin-1-yl)-2-
(trifluoromethoxy) phenyl] amino}- 4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-
carboxamide fumarate salt. 
Onvansertib will be supplied as 5 mg and 20 mg (as free base) hard gelatin capsules that will 
be administered p.o. 


 
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• A Size 4 opaque caramel body and Swedish orange cap hard gelatin capsule contains 
6.09 mg of onvansertib corresponding to 5 mg as free base, lactose monohydrate, 
pregelatinized starch, and glyceryl behenate. The capsule body shell contains gelatin, 
black iron oxide, red iron oxide, yellow iron oxide, and titanium dioxide; the capsule 
cap shell contains gelatin, red iron oxide, and titanium dioxide. 
• A Size 4 opaque Swedish orange body and cap hard gelatin capsule contains 24.36 mg 
of onvansertib corresponding to 20 mg as free base, lactose monohydrate, 
pregelatinized starch, and glyceryl behenate. The capsule shell contains gelatin, red iron 
oxide, and titanium dioxide. 
8.4.1.1.1 Storage Conditions 
Onvansertib is to be stored under refrigerated conditions (5°C ± 3°C; 36°F to 46°F) in the 
original packaging. 
8.4.1.1.2 Shelf-life 
When onvansertib is stored at 5°C±3°C (36°F to 46°F), on the basis of the available stability 
information, a shelf-life of 48 months is currently assigned to the 5 mg and 20 mg (as free 
base) hard gelatin capsules. 
Concurrent stability studies on the clinical batches are being conducted with 5 mg and 20 mg 
(as free base) hard gelatin capsules in order to evaluate the chemical, physical, and 
microbiological parameters. The onvansertib expiry date will be extended accordingly with the 
stability results. Any unexpected findings will be promptly communicated to study 
Investigators and to the applicable regulatory authorities. 
8.4.1.1.3 Dose Levels 
The Phase 1b onvansertib starting dose is 12 mg/m2 (Dose Level 0). The dose of onvansertib 
will be escalated in sequential dose cohorts as described (Section 8.1.1). Subjects will be 
assigned to a given dose regimen by the Principal Investigator based on prior dose levels tested 
and cohorts available. A subject will not be enrolled in the study until they complete all 
Screening evaluations, all eligibility criteria are met based on screening evaluations, and the 
eligibility criteria continues to be met following all baseline assessments on Day 1 of Cycle 1. 
Onvansertib will be administered p.o. on Day 1 through Day 5 every 21 to 28 days. 
Investigator assessment of subjects may allow them, at their discretion, to treat more frequently 
than every 28 days; however, in no case may a cycle length be less than 21 days. 
Note that additional dosing regimens and doses may be explored if, after review of the safety, 
PK/PD, and efficacy data for the Phase 1b and Phase 2, alternative dosing schedules and doses 
are deemed to be in the best interest of understanding the safety and efficacy of the drug, and 
agreed upon by the Sponsor, Medical Monitor, and Principal Investigator. 


 
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8.4.1.1.4 Dose Delays 
Subjects who experience any AE considered related to the study drug (ie, adverse reaction or 
suspected adverse reaction per criteria in Section 10.1) will have their next dose of onvansertib 
held until all study drug-related toxicities have reverted to Grade 1 or to Baseline. All AEs 
must be attributed to study drugs unless there is a reasonably acceptable alternate cause for the 
AEs. 
8.4.1.1.5 Dose Reduction 
Subjects who experience AEs of Grade ≥3 that is considered related to the study drug 
(ie, adverse reaction or suspected adverse reaction per criteria in Section 10.1) that do not show 
resolution with standard medical intervention by 7 days will have their next dose of 
onvansertib and all subsequent doses reduced by 1 dose level. If a second study drug-related 
toxicity such as this is encountered, the subject’s next dose will be further reduced by 1 dose 
level, to an intermediate dose level, or subject may be discontinued from the study, based on 
the Investigator’s discretion. All AEs must be attributed to study drugs unless there is a 
reasonably acceptable alternate cause for the AEs. 
8.4.1.2 Cytarabine 
The cytarabine dose will be 20 mg/m2 SC daily on Day 1 through Day 10 every 28 days in 
Phase 1b. The dose of cytarabine will not be modified. On days where both agents are 
administered (Days 1-5), cytarabine will be administered first followed by onvansertib. 
Investigator assessment of subjects may allow them, at their discretion, to treat more frequently 
than every 28 days; however, in no case may a cycle length be less than 21 days. 
Storage of cytarabine should be in accordance with the product package insert 
(Appendix 19.4). 
8.4.1.3 Decitabine 
The decitabine dose will be 20 mg/m2 IV over 1 hour on Day 1 through Day 5 every 28 days in 
Phase 1b and Phase 2. The dose of decitabine will not be modified. The daily dose of 
decitabine will be administered first followed by onvansertib. Investigator assessment of 
subjects may allow them, at their discretion, to treat more frequently than every 28 days; 
however, in no case may a cycle length be less than 21 days. 
Storage of decitabine should be in accordance with the product package insert 
(Appendix 19.4). 
8.4.2 Dosing Schedule 
Subjects will receive study drugs according to the dosing schedule outlined in tables in Section 
9.1. 
After review of the safety, PK, PD, and efficacy data from the Phase 1b portion of the study, 
and during the Phase 2 portion of the study, additional dosing schedules and doses (eg, fewer 


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days with higher doses and shorter treatment cycles) in a given cohort may be explored if 
agreed upon by the Sponsor, Medical Monitor, and Investigators, and are deemed to be 
important for the development of the study drug. 
8.4.3 Study Drug Inventory and Accountability 
In accordance with current Good Clinical Practice (GCP), each study site will keep an 
accounting of all study drug supplies. Details of receipt, storage, administration, and return or 
destruction will be recorded in the study drug accountability record according to the standard 
operating procedure of the study site. Copies of the study drug accountability record will be 
provided to the Sponsor. 
Study drug must only be dispensed to subjects enrolled in the study and only as directed by this 
protocol. Administration of study drugs will be accurately recorded in each subject’s source 
documents and case report form. 
8.4.4 Treatment Compliance 
The study drug will be administered p.o. as 5 mg and 20 mg hard gelatin capsules. Compliance 
will be ascertained by Investigational Site staff by individual subject assessment and 
monitoring/accounting for return of 5 mg and 20 mg hard gelatin capsules. 
8.4.5 Concomitant Medications and Treatments 
Concomitant medications are all medications (or treatments) other than study drugs that are 
taken or received by the subject at any time during the study starting at the time that the first 
dose of study drug was administered through the final study visit assessment. Use of all 
concomitant medications, including any change in therapy, must be recorded and updated in 
the source documentation and on the case report form. 
All inter-current medical conditions will be treated at the discretion of the Investigator 
according to acceptable community and/or institutional standards of medical care.  
Concomitant use of drugs with a known high risk of TdP should be avoided. For a list of drugs 
known to increase the risk of TdP, please refer to the published list of drugs at 
www.crediblemeds.org. Specific exception is allowed for the use of ciprofloxacin, which is 
commonly used in patients with AML and carries a low risk of TdP. Unplanned use of drugs 
known to increase the risk of TdP or the QTc interval should only occur during the conduct of 
the study with full consideration of the risks and benefits. Investigators should consult the TdP 
risk QT interval normogram included in Appendix 19.6. 
Prophylactic filgrastim, pegfilgrastim, or oprelvekin, or other drugs of this class will be 
allowed if clinically indicated; the subject may receive growth factor support if needed and 
according to American Society of Clinical Oncology/American Society of Hematology 
(ASCO/ASH) guidelines. Erythropoietin, blood products, anti-emetics, antimicrobials, and 
steroids may be given at the discretion of the Investigator based on established criteria. 


 
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No other anti-leukemia treatments are allowed in subjects while the subject is participating in 
this study.  
Subjects receiving warfarin or other coumarin-derivative anticoagulant should be monitored 
regularly for changes in prothrombin time or international normalized ratio (INR).  


 
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9 ASSESSMENTS 
9.1 Schedule of Assessments 
The schedule of events for Phase 1b Cycle 1, Phase 1b Cycle 2 and higher, and Phase 2 are 
provided in Table 9-1, Table 9-2, and Table 9-3, respectively. 
Every attempt should be made to have each subject attend each visit as scheduled. Per protocol 
blood collection time points for determination of PK parameters should be adhered to as 
closely as possible. 
 


 
 
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Table 9-1: Schedule of Events: Phase 1b Cycle 1 
Event 
Screening 
Baseline 
On Treatment  
Follow-up/EOS 
≤28 days 
prior to 
enrollment 
≤14 days 
prior to 
enrollment 
Days -2 
to 1 
Days 
(1-2 wks after 
Discontinuation) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
15k 
22k, l 
Informed consent 
X 
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
Relapsed/refractory AML: 
confirmation of diagnosis and 
cytogenetic analysis and 
molecular characterization 
obtained at diagnosis  
X 
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
ECOG performance status 
X 
  
X 
  
  
  
  
  
 
 
  
 
 
  
  
X 
History and physical 
examinationa 
X 
  
X 
  
  
  
  
  
 
 
  
 
 
  
  
X 
Triplicate ECGb 
  
X 
  
X 
  
  
  
X  
 
 
X 
 
 
  
  
  
Blood chemistryc 
  
X 
X  
  
  
  
  
  
 
 
X 
 
 
X 
 X 
X 
CBC, including differential, and 
platelet countd 
  
X 
     
X  
  
  
  
 X 
 
 
X 
 
 
X 
 X  
X 
Urinalysis 
  
X 
  
  
  
  
  
  
 
 
  
 
 
  
  
  
Pregnancy teste 
  
X 
X  
  
  
  
  
  
 
 
  
 
 
  
  
 X 
Confirmation of all eligibility 
criteria 
  
X 
  
  
  
  
  
  
 
 
  
 
 
  
  
  
 


 
 
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ECHO or MUGA scan 
  
X 
  
  
  
  
  
  
 
 
  
 
 
  
  
X 
Bone marrow aspirate & 
peripheral blood for measuring 
status of disease and diagnostic 
biomarker evaluationf 
  
  X 
 
  
  
  
  
  
 
 
  
 
 
X 
  
Blood samples for PK analysisg 
  
  
  
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
  
Blood samples for 
pharmacodynamic and 
biomarker analysish 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Onvansertib (PCM-075) 
administration 
  
  
  
X 
X 
X 
X 
X 
 
 
  
 
 
  
  
  
Cytarabine administrationi 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Decitabine administrationi 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
AE recording 
  
  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
recording 
X 
 X 
X 
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survivalj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Footnotes for Table 9-1: 
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AML=acute myeloid leukemia; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
CBC=complete blood count; ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group (performance score); EOS=end of 
study; LDH=lactate dehydrogenase; MUGA=multigated acquisition scan; PK=pharmacokinetics 
a 
Including height, weight, vital signs, and general physical exam 
b 
Triplicate ECGs should be collected at pre-dose and 3 hours (±15 minutes) after dosing of onvansertib (PCM-075) on Days 1 and 5 and once on Day 8.   
c 
Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, 
total bilirubin, AST, ALT, LDH, and uric acid 
d 
CBC, to include differential and platelet count should be repeated as clinically indicated 


 
 
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e 
A serum or urine pregnancy test should be performed for women of childbearing potential at least once per cycle prior to dosing, as well as during 
Screening and at the Follow-up/EOS visit.  
f 
Bone marrow aspirate and peripheral blood (complete blood count, differential, and platelet count; flow cytometry is optional) should be performed 
within 15 days prior to the first dose of study drug to document disease. If clinically appropriate, a bone marrow aspirate (or biopsy if necessary) should 
be performed 14-21 days after the start of therapy to document disease status. If hypoplasia is present, then a repeat aspirate/biopsy at the time of 
hematologic recovery based on peripheral blood counts should be obtained to document remission. If hypoplasia is not documented or is indeterminate, 
a repeat biopsy should be obtained, if clinically appropriate, in another 7-14 days to clarify the persistence of leukemia. If cytogenetics were initially 
abnormal, include cytogenetics as part of the remission documentation. For peripheral blood, include CBC, including differential and platelet count.   
g 
Blood samples for PK analysis will be collected predose, and 0.5, 1, 2, 3, 4, 8 (all ±10 minutes), and 24 hours (±1 hour) after administration of 
onvansertib on Days 1 and 5, as well as once each on Days 8, 15, and 22. 
h 
Blood samples for pharmacodynamic and diagnostic biomarker analysis will be obtained at screening in conjunction with the bone marrow aspirate; on 
Day 1 predose, 3 hours (±10 minutes) and 24 hours (±1 hour) after administration of onvansertib; on Day 5 predose, 3 hours (±10 minutes) after 
administration of onvansertib in conjunction with the PK sample being obtained at those time points, as well as once each on Days 8, 15, and 22. 
i 
Subjects will receive either cytarabine or decitabine based on the arm in which they are enrolled (Section 8.1.1). On days where both agents are 
administered (Days 1-5), cytarabine will be administered first followed by onvansertib. For patients receiving decitabine, the decitabine will be 
administered first followed by onvansertib. 
j 
After cessation of study treatment, subjects will be followed for survival every 2 months for 1 year (may be by telephone). 
k 
Visits on Days 15 and 22 may occur ±1 day for subject convenience. 
l 
Investigator assessment of subjects may allow them, at their discretion, to treat more frequently than every 28 days; however, in no case may a cycle 
length be less than 21 days. If an Investigator elects to re-treat a subject prior to 28 days (allowed no sooner than on Day 22), the DLT evaluation period 
will end at the time of initiation of the second cycle therapy. 
 


 
 
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Table 9-2: Schedule of Events: Phase 1b Cycle ≥2 
Event 
On Treatment  
Follow-up/EOS 
Days 
(1-2 wks after 
Discontinuation) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
15k 
22k, j, l 
ECOG performance status 
X 
  
  
  
  
 
 
  
 
 
  
  
X 
History and physical examinationa 
X 
  
  
  
  
 
 
  
 
 
  
  
X 
Triplicate ECGb 
X 
  
  
  
X 
 
 
  
 
 
  
  
  
Blood chemistryc 
X 
  
  
  
  
 
 
 X 
 
 
X 
X 
X 
CBC, including differential, and platelet countd 
X 
  
  
  
X  
 
 
 X 
 
 
 X 
X  
X 
Urinalysisd 
X 
  
  
  
  
 
 
  
 
 
  
  
  
Pregnancy teste 
X 
  
  
  
  
 
 
  
 
 
  
  
  
ECHO or MUGA scan 
  
  
  
  
  
 
 
  
 
 
  
  
X 
Bone marrow aspirate & peripheral blood for 
measuring status of disease and diagnostic biomarker 
evaluationf 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood samples for PK evaluationg 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Blood samples for pharmacodynamic and diagnostic 
biomarker evaluationh 
X 
  
  
  
X 
 
 
X 
 
 
X 
X 
  


 
 
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Event 
On Treatment  
Follow-up/EOS 
Days 
(1-2 wks after 
Discontinuation) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
15k 
22k, j, l 
Onvansertib (PCM-075) administration 
X 
X 
X 
X 
X 
 
 
  
 
 
  
  
  
Cytarabine administrationi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Decitabine administrationi 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
AE recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication recording 
 X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survivalj 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Footnotes for Table 9-2: 
Abbreviations: AE=adverse event; BUN=blood urea nitrogen; ALT= alanine aminotransferase; AST= aspartate aminotransferase; CBC=complete blood count; 
ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group (performance score); EOS=end of study; LDH=lactate 
dehydrogenase; MUGA=multigated acquisition scan; PK=pharmacokinetics; TBD=timing based on prior marrow and blood counts, as specified in (f). 
a 
Physical examination should include weight, vital signs, and general physical exam. 
b 
Triplicate ECGs will also be collected pre-dose and 3 hours (±15 minutes) after dosing of onvansertib on Days 1 and 5 (Cycle 2 only). ECGs are not 
required after Cycle 2. 
c 
Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, 
total bilirubin, AST, ALT, LDH, and uric acid. Day 1 chemistry values may be obtained up to 3 days prior. 
d 
CBC, to include differential and platelet count may be repeated as clinically indicated. A serum or urine pregnancy test should be performed for women 
of childbearing potential at least once per cycle prior to dosing, as well as at the Follow-up/EOS visit. Day 1 urinalysis and pregnancy tests may be 
obtained up to 3 days prior. 
e 
A serum or urine pregnancy test should be performed for women of childbearing potential at least once per cycle prior to dosing. 


 
 
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f 
Bone marrow aspirate (and biopsy if necessary) should be obtained to document remission status prior to Cycle 3 and every other cycle thereafter, 
which may be obtained at any time within 10 days to cycle Day 1. If cytogenetics were initially abnormal, include cytogenetics as part of the remission 
documentation. For peripheral blood, include CBC, differential & platelet count.  
g 
Blood samples for PK evaluation of onvansertib should be collected at Cycle 2 only, if feasible, on Days 1 and 5 at predose, 3 hours (±10 minutes), and 
24 hours (±1 hour) after administration of onvansertib, as well as once each on Days 8, 15, and 22.  
h 
Blood samples for pharmacodynamic and biomarker evaluation of onvansertib should be collected, if feasible, at Cycles 2 and 3 on Days 1 and 5 at pre-
dose and 3 hours (±10 minutes) after administration of onvansertib, as well as once each on Days 8, 15, and 22. For Cycle 4 and beyond, blood samples 
should be collected pre-dose on Days 1 and 15. 
i 
Subjects will receive either cytarabine or decitabine based on the arm in which they are enrolled (Section 8.1.1). On days where both agents are 
administered (Days 1-5), cytarabine will be administered first followed by onvansertib. For patients receiving decitabine, the decitabine will be 
administered first followed by onvansertib. 
j 
After cessation of study treatment, subjects will be followed for survival every 2 months for 1 year (may be by telephone). 
k 
Visits on Days 15 and 22 may occur ±1 day for subject convenience. 
l 
Investigator assessment of subjects may allow them, at their discretion, to treat more frequently than every 28 days; however, in no case may a cycle 
length be less than 21 days. 
 
 
 


 
 
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Table 9-3: Schedule of Events: Phase 2 (all cycles) 
Event 
Screening 
Baseline 
On Treatment  
Follow-up/EOS 
≤28 days 
prior to 
enrollment 
≤14 days 
prior to 
enrollment 
Days -2 to 
1 
Days 
(1-2 wks after 
Discontinuation) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
15k 
22k, 
l 
Informed consent 
X 
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
Confirmation of AML and 
prior therapy, either 
relapsed/refractory or newly 
diagnosed, cytogenetic 
analysis, and molecular 
characterization obtained at 
diagnosis 
X 
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
ECOG performance status 
X 
  
X 
  
  
  
  
  
 
 
  
 
 
  
  
X 
History and physical 
examinationa 
X 
  
X 
  
  
  
  
  
 
 
  
 
 
  
  
X 
Triplicate ECGb 
  
X 
 
X 
  
  
  
X 
 
 
X 
 
 
  
  
  
Blood chemistryc 
  
X 
X 
  
  
  
  
  
 
 
X 
 
 
X 
 X 
X 
CBC, including differential, 
and platelet countd 
  
X 
 
X  
  
  
  
X  
 
 
X 
 
 
 X 
X  
X 
Urinalysise 
  
X 
X 
 
  
  
  
  
 
 
  
 
 
  
  
  
Pregnancy teste 
  
X 
 X 
  
  
  
  
  
 
 
  
 
 
  
  
  


 
 
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Event 
Screening 
Baseline 
On Treatment  
Follow-up/EOS 
≤28 days 
prior to 
enrollment 
≤14 days 
prior to 
enrollment 
Days -2 to 
1 
Days 
(1-2 wks after 
Discontinuation) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
15k 
22k, 
l 
Confirmation of all eligibility 
criteria 
  
X 
  
  
  
  
  
  
 
 
  
 
 
  
  
  
ECHO or MUGA scan 
  
X 
  
  
  
  
  
  
 
 
  
 
 
  
  
X 
Bone marrow aspirate & 
peripheral blood for measuring 
status of disease and diagnostic 
biomarker evaluationf 
  
 X 
 
  
  
  
  
  
 
 
  
 
 
X 
  
Blood samples for PK 
analysisg 
  
  
  
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
  
Blood samples for 
pharmacodynamic and 
diagnostic biomarker 
evaluationh 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Onvansertib (PCM-075) 
administration 
  
  
  
X 
X 
X 
X 
X 
 
 
  
 
 
  
  
  
Decitabine administrationi 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
AE recording 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
recording 
X 
 X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
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Event 
Screening 
Baseline 
On Treatment  
Follow-up/EOS 
≤28 days 
prior to 
enrollment 
≤14 days 
prior to 
enrollment 
Days -2 to 
1 
Days 
(1-2 wks after 
Discontinuation) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
15k 
22k, 
l 
Survivalj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Footnotes for Table 9-3: 
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AML=acute myeloid leukemia; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
CBC=complete blood count; ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group (performance score); EOS=end of 
study; LDH=lactate dehydrogenase; MUGA=multigated acquisition scan; PK=pharmacokinetics 
 
a 
Physical examination should include height (screening only), weight, vital signs, and general physical exam. History and physical should be repeated 
prior to each cycle of therapy. 
b 
Triplicate ECGs should also be collected at pre-dose and 3 hours after dosing on Days 1 and 5 and on Day 8 during Cycle 1. Triplicate ECGs should 
also be collected at pre-dose and 3 hours after dosing on Days 1 and 5 during Cycle 2 (Day 8 not required for Cycle 2). ECGs are not required after 
Cycle 2. 
c 
Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, 
total bilirubin, AST, ALT, LDH, and uric acid. Day 1 chemistry values may be obtained up to 3 days prior.  
d 
CBC, to include differential and platelet count should be repeated as clinically indicated. 
e 
A serum or urine pregnancy test should be performed for women of childbearing potential at least once per cycle prior to dosing, as well as at the 
Follow-up/EOS visit. Day 1 urinalysis and pregnancy test may be obtained up to 3 days prior. 
f 
Bone marrow aspirate and peripheral blood (complete blood count, differential, and platelet count; flow cytometry is optional) should be performed 
within 15 days prior to the first dose of study drug to document disease. If clinically appropriate, a bone marrow aspirate (or biopsy if necessary) should 
be performed 14 to 21 days after the start of therapy to document disease status. If hypoplasia is present, then a repeat aspirate/biopsy at the time of 
hematologic recovery based on peripheral blood counts should be obtained to document remission. If hypoplasia is not documented or is indeterminate, 
a repeat biopsy should be obtained in clinically appropriate in another 7-14 days to clarify the persistence of leukemia. If cytogenetics were initially 
abnormal, include cytogenetics as part of the remission documentation. Bone marrow aspirate (and biopsy if necessary) should also be obtained to 
document remission status prior to Cycle 3 and every other cycle thereafter, which may be obtained at any time within 10 days prior to Cycle Day 1. If 


 
 
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                                                                                       Clinical Study Protocol 
 
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CONFIDENTIAL 
cytogenetics were initially abnormal, include cytogenetics as part of the remission documentation. For peripheral blood, include CBC, differential & 
platelet count.  
g 
Blood samples for PK analysis will be collected at Cycle 1 at pre-dose, and 0.5, 1, 2, 3, 4, 8 (all ± 10 minutes), and 24 hours (± 1 hour) after 
administration of onvansertib on Days 1 and 5, as well as once each on Days 8, 15, and 22. At Cycle 2, blood samples should be collected, if feasible, 
pre-dose, 3 hours (± 10 minutes) and 24 hours (± 1 hour) after administration of onvansertib on Days 1 and 5, and once each on Days 8, 15, and 22. 
h 
Blood samples for pharmacodynamic and diagnostic biomarker analysis will be obtained at screening in conjunction with the bone marrow aspirate; at 
Cycle 1: on Day 1 pre-dose, 3 hours (±10 minutes) and 24 hours (±1 hour) after administration of onvansertib; on Day 5 pre-dose, 3 hours (±10 minutes) 
after administration of onvansertib in conjunction with the PK sample being obtained at those time points, as well as once each on Days 8, 15, and 22. 
At Cycles 2 and 3, blood samples should be collected, if feasible on Days 1 and 5 at pre-dose, 3 hours (± 10 minutes) after administration of 
onvansertib, and once each on Days 8, 15, and 22. For Cycle 4 and beyond, blood samples should be collected, if feasible, on Days 1 (pre-dose) and 15. 
The schedule for obtaining these may be amended based on results of prior evaluations. 
i 
Decitabine will be administered first followed by onvansertib. 
j 
After cessation of study treatment, subjects will be followed for survival every 2 months for 1 year (may be by telephone). 
k 
Visits on Days 15 and 22 may occur ±1 day for subject convenience.  
l 
Investigator assessment of subjects may allow them, at their discretion, to treat more frequently than every 28 days; however, in no case may a cycle 
length be less than 21 days. 
 


 
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9.2 Study Visits 
The following sections describe the pretreatment, treatment, and post-treatment evaluations in 
this study. 
9.2.1 Phase 1b 
9.2.1.1 Pretreatment Evaluations (Screening and Baseline) 
The Investigator is responsible for keeping a record of all subjects screened for entry into the 
study and those that are subsequently excluded. The reason(s) for subject exclusion from the 
study must also be recorded.  
Each subject (or subject’s legal representative if applicable) must provide written informed 
consent before any study-specific assessments may be performed. 
The following screening procedures must be performed within 28 days prior to the first dose of 
study drug: 
1. Complete history of AML, to include date and confirmation of diagnosis; dates of prior 
therapies as well as date of documented recurrence/progression are required for Phase 1b 
only. Cytogenetic analysis and molecular characterization obtained at diagnosis will be 
recorded. 
2. Record ECOG performance status.  
3. Complete medical history to include pertinent medical conditions and a careful history of 
all prior medical treatments.  
4. Physical examination, including height (at screening only), weight, and vital signs.  
The following screening procedures must be performed within 14 days prior to the first dose of 
study drug: 
1. Perform triplicate ECG 
2. Blood sample collection for clinical chemistry laboratory testing  
3. Blood sample collection for hematology laboratory testing 
4. Blood sample collection for PD and diagnostic biomarker evaluation 
5. Urine sample collection  
6. Pregnancy test for women of childbearing potential within 72 hours prior to first dose of 
study drug.  
7. Recording of concomitant medication use 
8. Perform an echocardiography (ECHO) or multigated acquisition (MUGA) scan 
9. Confirmation of all eligibility criteria  
10. Bone marrow aspirate and peripheral blood sample for measuring status of disease and 
performing biomarker analysis 
The following baseline procedures must be performed within 2 days prior to the first dose of 
study drug: 
1. Record ECOG performance status  


 
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2. Interval medical history to update pertinent medical conditions  
3. Physical examination, including weight and vital signs 
4. Blood sample collection for clinical chemistry laboratory testing  
5. Blood sample collection for hematology laboratory testing 
6. Recording of concomitant medication use 
9.2.1.2 Evaluations During Treatment 
Day 1 through Day 28 procedures: 
1. Study drug administration: 
a. Onvansertib on Day 1 through Day 5 
i. Cytarabine on Day 1 through Day 10, or 
ii. Decitabine on Day 1 through Day 5 
b. On days where both agents are administered (Days 1-5), cytarabine will be 
administered first followed by onvansertib. For patients receiving decitabine, the 
decitabine will be administered first followed by onvansertib. 
c. Investigator assessment of subjects may allow them, at their discretion, to treat 
more frequently than every 28 days; however, in no case may a cycle length be 
less than 21 days. 
2. Triplicate ECGs will be collected at pre-dose and 3 hours (± 15 minutes) after dosing of 
onvansertib on Days 1 and 5 (Cycles 1 and 2) and once on Day 8 (Cycle 1 only) 
3. Pregnancy testing for women of childbearing potential will be performed prior to each 
cycle of therapy 
4. If clinically appropriate, a bone marrow aspirate (or biopsy if necessary) should be 
performed 14 to 21 days after the start of therapy to document disease status. If 
hypoplasia is present, then a repeat aspirate/biopsy at the time of hematologic recovery 
based on peripheral blood counts should be obtained to document remission. If 
hypoplasia is not documented or is indeterminate, a repeat biopsy should be obtained in 
clinically appropriate in another 7 to 14 days to clarify the persistence of leukemia. If 
cytogenetics were initially abnormal, include cytogenetics as part of the remission 
documentation. For peripheral blood, include complete blood count (CBC), including 
differential and platelet count. A repeat bone marrow aspirate (or biopsy if necessary) 
will be obtained prior to Cycle 3 and every other cycle thereafter or as clinically indicated 
5. Blood samples for PK analysis will be collected on Days 1 and 5 of the first cycle pre-
dose and at 0.5, 1, 2, 3, 4, 8, and 24 hours after administration of onvansertib. Blood 
samples for PD and diagnostic biomarker evaluation of onvansertib will be collected on 
Day 1 of the first cycle at pre-dose, 3 hours, and 24 hours, and on Day 5 at pre-dose and 
3 hours after administration of onvansertib. Blood samples for PK, PD, and diagnostic 
biomarker analysis will also be obtained for the first cycle weekly on Days 8, 15, and 22. 
For Cycle 2 (only), blood samples for PK analysis will be collected on Days 1 and 5 at 
pre-dose, 3 hours, and 24 hours post dose, and weekly on Days 8, 15, and 22. Blood 
samples for PD and diagnostic biomarker will be collected for Cycles 2 and 3 on Days 1 
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and 22; for Cycle 4 and beyond on Day 1 at pre-dose and Day 15. Visits on Days 15 and 
22 may occur ±1 day for subject convenience. 
6. Blood sample collection for CBC, including differential and platelet count, and blood 
chemistry will be performed on Days 1 and 5 and weekly after the start of the cycle 
(Days 8, 15, and 22) and as clinically indicated.   
7. Urine sample collection (once per cycle pre-dose) 
8. AE and concomitant medication recording daily during dosing and then weekly 
9.2.1.3 Post-Treatment Evaluations (Follow-up/End of Study) 
Within 14 days after decision to discontinue patient from further treatment, the following 
evaluations will be conducted:  
1. Record ECOG performance status 
2. Physical examination 
3. Pregnancy test for women of childbearing potential 
4. Blood sample collection for clinical chemistry laboratory testing  
5. Blood sample collection for hematology laboratory testing 
6. Perform ECHO or MUGA scan 
7. AE recording 
8. Recording of concomitant medication use 
Any subject with a suspected study drug-related toxicity at the last follow-up visit must be 
followed until resolution or until the event is considered irreversible. This may require additional 
clinical assessments and laboratory tests. The follow-up results will be recorded on the 
appropriate page of the case report form, as well as in the subject's source documentation. 
9.2.2 Phase 2 
9.2.2.1 Pretreatment Evaluations (Screening and Baseline) 
The Investigator is responsible for keeping a record of all subjects screened for entry into the 
study and those that are subsequently excluded. The reason(s) for subject exclusion from the 
study must also be recorded.  
Each subject (or subject’s legal representative if applicable) must provide written informed 
consent before any study-specific assessments may be performed. 
The following screening procedures must be performed within 28 days prior to the first dose of 
study drug: 
1. Complete history of AML, to include date and confirmation of diagnosis and prior 
therapy, and cytogenetic analysis and molecular characterization obtained at diagnosis 
2. Record ECOG performance status  
3. Complete medical history to include pertinent medical conditions and a careful history of 
all prior medical treatments 
4. Physical examination, including height (at screening only), weight, and vital signs 
5. Recording of concomitant medication use  


 
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The following screening procedures must be performed within 14 days prior to the first dose of 
study drug: 
1. Perform triplicate ECG 
2. Blood sample collection for clinical chemistry laboratory testing  
3. Blood sample collection for hematology laboratory testing 
4. Blood sample collection for PD and diagnostic biomarker evaluation 
5. Urine sample collection  
6. Pregnancy test for women of childbearing potential within 72 hours prior to first dose of 
study drug 
7. Confirmation of all eligibility criteria  
8. Record concomitant medication use 
9. Perform ECHO or MUGA scan 
10. Bone marrow aspirate and peripheral blood sample for measuring status of disease and 
performing biomarker analysis 
The following baseline procedures must be performed within 2 days prior to the first dose of 
study drug: 
1. Record ECOG performance status  
2. Complete medical history to include pertinent medical conditions and a careful history of 
all prior medical treatments 
3. Physical examination, including weight and vital signs 
4. Blood sample collection for clinical chemistry laboratory testing  
5. Blood sample collection for hematology laboratory testing 
6. Recording of concomitant medication use   
9.2.2.2 Evaluations During Treatment 
Day 1 through Day 28 procedures: 
1. Study drug administration: 
a. Onvansertib at the RP2D on Day 1 through Day 5 
i. Decitabine on Day 1 through Day 5 
b. On days where both agents are administered (Days 1-5), decitabine will be 
administered first followed by onvansertib. 
c. Dosing of onvansertib may be delayed for safety if any hematologic toxicity 
and/or toxicity determined to be related to drug administration remains >Grade 2 
d. Investigator assessment of subjects may allow them, at their discretion, to treat 
more frequently than every 28 days; however, in no case may a cycle length be 
less than 21 days. 
2. Triplicate ECGs will be collected at pre-dose and 3 hours after dosing on Days 1 and 5 
(Cycles 1 and 2), and once on Day 8 (Cycle 1 only). ECGs are not required after Cycle 2 
3. Pregnancy testing for women of childbearing potential will be performed prior to each 
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4. If clinically appropriate, a bone marrow aspirate (or biopsy if necessary) should be 
performed 14 to 21 days after the start of therapy to document disease status. If 
hypoplasia is present, then a repeat aspirate/biopsy at the time of hematologic recovery 
based on peripheral blood counts should be obtained to document remission. If 
hypoplasia is not documented or is indeterminate, a repeat biopsy should be obtained in 
clinically appropriate in another 7 to 14 days to clarify the persistence of leukemia. If 
cytogenetics were initially abnormal, include cytogenetics as part of the remission 
documentation. For peripheral blood, include CBC, including differential and platelet 
count. A repeat bone marrow aspirate (or biopsy if necessary) will be obtained prior to 
Cycle 3 and every other cycle thereafter or as clinically indicated 
5. Blood samples for PK analysis will be collected on Days 1 and 5 of the first cycle pre-
dose and at 0.5, 1, 2, 3, 4, 8, and 24 hours after administration of onvansertib. Blood 
samples for PD and diagnostic biomarker evaluation of onvansertib will be collected on 
Day 1 of the first cycle at pre-dose, 3 hours, and 24 hours and on Day 5 at pre-dose, 
3 hours after administration of onvansertib. Blood samples for PK, PD and diagnostic 
biomarker analysis will also be obtained for the first cycle weekly on Days 8, 15, and 22. 
For Cycle 2 (only), blood samples for PK analysis will be collected on Day 1 and Day 5 
at pre-dose, 3 hours and 24 hours post dose and weekly on Days 8, 15, and 22. Blood 
samples for PD and diagnostic biomarker will be collected for Cycles 2 and 3 on Day 1 
and 5 at pre-dose, 3 hours after administration of onvansertib and weekly on Days 8, 15, 
22; for Cycles 4 and beyond on Day 1 at pre-dose and Day 15. Visits on Days 15 and 22 
may occur ±1 day for subject convenience. 
6. Blood sample collection for CBC, including differential and platelet count, and blood 
chemistry will be performed on Day 5 and weekly after the start of the cycle (Days 8, 15, 
and 22) and as clinically indicated. 
7. Urine sample collection (once per cycle, pre-dose) 
8. AE and concomitant medication recording daily during dosing and then weekly 
9.2.2.3 Post-treatment Evaluations (Follow-up/End of Study) 
Within 14 days after the decision to discontinue the patient from further treatment, the following 
evaluations will be conducted:  
1. Record ECOG performance status 
2. Physical examination 
3. Pregnancy test for women of childbearing potential 
4. Blood sample collection for clinical chemistry laboratory testing  
5. Blood sample collection for hematology laboratory testing 
6. Perform ECHO or MUGA scan 
7. AE recording 
8. Recording of concomitant medication use 
Any subject with a suspected study drug-related toxicity at the last follow-up visit must be 
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clinical assessments and laboratory tests. The follow-up results will be recorded on the 
appropriate page of the CRF, as well as in the subject's source documentation. 
After completion of treatment, subjects will be followed every 2 months for survival for 1 year. 
Survival follow-up may be obtained by telephone. 
9.3 Efficacy Assessments 
All subjects evaluable for anti-leukemic activity will be assessed for response to treatment using 
the recommendations of the International Working Group (IWG) for standardization of response 
criteria, treatment outcomes, and reporting for therapeutic studies. [17]  
9.3.1 Efficacy Variables 
Response criteria will be based on the International Working Group for AML. [17] The primary 
efficacy variable is leukemia responses, evaluated by the Investigator based on bone marrow 
aspirate and peripheral blood examination. 
Efficacy endpoints are per NCCN. [18] Responders are subjects who obtain a complete response 
(CR), CR with incomplete blood count recovery (CRi), or partial response (PR), with or without 
cytogenetic response, hematologic improvements (HI), and morphologic leukemia-free (MLF) 
state. Other criteria include DOR, EFS, and OS. Briefly, criteria are defined as follows: 
9.3.1.1 Morphologic Leukemia-free State 
• Bone marrow <5% blasts in an aspirate with spicules (a BM biopsy should be performed 
if spicules are absent) 
• No blasts with Auer rods or persistence of extramedullary disease  
9.3.1.2 Complete Response 
Complete response is defined by the following criteria: 
• Morphologic leukemia-free state plus: 
- Subject is independent of transfusions  
- Absolute neutrophil count of >1000/mm3 
- Platelets of ≥100,000/mm3 
9.3.1.3 Complete Response with Incomplete Blood Count Recovery 
• Complete response with incomplete blood count recovery meets all criteria for CR 
except for either neutropenia (ANC <1000/mm3) or thrombocytopenia (<100,000/mm3) 
but must include transfusion independence 
9.3.1.4 Partial Response 
• All of the hematologic values for a CR but with a decrease of at least 50% in the 
percentage of blasts to 5% to 25% in the bone marrow aspirate and a normalization of 
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9.3.1.5 Duration of Response  
• Time from documentation of response until documentation of recurrence of or 
progression of disease. 
9.3.1.6 Event-free Survival  
• Time from enrollment until disease progression or death from any cause 
9.3.1.7 Overall Survival 
• Time from enrollment until death from any cause. 
9.4 Safety Assessments 
Toxicity will be graded using the National Cancer Institute Common Terminology Criteria 
(NCI-CTCAE version 4.03).  
• Safety analysis will be conducted on all subjects who have received at least one dose of 
study drug, and will include the frequency of all AEs and laboratory abnormalities as well as 
the frequency of dose interruptions, dose reductions, and treatment discontinuation. 
• In Phase 1b, DLTs will be considered to be any non-hematologic Grade 3 abnormalities that 
persist >7 days without decreasing in severity despite standards of care, are clinically 
significant, or that are Grade 4 and symptomatic. Exceptions and additional parameters for 
assessment of non-hematologic DLTs are provided in the protocol. For hematologic 
toxicities, only persistent pancytopenia resistant to current standards of care that continues 
for ≥42 days and is not related to leukemic infiltration or another cause unrelated to study 
therapy will be considered as a DLT, since marrow aplasia is an expected consequence of 
AML therapy. 
• Any subject that has not completed a full initial cycle and received at least 80% of study 
drug due to issues other than DLTs, including disease progression, will be replaced. 
Additional safety assessments will include physical examination; medical history; ECG; ECOG 
performance status; weight; vital signs measurements; clinical laboratory testing (hematology, 
clinical chemistry, and urinalysis) and MUGA or ECHO scans. 
Safety assessments will be performed as per the Schedule of Assessments (Section 9.1). Safety 
assessment may be performed at additional time points during the study at the discretion of the 
Investigator in the interest of subject safety. 
The SRC, consisting of the Principal Investigators and Medical Monitor, will monitor subjects 
for safety and to evaluate efficacy of onvansertib doses to minimize exposure of subjects to a 
non-efficacious dose level.  
9.5 Pharmacokinetic Assessments 
Pharmacokinetic analysis will be obtained as outlined in Section 9.2.1 and Section 9.2.2. 
Pharmacokinetic parameters to be determined will include: 
• Maximum concentration (Cmax) 


 
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• Time of maximum concentration (Tmax) 
• Area under the curve over the first 24 hours (AUC0-24) 
• Drug elimination half-life (t1∕2) 
9.6 Pharmacodynamic and Biomarker Evaluation 
Pharmacodynamic and biomarker evaluation will be obtained as outlined in Section 9.2.1 and 
Section 9.2.2. Details of the PD and biomarker evaluations will be included in the laboratory 
manual. 
10 ADVERSE EVENT REPORTING 
10.1 Definitions 
10.1.1 Adverse Event 
An AE is defined in Title 21 Code of Federal Regulations (CFR) 312.32(a) as follows: 
• Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
An AE (also referred to as an adverse experience) can be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug, and does not imply any judgment about causality. An AE can arise with any use of the 
drug (eg, off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose. 
10.1.2 Unexpected Adverse Events 
An unexpected AE is defined in 21 CFR 312.32(a) as follows: 
• An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
IB or is not listed at the specificity or severity that has been observed; or, if an IB is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended.  
10.1.3 Serious Adverse Event 
An SAE is defined in 21 CFR 312.32(a) as follows: 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening AE 
• Subject hospitalization or prolongation of existing hospitalization 


 
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• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in in subject hospitalization, or the development of drug 
dependency or drug abuse. 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject or subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
10.1.4 Definition of Dose-limiting Toxicities  
Dose-limiting toxicities are defined as events related to onvansertib that are considered an 
adverse reaction or suspected adverse reaction (per criteria in Section 10.1), during the first cycle 
of therapy and that fulfills at least one of the criteria listed below. Further information on the 
grading of AEs is presented in Section 10.2. 
Hematologic 
 
Since marrow aplasia is an expected consequence of AML therapy, only persistent 
pancytopenia resistant to current standards of care that continues for ≥42 days and is not 
related to leukemic infiltration or another cause unrelated to study therapy will be considered 
as a DLT. Bone marrow evaluation may be required. 
Non-Hematologic 
 
Any Grade 3 abnormalities that persist >7 days without decreasing in severity despite 
standards of care, are clinically significant, or that are Grade 4 and symptomatic. The 
following will also be considered DLTs: 
o Aminotransferase abnormality ≥Grade 3 in the presence of elevated total bilirubin to >2× 
ULN (at least a Grade 2) with no other reason that can be found to explain the 
combination of increased ALT and total bilirubin, such as viral hepatitis A, B, or C; 
preexisting or acute liver disease; or another drug capable of causing the observed injury 
(Hy’s Law) 
o Nausea, vomiting or diarrhea Grade ≥3 persisting for >2 days without evidence of 
decreased severity (to at least Grade 2) despite maximal medical intervention 
o Serum amylase or lipase ≥Grade 3 accompanied by symptoms consistent with pancreatic 
injury 
o Neurologic toxicity ≥Grade 3 persisting for >2 days and not attributable to central 
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10.1.5 Determination of the Maximum Tolerated Dose  
The planned dose-escalation strategy for onvansertib in combination with either cytarabine or 
decitabine is presented in Section 8.1.1. 
In Phase 1b, the dose of onvansertib will be escalated in sequential dose cohorts, while the dose 
of either cytarabine or decitabine will be administered in the doses and regimens as per product 
insert. The onvansertib starting dose will be 12 mg/m2 (Dose Level 0), and escalated or reduced 
in dosing cohorts based on criteria outlined in Section 8.1.1. Dose modifications, delays and 
reductions for individual subjects will be performed as described in Sections 8.4.1.1.3, 8.4.1.1.4, 
and 8.4.1.1.5, respectively. DLTs will be recorded for 28 days after initiation of therapy; 
however, if an Investigator elects to re-treat a subject prior to 28 days (allowed no sooner than on 
Day 22), the DLT evaluation period will end at the time of initiation of the second cycle therapy. 
Subjects may continue with additional cycles as long as the subject is receiving clinical benefit 
and there are no safety or tolerability issues.  
Subjects who have not received at least 80% of the dose of study drug(s) during the first cycle or 
who are discontinued for any reason other than DLT will be replaced.  
The MTD of onvansertib in combination with either low-dose cytarabine or decitabine in 
subjects with AML will be defined as the highest dose level achieved at which no more than 
1 out of 6 subjects experienced a DLT during the first cycle of therapy in Phase 1b.  
10.2 Severity of Adverse Events 
Each AE will be graded according to the NCI-CTCAE version 4.03 (Appendix 19.1). In most 
cases AE terms will be listed in the CTCAE, with grading criteria specific to that term. If the AE 
is not specifically defined in the CTCAE, it is to be reported using the “Other, specify” term 
under the appropriate system organ class and graded according to the general CTCAE severity 
guidelines. 
10.3 Relationship of Adverse Events to the Study Drug 
The Investigator must attempt to determine if an AE is in some way related to the use of 
onvansertib, the study drug. All AEs must be attributed to study drugs unless there is a 
reasonably acceptable alternate cause for the AEs. This relationship should be described as 
follows: 
• Unrelated: The event has no temporal relationship to study drug administration (too 
early or late or study drug not taken), or there is a reasonable causal relationship between 
the AE and another drug, concurrent disease, or circumstance.  
• Unlikely: The event with a temporal relationship to drug administration which makes a 
causal relationship improbable, and in which other drugs, chemicals, or underlying 
disease provide plausible explanations.  
• Possibly: The event follows a reasonable temporal sequence from administration of the 
study drug and the event follows a known response pattern to the study drug BUT the 
event could have been produced by an intercurrent medical condition which, based on the 


 
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pathophysiology of the condition, and the pharmacology of the study drug, would be 
unlikely related to the use of the study drug or the event could be the effect of a 
concomitant medication. 
• Probably: The event follows a reasonable temporal sequence from administration of the 
study drug and the event follows a known response pattern to the study drug AND the 
event cannot have been reasonably explained by an intercurrent medical condition or the 
event cannot be the effect of a concomitant medication. 
• Definitely: The event follows a reasonable temporal sequence from administration of the 
study drug, the event follows a known response pattern to the study drug and based on 
the known pharmacology of the study drug, the event is clearly related to the effect of the 
study drug. 
10.4 Monitoring of Adverse Events 
AEs will be monitored continuously during the study starting immediately after the first dose of 
study drug is administered. Subjects will be instructed to report all AEs experienced during the 
study, and subjects will be assessed for the occurrence of AEs throughout the study. 
All AEs will be followed until resolution or stabilization of the event. This may require 
additional clinical assessments and laboratory tests. 
10.5 Reporting Procedures 
10.5.1 Routine Reporting of Adverse Events 
AEs, whether or not associated with study drug administration, will be recorded on the AE form 
of the CRF and will be submitted to the Sponsor at regularly scheduled intervals. 
The information to be entered in the CRF will include: 
1. Time of onset of any new AE or the worsening of a previously observed AE. In most 
cases, date of onset will be adequate; however, for days when the subject is in the clinic 
and receives study drug(s), the time (based on a 24-hour clock) of onset should also be 
recorded 
2. Specific type of reaction in standard medical terminology 
3. Time of resolution of the event (or confirmation ongoing). In most cases, date of 
resolution will be adequate; however, for events that initiate and resolve on days where 
the subject is in the clinic and receives study drug(s), the time (based on a 24-hour clock) 
of resolution should also be recorded 
4. Severity/grade of AE. The severity should be rated according to NCI-CTCAE version 
4.03 (Appendix 19.1) 
5. An assessment should be made of the relationship of the AE to the study drug according 
to the definitions outlined in Section 10.3. 
6. Description of action taken in treating the AE and/or change in study drug administration 
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Follow-up assessments should be repeated to document return of any abnormalities to normal, or 
to document other outcome of the AE. 
10.5.2 Reporting of Serious Adverse Events, Including Death 
SAEs, including death due to any cause, which occur during this study or within 30 days 
following the last dose of the study drugs, whether or not related to the administration of study 
drugs, must be reported to the Medical Monitor by telephone or email within 24 hours of 
learning of the event.  
SAE Forms will be provided by the Sponsor or Sponsor designated CRO. The study site should 
send the SAE Form to the Medical Monitor as soon as possible so that the tracking procedure 
can begin immediately upon receipt of the information. Once the Medical Monitor is informed of 
an SAE with preliminary information obtained, the study site will be instructed to update the 
SAE Form with additional information, as per the following guidelines.  
If all information is not known at the time of the incident, an initial report should still be made. 
In the event there is a question as to whether the event is serious, the information should be 
forwarded to the Medical Monitor for review. The Investigator is responsible for following up on 
completion of the SAE Form. The Investigator will submit substantiating data in hard copy form, 
such as diagnostic test reports and progress notes, to the Medical Monitor. In the case of fatality, 
autopsy reports will be furnished to the Medical Monitor as soon as available. 
During the initial communication, the Medical Monitor will require the following information 
about the subject and the reported SAE: 
1. Subject identification including subject number, initials, and date of birth 
2. Date of first dose of study drugs and details of administration, including study drug 
names (including labeled strength and manufacturer), lot number, expiration date, and 
dose 
3. Date of last dose of study drugs (ie, prior to onset of SAE) and details of administration, 
including study drug names (including labeled strength and manufacturer, lot number, 
expiration date, and dose) 
4. Medical diagnosis of the event in standard medical terminology (if a medical diagnosis 
cannot be determined, a description of each sign or symptom characterizing the event) 
5. Date of onset of the AE 
6. Date of resolution of the AE (or confirmation ongoing) 
7. Severity of the AE (see Section 10.2) 
8. Assessment of the attribution of the AE to the study drug  (see Section 10.3) 
9. Reason AE is considered serious (per definition in Section 10.1.3) 
10. Whether the AE is expected (see Section 10.1) 
11. Action taken in treating the AE and/or change in study drug administration or dose 
(including concomitant medications or therapies administered, whether hospitalization or 
prolongation of hospitalization was required, diagnostic procedures performed, and 
whether the subject was discontinued from the study) 
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13. Pertinent clinical laboratory testing data 
14. Medical history 
The Investigator and the Medical Monitor will review each SAE report and evaluate the 
relationship of the adverse experience to study drugs and to underlying disease. Based on the 
Investigator’s and Medical Monitor’s assessment of the adverse experience, a decision will be 
made concerning the need for further action. The primary consideration governing further action 
is whether new findings affect the safety of subjects participating in the clinical study. If the 
discovery of a new adverse experience related to the study drug raises concern over the safety of 
continued administration of study drug, the Sponsor will take immediate steps to notify the 
regulatory authorities. 
Further action that may be required includes the following: 
1. Alteration of existing research by modification of the protocol 
2. Discontinuation or suspension of the study 
3. Alteration of the informed consent process by modification of the existing consent form 
and informing current study participants of new findings 
4. Modification of previously identified expected adverse experiences to include adverse 
experiences newly identified as study medication-related. 
Any SAE that is determined by the Sponsor to be reportable to FDA as an Investigational New 
Drug (IND) Safety Report [as defined in 21 CFR 312.32] will be reported to FDA by the 
Sponsor within the specified time frame. All IND Safety Reports will also be promptly provided 
to the Investigator for submission to his or her Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC). Similarly, any SAE that is determined by the Sponsor to require 
expedited reporting to other regulatory authorities will be reported to the appropriate authorities 
by the Sponsor within the specified time frames, and will be provided to the Investigator for 
submission to his or her IRB/IEC. 
10.5.3 Other Events Requiring Immediate Reporting 
10.5.3.1 Overdose 
An overdose is defined as a subject receiving a dose of investigational product in excess of that 
specified in the IB, unless otherwise specified in this protocol. Any overdose of a study subject 
with the investigational product, with or without associated AEs/SAEs, is required to be reported 
to the Medical Monitor within 24 hours of knowledge of the event. Overdose does not 
automatically make an AE serious, but if the consequences of the overdose are serious, for 
example death or hospitalization, the event is serious and must be reported as an SAE. 
10.5.3.2 Pregnancy 
Pregnancy in a female subject who has received investigational product is required to be reported 
within 24 hours of knowledge of the event. Should the Investigator become aware of a pregnancy 
of a female partner of a male participant, the pregnancy should be reported within 24 hours of 
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Form (Please refer to the Site Operations Manual). After obtaining the subject’s consent (or 
subject and pregnant partner’s consent in the case of a male participant), monitoring of the 
pregnancy should continue until conclusion of the pregnancy whereby the Investigator will 
notify PRA of the outcome on the Pregnancy Outcome Report Form (Please refer to the Site 
Operations Manual). 
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study.  
 
 


 
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11 SUBJECT DISCONTINUATION AND TRIAL DISCONTINUATION 
11.1 Subject Discontinuation 
A subject may choose to withdraw from this study at any time for any reason without penalty of 
jeopardizing their health care or loss of benefits to which the subject is otherwise entitled.  
Subjects will be discontinued from study drug (onvansertib) treatment if one or more of the 
following events occur: 
1. Clinically significant progressive disease 
2. Subject refusal to remain on study 
3. Pregnancy 
4. Non-compliance or inability to comply with protocol requirements by subject 
5. Development of unacceptable toxicity (regardless of study drug relationship) 
6. Determination by the Investigator that it is no longer safe for the subject to continue 
therapy. 
Subjects who have an ongoing AE at the time of discontinuation will continue to be followed 
until resolution of the event to Grade ≤1 or baseline, or until the event is considered irreversible. 
Subjects who are discontinued prior to completing the first treatment cycle for any reason other 
than toxicity, or who have not received at least 80% of the intended doses, will be replaced.  
11.2 Study Discontinuation 
Treatment may be continued longer at the discretion of the treating physician if there is no 
evidence of disease progression and the subject is not experiencing unacceptable toxicity, and if 
both the subject and physician agree that further therapy is in the subject’s best interest. 
The Sponsor has the right to terminate this study, and the Investigator/Investigational Site has the 
right to close the site, at any time, although this should occur only after consultation between 
involved parties. The Investigator must notify the IRB/IEC in writing of a premature termination 
of a study or closure of Investigational Site, and must send a copy of the notification to the 
Sponsor.  
Events that may trigger premature termination of a study or closure of an Investigational Site 
include, but are not limited to, a new toxicity finding, a request to discontinue the study from a 
regulatory authority, non-compliance with the protocol, slow recruitment, or change in 
development plans for the study drug.  
 
 


 
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12 STATISTICAL METHODS 
12.1 Dosing Algorithm and Determination of Sample Size 
The planned sample size in the Phase 1b portion of the study is up to 84 subjects (42 in each 
arm), which is considered sufficient for the determination of safety and PK parameters for the 
study drug. 
This study is a dose-escalation study that initially utilizes a 3+3 design [19] with a starting dose 
of onvansertib of 12 mg/m2 (Dose Level 0) administered Day 1 through Day 5 every 21 to 
28 days. If an Investigator elects to re-treat a subject prior to 28 days (allowed no sooner than on 
Day 22), the DLT evaluation period will end at the time of initiation of the second cycle of 
therapy. The sample size is anticipated to be up to 84 subjects (42 per arm) in Phase 1b, 
depending on the dose level at which toxicity is observed. The 3+3 dose-escalation algorithm is 
as follows:  
1. If 0 out of 3 subjects experience DLT (as defined in Section 10.1.4) during the first cycle 
of therapy, the next cohort of 3 subjects will be treated at the next higher dose level.  
2. If 1 out of 3 subjects develop DLT during the first cycle of therapy (ie, 28 days from start 
of therapy), an additional 3 subjects will be treated at the same dose level. If no additional 
DLTs occur during the first cycle of therapy for the additional 3 subjects treated (ie, 1 out 
of a total of 6 subjects develops DLT that initiates within the specified period), the dose 
escalation continues to next higher level for a cohort of 3 subjects.  
3. If at any time there are 2 or more subjects who experience DLTs in the 3 to 6 subjects at a 
given dose, the next cohort will receive a prior dose level or an intermediate dose level, 
agreed upon by the Sponsor, Medical Monitor, and Principal Investigator.  
With this 3+3 design, a dose with a ≥ 50% probability of causing a DLT has at most a 12.5% 
chance of satisfying the conditions for dose escalation after the first 3 subjects and a ≥50% 
chance of stopping at 3. With 6 subjects, there is at most a 17.2% chance of satisfying the 
conditions for dose escalation after 6 subjects. Phase 2 will proceed with a total of 32 subjects at 
the identified RP2D; however, if at any time during this phase more than 33% of subjects 
develop a DLT-level AE (as per protocol), accrual will stop, and the RP2D will be reassessed in 
additional cohorts. 
Subjects who are discontinued prior to completing the first cycle for any reason other than 
toxicity or who have not received at least 80% of the intended doses, without experiencing DLT 
will be replaced. 
12.2 Statistical Analysis of Safety Data 
Data from all subjects who receive at least one dose of study drug (onvansertib) will be included 
in the safety analysis.  
Safety will be assessed primarily based on AEs. The severity of AEs will be graded as mild, 
moderate, severe, or life-threatening according to NCI-CTCAE version 4.03 (Appendix 19.1). 
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Regulatory Activities [MedDRA]), and will be further categorized by onvansertib dose level, 
severity, and assigned relationship to study drug. The incidence for each AE will be provided as 
the total number of subjects who experienced the AE, as well as the percentage of the population 
that this represents. If an AE is reported more than once during treatment for a given subject, the 
greatest severity and the worst-case attribution will be presented in the AE summary tables. 
AEs will also be listed for individual subjects, along with information regarding onset, duration, 
severity, relationship to study drug, and outcome. AEs that lead to withdrawal from the study 
will be listed and summarized. A separate tabulation and listing of SAEs will also be generated.  
Secondary safety assessments, including physical examination, ECOG performance status, 
weight (for body surface area [BSA] calculation), vital signs, ECG measurements and clinical 
laboratory testing (hematology, clinical chemistry, and urinalysis) will be listed and summarized. 
Descriptive statistics will be generated as appropriate (ie, mean, median, range, and SD for 
continuous data and frequency for categorical data). 
Inferential statistical analysis comparing the safety data among onvansertib dose levels or 
historical data is not planned. 
12.3 Statistical Analysis of Efficacy Data 
Data from all subjects who receive at least one dose of onvansertib in combination with either 
cytarabine or decitabine will be included in the intention-to-treat (ITT) efficacy analysis. 
Subjects completing at least one cycle of treatment will be included in the per protocol efficacy 
analysis. 
The efficacy endpoints for this study include CR, CRi, PR, MLF, DOR, and OS. Further 
description of the efficacy measurements and response criteria for this study is presented in 
Section 9.3.1. 
Descriptive statistics will be generated as appropriate (ie, mean, median, range, and SD). Median 
survival statistics will be estimated using the Kaplan-Meier Time-to-Event. 
Inferential statistical analysis comparing efficacy data among onvansertib dose levels or 
historical data is not planned. 
The primary efficacy endpoint is the rate of CR + CRi in the Phase 2 portion of the study. Based 
on a population CR + CRi rate of 20% for either the combination of cytarabine plus onvansertib 
or decitabine plus onvansertib, with 32 evaluable patients in the primary analysis the 90% CI for 
the CR + CRi rate from the study will have an estimated precision of approximately 58% and 
width 0.23, and a 95% CI would have an estimated precision of approximately 70% and width 
0.28. 
PK parameters to be determined will include Cmax, Tmax, AUC0-24, and t1∕2, which will be 
estimated from plasma concentration data. The geometric mean and 95% CIs will be reported for 
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13 ACCESS TO SOURCE DOCUMENTS AND RETENTION OF 
RECORDS 
The Investigator will make the source documents for this study available for monitoring by the 
Sponsor or its representatives, or by regulatory authorities or health authority inspectors. 
Subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties other than those noted below is prohibited. All reports and 
communications relating to subjects in this study will identify each subject only by their initials 
and number. Medical information resulting from a subject’s participation in this study may be 
given to the subject’s personal physician or to the appropriate medical personnel responsible for 
the subject’s welfare. Data generated as a result of this study are to be available for inspection on 
request by FDA or other government regulatory agency auditors, the Sponsor (or designee), and 
the IRB/IEC. 
The information developed in this clinical study will be used by the Sponsor in the clinical 
development of the study drug and therefore may be disclosed by the Sponsor as required for 
disclosure as a public company to other clinical Investigators, to other pharmaceutical 
companies, to the FDA, and to other government agencies. 
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports made or developed by the Investigator(s) as a result of conducting 
this study shall be promptly disclosed to the Sponsor and shall be the sole property of the 
Sponsor. The Investigator agrees, upon the Sponsor’s request and at the Sponsor's expense, to 
execute such documents and to take such other actions as the Sponsor deems necessary or 
appropriate to obtain patents in the Sponsor’s name covering any of the foregoing. 
The Investigator will retain all study documents for at least 2 years after the last approval of a 
marketing application in an International Council for Harmonisation (ICH) region (ie, US, 
Europe, or Japan), and until there are no pending or contemplated marketing applications in an 
ICH region. If no application is filed or if the application is not approved for such indication, the 
Investigator will retain all study documents for at least 2 years after the Investigation is 
discontinued and regulatory authorities have been notified.  
The Investigator will notify the Sponsor prior to destroying any study records. Should the 
Investigator wish to assign the study records to another party or move them to another location, 
the Sponsor must be notified in writing in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements will be made between the Investigator and the Sponsor for 
storage. If source documents are required for continued care of the subject, appropriate copies for 
storage off-site will be made. 


 
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14 QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 Data Collection 
All data required by the study protocol will be entered onto case report forms and must be 
verifiable against source documents. Case report forms will be completed for every subject who 
is enrolled in this study.  
Only authorized Investigational Site personnel will enter data on the case report forms. Any 
corrections to data entered into the case report form will be made in such a way that the original 
entry is not obscured. The date of the correction and the initials of the person making the 
correction will be documented.  
The case report forms will be kept up-to-date by the Investigator and the research staff at the 
Investigational Site. The Investigator will be responsible for reviewing all data and case report 
form entries and will sign and date each subject’s case report form, verifying that the information 
is true and correct.  
14.2 Study Monitoring 
The study will be monitored to evaluate the progress of the study, to verify the accuracy and 
completeness of the case report forms, to assure that all protocol requirements, applicable laws 
and/or regulations, and Investigator’s obligations are being fulfilled, and to resolve any 
inconsistencies in the study records.  
The Investigator will allow the study monitor to periodically review, at mutually convenient 
times during the study and after the study has been completed, all case report forms and office, 
hospital, and laboratory records supporting the participation of each subject in the study.  
The study monitor will compare the case report form data against source documentation in order 
to verify its accuracy and completeness. The Investigator and research staff will collaborate with 
the study monitor to resolve any identified data discrepancies in a timely manner.  
The study monitor will record any protocol deviations identified, including, but not limited to, 
subjects who were enrolled even though they did not meet all eligibility criteria, subjects who 
took concomitant medications specifically prohibited by the protocol, and subjects who received 
the wrong study drug or incorrect dose. The Investigator and research staff will collaborate with 
the study monitor to identify the reason for each protocol deviation.  
The study monitor will compare the Investigational Site study drug accountability record against 
the study drug inventory (unused and used) at the site. The Investigator and research staff will 
collaborate with the study monitor to resolve any identified discrepancies in a timely manner. 
Each issue identified during study monitoring visits will be documented and reported to both the 
Sponsor and the Investigator.  


 
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14.3 Data Management 
After the case report forms have been reviewed by the study monitor and all identified 
discrepancies have been identified, the Investigator signed copy of the case report forms will be 
forwarded to Data Management. Queries generated by Data Management will be sent to the 
study site for resolution. The Investigator is responsible for the review and approval of all 
responses. 
All case report form data will be entered into a validated database and an electronic audit study 
of edits maintained. Laboratory data may be imported to the database electronically. 
The database will be authorized for lock once no data queries are outstanding, all study data are 
considered clean, and all defined procedures completed. 
14.4 Sponsor Audits 
At some point during the study, individuals from the Sponsor’s Quality Assurance group or their 
authorized representative may visit the Investigator’s site to conduct an audit of the study. The 
purpose of this visit will be to determine the Investigator’s adherence to the protocol, applicable 
regulations, and the Sponsor’s procedures, in addition to assessing the accuracy of the study data. 
Prior to initiating this audit, the Investigator will be contacted by the Sponsor to arrange a 
convenient time for this visit. The Investigator and staff will cooperate with the auditors and 
allow access to all subject records supporting the case report forms and other study-related 
documents. 
14.5 Inspection by Regulatory Authorities 
At some point during the study, a regulatory authority may visit the Investigator to conduct an 
inspection of the study. The Investigator and staff will cooperate with the inspectors and allow 
access to all source documents supporting the case report forms and other study-related 
documents. The Investigator will immediately notify the Sponsor when contacted by any 
regulatory authority for purposes of conducting an inspection. 
 
 


 
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15 ETHICS 
15.1 Declaration of Helsinki 
The study will be conducted in accordance with the Declaration of Helsinki. [20]  
15.2 Good Clinical Practice and Regulatory Compliance 
This study will be conducted in accordance with the principles of GCP (current ICH guideline) 
and the requirements of all local regulatory authorities regarding the conduct of clinical studies 
and the protection of human subjects.  
15.3 Institutional Review Board/Independent Ethics Committee 
The protocol, ICF, IB, and any materials (such as advertisements, subject information sheets, or 
descriptions of the study used to obtain informed consent) for this study will be reviewed and 
approved by a duly constituted IRB/IEC. 
The Investigator will ensure that all aspects of the IRB/IEC review are conducted in accordance 
with current institutional, local, and national regulations. A letter documenting the IRB/IEC 
approval will be provided to the Sponsor prior to initiation of the study.  
Amendments to the protocol will be subject to the same requirements as the original protocol. A 
letter documenting the IRB/IEC approval will be provided to the Sponsor prior to 
implementation of the changes described in the protocol amendment. 
Revisions to the ICF will be reviewed and approved by the IRB/IEC prior to use in the study. 
The Investigator will inform the IRB/IEC of all reportable AEs. IND Safety Reports provided by 
the Sponsor to the Investigator will be promptly forwarded to the IRB/IEC by the Investigator. 
Updates to the IB provided by the Sponsor to the Investigator will be submitted to the IRB/IEC 
by the Investigator. 
The Investigator will submit all periodic reports and updates that the IRB/IEC may require. After 
completion or termination of the study, the Investigator will submit a final report to the IRB/IEC. 
The structure and content of the report will meet that described in Structure and Content of 
Clinical Study Reports E3 (ICH Harmonized Tripartite Guideline, dated 30 Nov 1995). 
15.4 Informed Consent 
No study-related procedures, including screening evaluations, will be performed until the subject 
has given written informed consent.  
The ICF will clearly describe the nature, scope, and potential risks and benefits of the study, in a 
language that the subject understands. The ICF will conform to all the requirements for informed 
consent according to ICH GCP and US FDA guidelines (21 CFR 50) and any additional 
elements required by the Investigator’s institution or local regulatory authorities. The 
Investigator will submit the ICF to the IRB/IEC for review, and will provide the Sponsor with a 
letter documenting the IRB/IEC approval prior to initiation of the study. 


 
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The IRB/IEC approved ICF will be given to each prospective participant. The subjects will be 
given adequate time to discuss the study with the Investigator or site staff and to decide whether 
or not to participate. Each subject who agrees to participate in the study and who signs the ICF 
will be given a copy of the signed, dated, and witnessed document. The original signed ICF will 
be retained by the Investigator in the study files. 
The Investigator will also obtain authorization from the subject to use and/or disclose Protected 
Health Information (PHI) in compliance with Health Insurance Portability and Accountability 
Act (HIPAA) or equivalent. Written HIPAA authorization may be obtained as part of the 
informed consent process. 
If a protocol amendment substantially alters the study design or increases the potential risk to the 
subject, or the known risks of the study drug change over the course of the study, the ICF will be 
revised and submitted to the IRB/IEC for review and approval. The revised ICF must be used to 
obtain consent from subjects currently enrolled in the study if they are affected by the 
amendment and to obtain consent from new subjects prior to enrollment. 
15.5 Emergency Departure from Protocol 
When an emergency occurs that requires a departure from the protocol for an individual, a 
departure will be only for that subject. The Investigator or other physician in attendance in such 
an emergency will, if circumstances and time permit, contact the Sponsor’s Medical Monitor 
immediately by telephone. Such contacts will be made as soon as possible to permit a decision as 
to whether or not the subject (for whom the departure from protocol was affected) is to continue 
in the study. The case report form and source documents will completely describe the departure 
from the protocol and state the reasons for such departure. In addition, the IRB/IEC will be 
notified in writing of such departure from protocol. 
 
 


 
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16 PUBLICATION POLICY 
All information and data obtained in the course of the study are the property of the Sponsor and 
are considered confidential. To avoid disclosures that could jeopardize proprietary rights, the 
institution and/or the Investigator agree to certain restrictions on publications (eg, abstracts, 
speeches, posters, manuscripts, and electronic communications), as detailed in the clinical study 
agreement. 
The publication or presentation of any study results shall comply with all applicable privacy 
laws, including, but not limited to, HIPAA or equivalent. 
 
 


 
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17 PROTOCOL AMENDMENTS AND MODIFICATIONS 
The Investigator will ensure that the study is conducted in accordance with the procedures and 
evaluations described in this protocol. The Investigator will not modify the protocol without first 
receiving Sponsor authorization to do so, except in those cases intended to reduce immediate risk 
of the subjects. The Sponsor is responsible for submitting protocol amendments to the 
appropriate governing regulatory authorities. The Investigator is responsible for submitting 
protocol amendments to the appropriate IRB/IEC. Approval by the IRB/IEC will be obtained 
before protocol modifications are implemented, except in those cases intended to reduce 
immediate risk to subjects. 
 
 


 
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16. Vandenberk B, Vandael E, Robyns T, et al. Which QT correction formulae to use for QT 
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17. Cheson BD, Bennett JM, Kopecky KJ,  et al. Revised recommendations of the International 
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19.1 Appendix 1: National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03 
NCI-CTCAE version 4.03 will be used in this study for AE reporting. 
A copy of CTCAE version 4.03 can be downloaded from the Cancer Therapy Evaluation 
Program (CTEP). 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
19.2 Appendix 2: New York Heart Association Functional Classification 
The New York Heart Association (NYHA) Functional Classification [21] provides a simple way 
of classifying the extent of heart failure. It places subjects in one of 4 categories based on how 
much they are limited during physical activity; the limitations/symptoms are in regards to normal 
breathing and varying degrees in shortness of breath and or angina pain: 
Functional Capacity 
Objective Assessment 
Class I 
Subjects with cardiac disease but without 
resulting limitation of physical activity. 
Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal 
pain. 
No objective evidence of 
cardiovascular disease 
Class II 
Subjects with cardiac disease resulting in slight 
limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence of minimal 
cardiovascular disease 
Class III 
Subjects with cardiac disease resulting in marked 
limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence of moderately 
severe cardiovascular disease 
Class IV 
Subjects with cardiac disease resulting in inability 
to carry on any physical activity without 
discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If 
Objective evidence of severe 
cardiovascular disease  


TROV-052
Clinical Study Protocol 
Amendment 2, Version 6.0 
Onvansertib (PCM-075) 
Date: 07 Aug 2019 
Page 82 of 83 
CONFIDENTIAL 
any physical activity is undertaken, discomfort 
increases. 
19.3 Appendix 3: ECOG Performance Status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Note: As previously published. [22] 
19.4 Appendix 4: Package Insert for Cytarabine and Dacogen™ (Decitabine) 
•
Conventional cytarabine is no longer a branded product in the US. A copy of the product 
insert for generic cytarabine can be downloaded from the following link:
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34803a0e-f54d-4147-8f9f- 
7d0e3a007756 
•
A copy of the Package Insert for Dacogen (decitabine) can be downloaded from the 
following link:
https://www.otsuka-us.com/media/static/DACOGEN-PI.pdf
Note that generic equivalents are available. 
19.5 Appendix 5: Clinical Study Report PLKA-937-001 
A Phase 1 Dose Escalation Study of NMS-1286937 Administered to Adult Patients with 
Advanced/Metastatic Solid Tumors, dated 06 Apr 2016 


TROV-052
Clinical Study Protocol 
Amendment 2, Version 6.0 
Onvansertib (PCM-075) 
Date: 07 Aug 2019 
Page 83 of 83 
CONFIDENTIAL 
19.6 Appendix 6: Torsades de Pointes Risk QT Interval Normogram 
Derived from: https://missouripoisoncenter.org/qt-nomogram-assessing-risk-torsades-de-pointes/ 

SAP_001.pdf: 
Protocol Number: TROV-052 
Official Title: A Phase 1b/2 Study of Onvansertib (PCM-075) in
Combination with Either Low-dose Cytarabine or Decitabine
in Subjects with Acute Myeloid Leukemia (AML)
NCT Number: NCT03303339 
Document Date:  22 Oct 2020 


Statistical Analysis Plan (SAP) 
Version Date: 22-Oct-2020  
Sponsor: Cardiff Oncology 
Protocol no: TROV-052 
 
 
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Statistical Analysis Plan (SAP) 
Protocol Title: 
A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination 
with Either Low-dose Cytarabine or Decitabine in Subjects with 
Acute Myeloid Leukemia (AML)  
Protocol Version No./Date: 
6.0 Amendment 2/09-Aug-2019 
CRF Version No./Date: 
5.0/31-Jan-2020 
SAP Version No./Date: 
1.7/22-Oct-2020 
 
 Approvals 
Sponsor 
Sponsor Name: 
Cardiff Oncology, Inc. 
Representative/ Title: 
 
Signature /Date: 
<Signature of Sponsor Representative /Date> 
 
This space reserved for eSignature block (if applicable). 
PRA 
Biostatistician / Title: 
 
Signature /Date: 
<Signature of Biostatistician /Date> 
 
 
 
 
This space reserved for eSignature block (if applicable). 
 (NOTE: Electronic Signatures should only be used if all parties have the ability to eSign.) 
 
 


Statistical Analysis Plan (SAP) 
Version Date: 22-Oct-2020  
Sponsor: Cardiff Oncology 
Protocol no: TROV-052 
 
 
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 Change History 
Version/Date 
Change Log 
0.1 
Created as new 
1.0 
Version reviewed by Trovagene Oncology (2018) 
1.1 
Updated with comments from Trovagene Oncology 
1.2 
Updated with protocol amendment (protocol V 6.0) 
1.3 
Minor changes per 
 and 
 
1.4 
• 
Updated to reflect PRA current SAP template  
• 
Reflect change in name from Trovagene Inc to Cardiff Oncology, Inc 
• 
Clarify Cardiff Oncology Inc. responsibility for PD and biomarker data and 
analysis 
• 
Clarify objectives and endpoints 
• 
Remove per protocol sensitivity analysis 
• 
Cross-checked SAP with current CRF 
• 
Remove references to cytarabine arm in Phase 2 where appropriate 
• 
Minor wording changes and clarifications 
• 
Added deviations from protocol 
1.5 
• 
Separate PK analysis by cycle and time point 
• 
Update efficacy evaluable definition in PP analysis set 
• 
Update PK sections per PK specialist 
• 
Added definition of RP2D 
• 
Added BOR to a listing 
• 
Add PP efficacy listings 
• 
Clarify that dose adjustment (increase and decrease) will be summarized 
separately 
• 
Formatting and clarification 
1.6 
• 
Change all references to Cytarabine to low-dose Cytarabine 
• 
Updated description of summaries to indicate that Phase 1b demographic 
tables will not be presented by dose level. 
• 
Remove AE tables by PT only 
• 
Remove reference to tables and listings not reflected in new version of TFL 
specification  
• 
Removed reference to individual PK figures 
• 
Clarified wording and minor formatting changes 
1.7 
• 
Changed any reference to Cri to Cri 
• 
Section 10.6.4 – removed reference to progressive disease in association 
ith treatment failure to match 10.6.5 and CRF.  
• 
Clarified that recurrence and progressive disease will come from the 
discontinuation CRF page while treatment failure will com from the bone 
marrow aspirate CRF pages.  
 
 
 


Statistical Analysis Plan (SAP) 
Version Date: 22-Oct-2020  
Sponsor: Cardiff Oncology 
Protocol no: TROV-052 
 
 
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 Table of Contents 
 Approvals ................................................................................................................................................ 1 
 Change History ....................................................................................................................................... 2 
 Table of Contents .................................................................................................................................... 3 
 Purpose ................................................................................................................................................... 5 
 Scope ...................................................................................................................................................... 5 
 Introduction ............................................................................................................................................. 5 
6.1 Changes from Protocol .................................................................................................................... 5 
 Study Objectives ..................................................................................................................................... 5 
7.1 Secondary Objectives ...................................................................................................................... 6 
7.2 Exploratory Objectives ..................................................................................................................... 6 
 Study Design ........................................................................................................................................... 6 
8.1 Sample Size Considerations ............................................................................................................ 9 
8.2 Randomization ................................................................................................................................. 9 
 Study Endpoints ...................................................................................................................................... 9 
9.1 Primary Endpoints ............................................................................................................................ 9 
9.2 Secondary Endpoints ..................................................................................................................... 10 
9.3 Exploratory Endpoints .................................................................................................................... 11 
 Conventions and Derivations .............................................................................................................. 11 
10.1 Study Day .................................................................................................................................... 11 
10.2 Baseline ....................................................................................................................................... 11 
10.3 Change from Baseline ................................................................................................................. 11 
10.4 Past and Current Medical History ................................................................................................ 11 
10.5 Prior and Concomitant Medications ............................................................................................. 11 
10.6 Derivation of Efficacy Variables ................................................................................................... 12 
10.6.1 Rate of Complete Response ............................................................................................. 12 
10.6.2 Rate of Achievement of a Morphologic Leukemia-Free State ........................................... 12 
10.6.3 Rate of Partial Response ................................................................................................... 12 
10.6.4 Best Overall (Leukemic) Response ................................................................................... 12 
10.6.5 Duration of Response ........................................................................................................ 12 
10.6.6 Event-free Survival ............................................................................................................ 13 
10.6.7 Overall Survival .................................................................................................................. 13 
10.7 Study Drug Exposure Variables ................................................................................................... 13 
10.7.1 Duration of Exposure ......................................................................................................... 13 
10.7.2 Number of Cycles .............................................................................................................. 13 
10.7.3 Dose Interruption ............................................................................................................... 13 
10.7.4 Dose Adjustment ............................................................................................................... 14 
10.7.5 Total Dose Administered ................................................................................................... 14 
10.7.6 Missed Doses .................................................................................................................... 14 
10.8 Safety Variables ........................................................................................................................... 14 
10.8.1 Adverse Events .................................................................................................................. 14 
10.8.2 Dose Limiting Toxicities ..................................................................................................... 16 
10.8.3 Maximum Tolerated Dose ................................................................................................. 16 
10.8.4 Recommended Phase 2 Dose ........................................................................................... 16 
10.8.5 Clinical Laboratory Parameters ......................................................................................... 16 
10.8.6 Physical Examination and Vital Signs ............................................................................... 17 
10.8.7 Electrocardiograms ............................................................................................................ 17 
10.8.8 Echocardiography or Multigated Acquisition Scans .......................................................... 18 
10.8.9 Eastern Cooperative Oncology Group Performance Status ............................................. 18 
10.9 Other Derived Variables............................................................................................................... 18 
10.9.1 Body Mass Index ............................................................................................................... 18 
10.9.2 Age..................................................................................................................................... 18 
10.9.3 Differentials ........................................................................................................................ 18 
10.10 Partial Dates .............................................................................................................................. 19 


Statistical Analysis Plan (SAP) 
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Protocol no: TROV-052 
 
 
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10.10.1 AE and Concomitant Medication Start and Stop Dates ................................................... 19 
10.11 Missing Data .............................................................................................................................. 19 
10.11.1 Missing Neutrophils ......................................................................................................... 19 
10.11.2 Missing Absolute Differential ........................................................................................... 19 
10.12 Completed Trial .......................................................................................................................... 19 
 Analysis Sets ....................................................................................................................................... 20 
11.1 Safety ........................................................................................................................................... 20 
11.2 Intention-to-Treat ......................................................................................................................... 20 
11.3 Per Protocol ................................................................................................................................. 20 
11.4 Pharmacokinetics ......................................................................................................................... 20 
 Interim Analyses .................................................................................................................................. 20 
 Statistical Methods .............................................................................................................................. 20 
13.1 Subject Disposition ...................................................................................................................... 20 
13.2 Demographic and Baseline Characteristics ................................................................................. 21 
13.3 Treatments ................................................................................................................................... 21 
13.3.1 Extent of Study Drug Exposure ......................................................................................... 21 
13.3.2 Concomitant Medications .................................................................................................. 21 
13.4 Important Protocol Deviations ...................................................................................................... 21 
13.5 Efficacy Analyses ......................................................................................................................... 22 
13.5.1 Leukemic Response .......................................................................................................... 22 
13.5.2 Duration of Response ........................................................................................................ 22 
13.5.3 Event-Free Survival ........................................................................................................... 22 
13.5.4 Overall Survival .................................................................................................................. 23 
13.5.5 Exploratory Efficacy Analyses ........................................................................................... 23 
13.6 Safety Analyses ........................................................................................................................... 23 
13.6.1 Adverse Events .................................................................................................................. 23 
13.6.2 Deaths ............................................................................................................................... 23 
13.6.3 Laboratory Data ................................................................................................................. 23 
13.6.4 Vital Signs .......................................................................................................................... 24 
13.6.5 Physical Examinations, ECGs, and Other Observations Related to Safety ...................... 24 
13.7 Pharmacokinetic Analyses (PK) .................................................................................................. 25 
13.7.1 Pharmacokinetic Variables ................................................................................................ 25 
13.7.2 Plasma Pharmacokinetic Summaries ................................................................................ 25 
13.8 Pharmacodynamic and Diagnostic Biomarkers ........................................................................... 27 
13.9 Methods for Handling Dropouts and Missing Data ...................................................................... 27 
13.10 Multiplicity .................................................................................................................................. 27 
 References .......................................................................................................................................... 27 
 Glossary of Abbreviations ................................................................................................................... 27 
 


Statistical Analysis Plan (SAP) 
Version Date: 22-Oct-2020  
Sponsor: Cardiff Oncology 
Protocol no: TROV-052 
 
 
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Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
 Purpose 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Cardiff Oncology, Inc. Protocol TROV-052. 
 Scope 
The Statistical Analysis Plan outlines the following: 
• 
Study Objectives 
• 
Study Design 
• 
Study Endpoints 
• 
Applicable Study Definitions 
• 
Statistical Methods 
See Glossary of Abbreviations for a list of abbreviations used throughout this document. The list of the 
mock tables, figures, and listings (TFLs) depicting the analyses described in this SAP are presented in a 
separate document. 
 Introduction 
This SAP describes the statistical methods to be used during the reporting and analyses of data collected 
under Cardiff Oncology, Inc. Protocol TROV-052.  
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol dated 07-Aug-2019 and CRF dated 31-Jan-2020. Any 
changes to the protocol or CRF may necessitate updates to the SAP. 
Changes following approval of the first draft of the SAP will be tracked in the SAP Change Log; the final 
version of the SAP will be issued for sponsor approval prior to database lock. Any deviations from the 
final version of the SAP will be documented in the final Clinical Study Report (CSR). 
6.1 Changes from Protocol 
The definition of the per protocol analysis set differs from the protocol by requiring at least one post baseline 
efficacy assessment (bone marrow) and also excluding subjects who have important protocol deviations 
that have the potential to affect efficacy. Efficacy endpoints from investigator response on bone marrow 
aspirate response form in CRF differ from the endpoints reflected in the protocol. Additional choices of 
stable disease and treatment failure are available in the CRF. These efficacy endpoints are incorporated 
into the statistical sections of this SAP and the TFL shells.   
 Study Objectives 
Phase 1b: 
• To evaluate the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), or Recommended 
Phase 2 Dose (RP2D), of onvansertib (PCM-075) in combination with either low-dose cytarabine or 
decitabine in subjects with acute myeloid leukemia (AML). 
 
Phase 2: 
• To assess the safety and tolerability of the combination of onvansertib (PCM-075) at the MTD (or RP2D) 
and low-dose cytarabine, or the combination of onvansertib (PCM-075) at the MTD (or RP2D) and 
decitabine in subjects with AML. 
• To evaluate the preliminary anti-leukemic activity of the combination of onvansertib (PCM-075) at the 
MTD (or RP2D) and low-dose cytarabine, or the combination of onvansertib (PCM-075) at the MTD (or 
RP2D) and decitabine in subjects with AML. 
 


Statistical Analysis Plan (SAP) 
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Sponsor: Cardiff Oncology 
Protocol no: TROV-052 
 
 
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7.1 Secondary Objectives 
Phase 1b: 
• To assess the incidence and severity of adverse events (AEs) according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.03) of onvansertib (PCM-075) 
in combination with either low-dose cytarabine or decitabine in subjects with AML. 
• To analyze the pharmacokinetics (PK) of onvansertib (PCM-075) when given in combination with either 
low-dose cytarabine or decitabine in subjects with AML. 
 
Phase 2: 
• To assess the incidence and severity of AEs according to the NCI-CTCAE version 4.03 of onvansertib 
(PCM-075) in combination with either low-dose cytarabine or decitabine in subjects with AML. 
• To analyze the PK of onvansertib (PCM-075) when given in combination with either low-dose cytarabine 
or decitabine in subjects with AML. 
7.2 Exploratory Objectives 
Phase 1b and Phase 2: 
• To explore additional analyses evaluating potential pharmacodynamic (PD) and diagnostic biomarkers 
of onvansertib (PCM-075) in subjects with AML. 
 Study Design 
This is a Phase 1b/2, open-label study of the safety and anti-leukemic activity of onvansertib in 
combination with either low-dose cytarabine or decitabine in subjects with AML. 
 
This study is being conducted at 8 study centers in the United States, with a total enrollment up to 116 
subjects. This study will have 2 arms. In Arm A, onvansertib will be combined with low-dose cytarabine. In 
Arm B onvansertib will be combined with decitabine. Up to 84 subjects will be enrolled in Phase 1b (42 
subjects in each arm), dependent on the number of dose escalation cohorts required to determine MTD 
or RP2D. Phase 2 will enroll 32 subjects at RP2D identified in Phase 1b.   
 
In Phase 1b, subjects will have relapsed or refractory disease and must have received no more 
than 3 prior regimens for the treatment of their AML.  
 
In Phase 2, subjects must have received no more than one prior regimen for the treatment of their AML.  
 
In both phases, subjects may be treatment naïve as long as they are not candidates for or have refused 
intensive induction therapy, nor received prior treatment with either low-dose cytarabine or decitabine for 
myelodysplastic syndromes (MDS). Neither of these circumstances will be considered a prior regimen. 
For subjects who have undergone hematopoietic stem cell transplantation, the preparative (conditioning) 
regimen and transplant will be considered to be a single line of prior therapy. 
 
Phase 1b 
Subjects in Phase 1b will receive either a combination of onvansertib and low-dose cytarabine, or a 
combination of onvansertib and decitabine in 2 separate arms using a standard 3+3 design in each arm. 
 
In Arm A, onvansertib will be administered in escalating doses orally (p.o). Day 1 through Day 5 every 21 
to 28 days in combination with low-dose cytarabine which will be administered consistently in all cohorts 
as 20 mg/m2 subcutaneously (SC) once daily on Day 1 through Day 10 every 28 days. The starting dose 
of onvansertib in combination with low-dose cytarabine, will be 12 mg/m2 p.o. daily for 5 days (Dose Level 
0). On days where both agents are administered (Days 1-5), low-dose cytarabine will be administered first 
followed by onvansertib. Investigator assessment of subjects may allow them, at their discretion, to treat 
more frequently than every 28 days; however, in no case may a cycle length be less than 21 days. 


Statistical Analysis Plan (SAP) 
Version Date: 22-Oct-2020  
Sponsor: Cardiff Oncology 
Protocol no: TROV-052 
 
 
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In Arm B, onvansertib will be administered in escalating doses p.o. Day 1 through Day 5 every 21 to 28 
days in combination with decitabine, which will be administered consistently in all cohorts as 20 mg/m2 
intravenously (IV) over 1 hour. Onvansertib administration, in combination with decitabine, will be initiated 
at a starting dose of 12 mg/m2 p.o. daily for 5 days (Dose Level 0). The daily dose of decitabine will be 
administered first followed by onvansertib. Investigator assessment of subjects may allow, at investigator 
discretion, to treat more frequently than every 28 days; however, in no case may a cycle length be less 
than 21 days. 
The first 3 subjects will be allocated to Arm A asCohort A1.  
After all subjects are enrolled in Cohorts A1 and B1, subjects will enroll in subsequent cohorts based on 
the following decision rules: 
• 
If Arm A is open for enrollment, subjects will enroll in the open Arm A cohort regardless of dose 
level 
• 
If Arm A is closed to enrollment, subjects will enroll in the open Arm B cohort regardless of dose 
level   
Dose escalation 
Dosing in each arm will proceed independently. Each arm will follow a standard 3+3 dose- escalation 
design in which the onvansertib dose will be escalated by 50% increments in successive cohorts of 3 
subjects (Table 1). If none of the 3 subjects enrolled at any dose level experience a DLT, the dose of 
onvansertib will be escalated by 1 dose level in each successive cohort. If 1 subject in the first 3 subjects 
experiences a DLT, up to 3 additional subjects will be enrolled at that dose level. If there are no additional 
DLTs (ie, ≤1 of 6 subjects with DLT), then dose escalation will again proceed. If there are 2 subjects who 
experience DLTs among the first 3 subjects enrolled, or there is a second DLT in up to 6 subjects enrolled 
at any dose level, the MTD will be judged to have been exceeded and no additional subjects will be 
started at that dose. The MTD will then be established at a preceding lower dose level or an additional 
cohort may be enrolled at an intermediate dose level upon agreement with the Sponsor, Medical Monitor, 
and Principal Investigator. 
The RP2D can be determined based on the assessment of safety, PK, PD, and preliminary efficacy of 
subjects treated at an onvansertib dose level that has been cleared for safety, regardless of whether or 
not an MTD has been reached. In this case, no further dose escalation will be done to determine an MTD. 
Each cohort will be evaluated for toxicity, recovery of blood counts, and PK. DLTs will be evaluated for 
the first 28 days after initiation of therapy. In the case of pancytopenia present at Day 28 in the absence 
of other toxicity that constitutes a DLT, the duration for DLT evaluation will be extended to 42 days 
(unless the pancytopenia resolves between Days 28 and 42, or is determined to be due to persistent 
leukemic involvement of the bone marrow or another cause unrelated to study therapy). Pancytopenia in 
the absence of another cause unrelated to study therapy that persists beyond Day 42 will be considered a 
DLT. If an Investigator elects to re-treat a subject prior to 28 days (allowed no sooner than on Day 22), 
the DLT evaluation period will end at the time of initiation of the second cycle therapy. Dose modifications 
and delays for safety will be performed as described in the protocol. After the first cycle, additional cycles 
can be administered to individual subjects based on Investigator judgment. This may occur if 
hematopoietic recovery is documented, and may incorporate delays or supportive care until 
hematopoietic function returns to baseline or Grade ≤1, as long as the subject is receiving clinical benefit 
without safety or tolerability issues. In the case that failure to achieve hematopoietic recovery is judged to 
be related to persistent leukemic involvement in the bone marrow, Investigators may re-initiate therapy 
according to their clinical judgment upon discussion with the Medical Monitor. 
 
Table 1: Onvansertib Dose and Dosing Levels 
Dose Level 
Dose* 
-1 
6 mg/m2 


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0 (Initial Dose) 
12 mg/m2 
+1 
18 mg/m2 
+2 
27 mg/m2 
+3 
40 mg/m2 
+4 
60 mg/m2 
+5 
90 mg/m2 
+6 
135 mg/m2 
*Initial starting dose is Dose Level 0. If there are >1 DLTs at a dose level and the prior dose level was associated with 1 or fewer 
DLTs, an additional cohort may be enrolled at an intermediate dose level upon agreement with the Sponsor, Medical Monitor, and 
Principal Investigator. 
Preliminary Safety and Efficacy Assessment 
 
Following assessment of safety and preliminary efficacy in the first 5 dose level escalation cohorts (0: 12 
mg/m2; +1: 18 mg/m2; +2: 27 mg/m2; +3: 40 mg/m2; +4: 60 mg/m2) in both Arm A (onvansertib plus low-
dose cytarabine) and Arm B (onvansertib plus decitabine), the decision was made to discontinue Arm A 
from further dose escalation and subject enrollment. 
Arm B will continue forward with dose escalation as outlined in the protocol or until such time as the 
RP2D is determined at a dose level previously cleared for safety. 
The RP2D can be determined based on the assessment of safety, PK, PD, and preliminary efficacy of 
subjects treated at a dose level that has been cleared for safety. In this case, no further dose escalation 
will be done to determine an MTD. 
 
Phase 2 
 
In Phase 2, a total of 32 subjects will be enrolled at the RP2D to further evaluate safety and preliminary 
efficacy of onvansertib. Onvansertib will be administered p.o. on Day 1 through Day 5 every 21 to 28 
days, in combination with decitabine, administered consistently as 20 mg/m2  IV over 1 hour on Day 1 
through Day 5 every 28 days, with treatment modifications or delays based on return of hematopoietic 
function to baseline or Grade ≤1 toxicity for optimal subject management. The daily dose of decitabine will 
be administered first followed by onvansertib. Investigator assessment of subjects may allow, at 
investigator discretion, to treat subjects more frequently than every 28 days; however, in no case may a 
cycle length be less than 21 days. 
Subjects may continue treatment in the study at any dose until clinically significant disease progression or 
death, unacceptable toxicity, withdrawal of consent, or discontinuation based on Investigator discretion. 
Subjects will be followed for survival for up to 1 year after enrollment.  
AEs and concomitant medication use will be recorded throughout the study. Safety evaluations will 
include: physical examinations, performance status, vital signs, electrocardiograms (ECGs), hematology 
and serum chemistry laboratory tests, and urinalysis. 
Efficacy evaluations include leukemic response, duration of response, event-free survival and overall 
survival.  
 
If at any time during Phase 2 more than 33% of subjects develop a DLT, accrual will stop and the RP2D 
will be reassessed in additional cohorts. 


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Protocol no: TROV-052 
 
 
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8.1 Sample Size Considerations 
The planned sample size in the Phase 1b portion of the study is up to 84 subjects (42 in each arm; 
combination of onvansertib and low-dose cytarabine, combination of onvansertib and decitabine), which 
is considered sufficient for the determination of safety and PK parameters for the study drug. 
 
This study is a dose-escalation study that initially utilizes a standard 3+3 design with a starting dose of 
onvansertib of 12 mg/m2 (Dose Level 0) administered Day 1 through Day 5 every 21 to 28 days. If an 
Investigator elects to re-treat a subject prior to 28 days (allowed no sooner than on Day 22), the DLT 
evaluation period will end at the time of initiation of the second cycle of therapy. The sample size is 
anticipated to be up to 84 subjects (42 per arm) in Phase 1b, depending on the dose level at which 
toxicity is observed. The 3+3 dose-escalation algorithm is as follows: 
 
• 
If 0 out of 3 subjects experience DLT (as defined in Section 10.1.4 of the protocol) during the first 
cycle of therapy, the next cohort of 3 subjects will be treated at the next higher dose level. 
• 
If 1 out of 3 subjects develop DLT during the first cycle of therapy (ie, 28 days from start of 
therapy), an additional 3 subjects will be treated at the same dose level. If no additional DLTs 
occur during the first cycle of therapy for the additional 3 subjects treated (ie, 1 out of a total of 6 
subjects develops DLT that initiates within the specified period), the dose escalation continues to 
next higher level for a cohort of 3 subjects. 
• 
If at any time there are 2 or more subjects who experience DLTs in the 3 to 6 subjects at a given 
dose, the next cohort will receive a prior dose level or an intermediate dose level, agreed upon by 
the Sponsor, Medical Monitor, and Principal Investigator. 
With this 3+3 design, a dose with a ≥ 50% probability of causing a DLT has at most a 12.5% chance of 
satisfying the conditions for dose escalation after the first 3 subjects are dosed and a ≥50% chance of 
stopping with 3 subjects. With 6 subjects, there is at most a 17.2% chance of satisfying the conditions for 
dose escalation after 6 subjects have been dosed. Phase 2 will proceed with a total of 32 subjects at the 
identified RP2D; however, if at any time during this phase more than 33% of subjects develop a DLT-level 
AE (as per protocol), accrual will stop, and the RP2D will be reassessed in additional cohorts. 
 
Subjects who are discontinued prior to completing the first cycle for any reason other than toxicity or who 
have not received at least 80% of the intended doses, without experiencing DLT will be replaced. 
8.2 Randomization 
This is an open-label, non-randomized study.  
 Study Endpoints 
9.1 Primary Endpoints 
Phase 1b 
• 
Characterization of DLTs 
• 
MTD or RP2D dose of onvansertib in combination with either low-dose cytarabine or decitabine 
• 
Characterization of AEs by incidence and severity (graded by NCI-CTCAE version 4.03) 
Phase 2 
• 
Safety And Tolerability 
o 
Characterization of AEs by type, incidence, severity (graded by NCI-CTCAE version 4.03), 
seriousness, and relationship to treatment 
o 
Effects on vital signs and laboratory parameters 


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o 
Frequency of dose interruptions, dose reductions, and treatment discontinuation 
o 
Frequency of lab abnormalities 
o 
Medical history 
o 
Changes from baseline in ECGs, physicalexaminations, weight, and ECOG performance, 
echocardiograph (ECHO)/ multigated acquisition scan (MUGA) 
• 
Efficacy 
o 
Rate of complete response (CR + CRi) in Phase 2, defined as a morphologic leukemia-free 
state (MLF; see below) plus: 
 For CR: 
o 
Subject is independent of transfusions 
o 
Absolute neutrophil count (ANC) of >1000/mm3 
o 
Number of platelets of ≥100,000/mm3 
For complete response with incomplete blood count recovery (CRi): 
o 
Meets all criteria for CR except for neutropenia (ANC<1000/mm3) or 
thrombocytopenia (<100,000/mm3) but must include transfusion 
independence 
 
9.2 Secondary Endpoints 
Phase 1b 
• 
Characterization of AEs by incidence and severity (graded by NCI-CTCAE version 4.03) 
• 
Concentrations of onvansertib in plasma samples collected at prespecified time points before and 
after administration of onvansertib, including maximum plasma concentration (Cmax), trough plasma 
concentration (Ctrough), time to maximum plasma concentration (Tmax), area under the 
concentration-time curve from 0 to time of last quantifiable concentration (AUClast), and plasma 
terminal elimination half-life (T-HALF) 
Phase 2 
• 
Note that Phase 2 analysis will only include onvansertib in combination with decitabine 
• 
Characterization of AEs by incidence and severity (graded by NCI-CTCAE version 4.03) 
• 
Concentrations of onvansertib in plasma samples collected at prespecified time points before and 
after administration of onvansertib, including maximum plasma concentration (Cmax), trough plasma 
concentration (Ctrough), time to maximum plasma concentration (Tmax), area under the 
concentration-time curve from 0 to time of last quantifiable concentration (AUClast), and plasma 
terminal elimination half-life (T-HALF) 
• 
Efficacy 
o 
Rate of MLF in Phase 2, defined as: 
▪ 
Bone marrow (BM) <5% blasts in an aspirate with spicules (a BM biopsy should be 
performed if spicules are absent) 
▪ 
 No blasts with Auer rods or persistence of extramedullary disease 
o 
Rate of partial response (PR) in Phase 2: All of the hematologic values for a CR but with a 
decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow 
aspirate and a normalization of blood counts as noted above 
o 
Duration of response (DOR) in Phase 2: Time from documentation of response until 
documentation of recurrence of or progression of disease 
o 
Event-free survival (EFS) in Phase 2: Time from enrollment until disease 


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progression or death from any cause 
o 
Overall survival (OS) in Phase 2: Time from enrollment until death from any cause 
9.3 Exploratory Endpoints 
• 
Blood samples for PD and diagnostic biomarker evaluation  
• 
Evaluation of the rate of complete response (CR + CRi), MLF state, PR, DOR, EFS and OS in all 
enrolled subjects (Phases 1b and 2) 
• 
Note that PRA will not receive PD or biomarker data and will not provide this evaluation 
 Conventions and Derivations 
10.1 Study Day 
Study day is defined as: 
 
 (study date – Cycle 1/Day 1 date +1) 
 
Cycle 1/Day 1 is the start date of study treatment. Study days before the first administration of study 
treatment will be calculated as date of assessment minus date of first administration of study treatment. 
Every effort will be made to avoid missing and/or incomplete dates. In case of missing and/or incomplete 
dates no study days will be calculated. 
10.2 Baseline 
The baseline value is defined as the last measurement prior to the first dose of study drug on Day 1 of 
Cycle 1 (the earliest of onvansertib, plus low-dose cytarabine or decitabine). If assessment time is 
missing and there is no way to determine if the assessment occurred pre-dose, Cycle 1/Day 1 
assessments will be considered for baseline, including for assessments occurring on Cycle 1/Day 1. 
10.3 Change from Baseline 
Change from baseline is defined as: 
 
 (value at post-baseline visit – value at baseline) 
 
In summary tabulations over time, unscheduled post-baseline values will be excluded.  
10.4 Past and Current Medical History 
Past medical histories are those with a stop date prior to the first administration of study treatment. 
 
Current medical histories are those which started prior to enrollment in the study but which are ongoing at 
the start date on or after the first administration of study treatment.    
 
10.5 Prior and Concomitant Medications 
Concomitant medications are all medications (or treatments) other than study drugs that are taken or 
received by the subject at any time during the study starting at the time that the first dose of study drug 
was administered through the end of study treatment. Use of all concomitant medications, including any 
change in therapy, will be recorded, categorized and summarized according to WHO Drug Global B3 
SEP2017. Prior medications are medications that end prior to a subject’s first dose of study drug.  Prior 
and concomitant medications are medications that begin prior to a subject’s first dose of study drugRefer 
to Section 10.11.1 for rules of imputing partial/missing concomitant medications start and stop dates. 


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10.6 Derivation of Efficacy Variables 
The primary efficacy measure is leukemia response in Phase 2, which is evaluated at the timepoints 
indicated in the schedule of events in the clinical protocol (tables 9-1, 9-2, and 9-3) and is based on BM 
aspirate results and peripheral blood examinations. Response criteria will be based on the International 
Working Group for AML (Cheson et. al. 2003). Baseline efficacy assessments are required to be completed 
within 14 days of enrollment.  
10.6.1 Rate of Complete Response 
The primary efficacy variable is the rate of complete response (CR + CRi), where complete response is 
defined as follows: 
CR  
subject has MLF, plus: 
o 
subject is independent of transfusions 
o 
has an absolute neutrophil count (ANC) >1000/mm3, and  
o 
platelets ≥ 100,000/mm3 
 
or 
 
CRi  
o 
subject meets all criteria for CR except for either neutropenia (ANC<1000/mm3) or 
thrombocytopenia (platelets<100,000/mm3) but also must include transfusion 
independence 
 
CR or CRi are indicated on the Bone Marrow Aspirate Response CRFs as an Investigator Response of 
“Morphologic complete remission (CR)” or  “Morphologic complete remission with incomplete blood count 
recovery (CRi)”, respectively. The rate of complete response is defined as the proportion of subjects where 
best overall response (BOR) is CR or CRi at the 14 to 21 days post-treatment assessment. 
10.6.2 Rate of Achievement of a Morphologic Leukemia-Free State  
Achievement of MLF is indicated by a ‘Y’ response to the “Morphologic leukemia-free state present?” field 
of the Bone Marrow Aspirate Response CRFs. The rate of achievement of MLF is defined as the proportion 
of subjects with MLF indicated at the 14 to 21 days post-treatment assessment. 
10.6.3 Rate of Partial Response  
A Partial Response (PR) is indicated on the Bone Marrow Aspirate Response CRFs as an Investigator 
Response of “Partial response (PR)”. The rate of partial response is defined as the proportion of subjects 
with a response of PR at the 14 to 21 days post-treatment assessment. 
10.6.4 Best Overall (Leukemic) Response  
The Best Overall (Leukemic) Response (BOR) for each subject is defined as the best response per 
Investigator assessment among all responses recorded after start of treatment through to disease 
progression or end of treatment, whichever comes first, with a decreasing response ranking of CR, CRi, 
MLF state, PR, stable disease, then Treatment Failure. Stable disease and treatment failure are indicated 
as Investigator Responses on the Bone Marrow Aspirate Response CRFs. 
10.6.5 Duration of Response  
The Duration fo Response (DOR) is defined as the time in months from documentation of response until 
documentation of recurrence of or progression of disease, i.e.: 
 


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(date of documentation of recurrence or progression of disease – date of first observation of CR, 
CRi, MLF state, or PR + 1)/30.4375 
 
Disease progression is captured on the Discontinuation CRF as a Reason for Discontinuation of 
“Progressive Disease” along with the Date of Discontinuation (progression of disease). 
Recurrent disease is captured on the Discontinuation CRF as an Reason for Discontinuation of “Recurrent 
Disease” along with the Date of Discontinuation (progression of disease). 
 
The DOR will only be calculated for the subgroup of subjects achieving CR, CRi, MLF state, or PR at the 
14 to 21 days post-treatment assessment. Event times will be censored either on the date of the last 
evaluable assessment documenting response and recurrence-free or progression-free at the time of 
analysis or on date of death. 
10.6.6 Event-free Survival  
Event-free Survival (EFS) is defined as the time in months from enrollment until disease progression or 
death from any cause, i.e.: 
 
(earlier of date of documentation of progression of disease or death – date of enrollment + 
1)/30.4375 
 
Disease progression is captured on the Discontinuation CRF as a Reason for Discontinuation of 
“Progressive Disease” along with the Date of Discontinuation (progression of disease). Deaths are captured 
on the Adverse Events or Survival Status CRFs. Event times will be censored on the date of the last 
evaluable assessment documenting response and progression-free at the time of analysis. 
10.6.7 Overall Survival  
Overall Survival (OS) is defined as the time in months from enrollment until death from any cause, i.e.: 
 
 (date of death – date of enrollment + 1)/30.4375 
 
Deaths are captured on the Adverse Events or Survival Status CRFs. Event times will be censored on the 
date last known to be alive at the time of analysis for subjects who do not have death documented. Last 
alive dates will come from the Survival Status CRFs. 
 
10.7 Study Drug Exposure Variables 
10.7.1 Duration of Exposure 
Duration of exposure (months) is defined as (last dose date – first dose date +1)/30.4375 and will be 
computed for each study treatment. Treatment free periods within cycles are included. 
10.7.2 Number of Cycles 
The number of cycles, regardless of length, initiated where a dose was administered > 0 mg. This is 
defined for each study treatment. 
10.7.3 Dose Interruption 
A dose interruption is defined for decitabine only as any interruption during the administration (infusion) of 
a dose. Dose interruptions of decitabine are recorded on the Decitabine Administration CRF page as a ‘Y’ 
response to “Was the treatment administration interrupted?” The duration and units of the duration of the 
interruptions are also recorded in the EXINTRP and EXINTRPU fields, respectively. Duration will be 


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summarized in minutes. A dose interruption recorded in hours or days will be transformed to minutes 
using the following calculations: 
 
Recorded in hours: (dose interruption (hours))/60 
Recorded in days:  (dose interruption (days))/(60*24) 
 
10.7.4 Dose Adjustment 
A dose adjustment is defined for onvansertib only as any change in the dose assigned for ingestion. Dose 
adjustments of onvansertib are captured as a ‘Y’ response in the EXDPSADJ field (Was the dose level 
adjusted from planned?) along with the adjusted dose (mg) in the EXDSADJ field of the Onvansertib 
Administration CRF pages. 
10.7.5 Total Dose Administered 
Total dose administered (mg/m2) is defined as the total amount of study drug received as recorded in the 
EXDSTXT field on the Onvansertib Administration, Decitabine Administration, and the low-dose 
Cytarabine  Administration CRF pages, i.e., the sum of all doses (mg/m2) administered. This is computed 
separately for each study treatment. 
10.7.6 Missed Doses 
A missed dose is defined as any planned dose not administered and is captured as a ‘N’ response in the 
EXADM field (Was dose administered?) on the Onvansertib Administration, Decitabine Administration, 
and the low-dose Cytarabine  Administration CRF pages. Treatment free periods within cycles are not 
considered in this definition. 
10.8 Safety Variables 
10.8.1 Adverse Events  
An Adverse Event (AE) is defined in Title 21 Code of Federal Regulations (CFR) 312.32(a) as follows: 
• 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. 
An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a drug, and does not imply any judgment about causality. An 
AE can arise with any use of the drug (e.g., off-label use, use in combination with another drug) and with 
any route of administration, formulation, or dose, including an overdose. 
All reported AEs will be mapped to standard coding terms using Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.1, and grouped by system organ class (SOC) and preferred term (PT). 
10.8.1.1 Serious Adverse Events (SAEs) 
An SAE is defined in 21 CFR 312.32(a) as follows: 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes: 
• 
Death 
• 
Is life-threatening 
• 
Subject hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 


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• 
A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in in subject 
hospitalization, or the development of drug dependency or drug abuse. 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the  subject at immediate risk of death. It does not include 
an AE or suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
10.8.1.2 Severity of Adverse Events 
Each AE will be graded according to the NCI-CTCAE version 4.03. In most cases AE terms will be listed 
in the CTCAE, with grading criteria specific to that term. If the AE is not specifically defined in the CTCAE, 
it is to be reported using the “Other, specify” term under the appropriate SOC and graded according to the 
general CTCAE severity guidelines (see protocol, Appendix 1). 
10.8.1.3 Relationship of Adverse Events to the Study Drug 
The Investigator must attempt to determine if an AE is in some way related to the use of the onvansertib, 
decitabine, or low-dose cytarabine. All AEs must be attributed to study drugs unless there is a reasonably 
acceptable alternate cause for the adverse events. This relationship should be described as follows: 
• 
Unrelated: The event has no temporal relationship to study drug administration (too early or late 
or study drug not taken), or there is a reasonable causal relationship between the AE and another 
drug, concurrent disease or circumstance. 
• 
Unlikely: The event with a temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or underlying disease provide 
plausible explanations. 
• 
Possibly: The event follows a reasonable temporal sequence from administration of the study 
drug and the event follows a known response pattern to the study drug BUT the event could have 
been produced by an intercurrent meiecondition which, based on the pathophysiology of the 
condition, and the pharmacology of the study drug, would be unlikely related to the use of the 
study drug or the event could be the effect of a concomitant medication. 
• 
Probably: The event follows a reasonable temporal sequence from administration of the study 
drug and the event follows a known response pattern to the study drug AND the event cannot 
have been reasonably explained by an intercurrent medical condition or the event cannot be the 
effect of a concomitant medication. 
• 
Definitely: The event follows a reasonable temporal sequence from administration of the study 
drug, the event follows a known response pattern to the study drug and based on the known 
pharmacology of the study drug, the event is clearly related to the effect of the study drug. 
10.8.1.4 Treatment-Emergent Adverse Events (TEAEs) 
AEs that occur or start, or increase in severity on or after the first dose of study drug and no later than 30 
days after the last dose of study drug will be considered treatment-emergent. See Section 10.11.1 for 
imputation rules for AE dates.   
The earliest date of the first dose of onvansertib, low-dose cytarabine or decitabine will be considered the 
first study drug dose date; the latest date of the last dose of onvansertib, low-dose cytarabine or 
decitabine will be considered the last dose of study drug date.   


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10.8.1.5 Treatment-Related Adverse Events 
All AEs for which the relationship to study treatment is classified as “possibly”, “probably” or “definitely” 
related will be classified as treatment-related. If the relationship to study treatment is missing, the 
relationship will be assumed to be treatment-related. 
10.8.2 Dose Limiting Toxicities  
Dose-limiting toxicities (DLTs) are defined as events related to onvansertib that are considered an 
adverse reaction or suspected adverse reaction occurring during the first cycle of therapy, per criteria 
outlined in protocol Section 10.1.4. 4An AE with a response ‘Y’ to the question “Was the AE classified as 
Dose Limiting Toxicity (DLT)?” on the AE CRF page will be classified as a DLT. An AE with a missing 
response to the question “Was the AE classified as Dose Limiting Toxicity (DLT)?” will be classified as a 
DLT. 
DLTs will be recorded for 28 days after initiation of therapy; however, if an Investigator elects to re-treat a 
subject prior to 28 days (allowed no sooner than on Day 22), the DLT evaluation period will end at the 
time of initiation of the second cycle therapy. Subjects may continue with additional cycles as long as the 
subject is receiving clinical benefit and there are no safety or tolerability issues.Subjects who have not 
received at least 80% of the dose of study drug(s) during the first cycle or who are discontinued for any 
reason other than DLT will be replaced.  
10.8.3 Maximum Tolerated Dose  
The maximum tolerated dose (MTD) of onvansertib in combination with either low-dose cytarabine or 
decitabine in subjects with AML will be defined as the highest dose level achieved at which no more than 
1 out of 6 subjects experienced a DLT during the first cycle of therapy in Phase 1b. 
10.8.4 Recommended Phase 2 Dose  
 
The Recommended Phase 2 Dose (RP2D) may be as high as the MTD and will be determined based on 
the assessment of safety, PK, PD, and preliminary efficacy of subjects treated at a dose level that has 
been cleared for safety. In this case, no further dose escalation will be done to determine an MTD. 
10.8.5 Clinical Laboratory Parameters 
Clinical laboratory parameters to be collected routinely on study are listed in Table 2 below. All 
parameters will be tested by local laboratories. Clinical laboratory data will be entered into the electronic 
data capture (EDC) system and converted to International System (SI) units for analysis. Normal ranges 
will be merged in during dataset programming. Baseline laboratory parameters are the last collected any 
time prior to start of treatment on Cycle 1 Day 1 in each phase. 
Table 2: Laboratory Safety Parameters 
Hematology Panel 
Blood Chemistry Panel 
Hematocrit (HCT) 
Alkaline Phosphatase (ALP) 
Hemoglobin (HGB) 
Alanine aminotransferase (ALT) 
Red Blood Cell Count (RBCC) 
Aspartate aminotransferase (AST) 
Platelet Count 
Total Bilirubin 
White blood cell count (WBC) with Differential 
(absolute and %) 
Lactate Dehydrogenase (LDH) 
Basophils  
Total Protein 
Eosinophils 
Albumin 


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Lymphocytes 
Bicarbonate 
Monocytes 
Calcium 
Neutrophils 
Sodium 
Immature cells 
Potassium 
 
Magnesium 
Urinalysis (only at baseline) 
Phosphorus 
Specific Gravity 
Glucose 
pH 
Chloride 
Leukocyte Esterase 
Creatinine 
Nitrite 
Blood Urea Nitrogen (BUN) 
Protein 
Urea 
Glucose 
Uric acid 
Ketones 
 
Urobilinogen 
 
Bilirubin 
 
Blood 
 
 
 
10.8.6 Physical Examination and Vital Signs 
Abnormal results of physical examinations of body systems will be captured on the Medical History CRFs 
(screening examinations) and the Adverse Events CRFs (after screening examinations). The vital signs 
collected on this study are height (cm), weight (kg), body temperature (°C), systolic and diastolic blood 
pressure (mmHg), pulse (beats/min), and respiratory rate (breaths/min). These will be entered on the Vital 
Signs – Screening and Vital Signs CRFs. Baseline vital signs are the last collected any time prior to start 
of treatment on Cycle 1 Day 1 in each phase. 
10.8.7 Electrocardiograms  
Twelve-Lead electrocardiograms (ECGs) will periodically be performed in triplicate and the following 
information entered on the EGLR1 and EGLR2 CRFs for analysis: 
• 
mean heart rate (beats/min) 
• 
mean P-R interval (msec) 
• 
mean QRS interval (msec) 
• 
mean QT interval (msec) 
• 
mean R-R interval (msec) 
• 
mean QTc (msec) by the Fridericia’s formula, QTcF 
• 
indicator of clinically significant ECG 
 
Categories for QTcF are described as follows: 
• 
  ≤ 450 msec 


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• 
  > 450 to ≤ 480 msec 
• 
  > 480 to ≤ 500 msec 
• 
  > 500 msec 
 
Categories for change from baseline in QTcF as described as follows: 
• 
  ≤ 30 msec 
• 
  > 30 to ≤ 60 msec 
• 
  > 60 msec 
 
Baseline values are reported any time prior to start of treatment on Cycle 1 Day 1 in each phase. 
10.8.8 Echocardiography or Multigated Acquisition Scans  
In Phase 1b and Phase 2, electrocardiography (ECHO) or multigated acquisition (MUGA) scans will be 
performed at screening and the end -of -study visit (1 to 2 weeks after discontinuation). Indications of 
abnormal or clinically significant scan results are reported on the ECHO/MUGA CRFs. 
10.8.9 Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status (grade or score ranging from 0-5; 
Appendix 19.3 of the protocol) will be collected at baseline and within 1 to 2 weeks after study treatment 
discontinuation and reported on the ECOG CRF. 
 
10.9 Other Derived Variables 
10.9.1 Body Mass Index 
Body mass index (BMI) will be calculated based on baseline weight and baseline height using the following 
formula: 
BMI = Weight (kg) / Height2 (m) 
10.9.2 Age 
Besides being analyzed as a continuous variable, baseline age, from Demography CRF page, will be 
categorized into the following groups: 
• 
< 65 years old 
• 
65 to 75 years old 
• 
> 75 years old 
10.9.3 Differentials 
When both absolute and % differentials are collected for a particular visit then data will be handled as 
follows: 
• 
If absolute reported (or absolute and %) then report absolute 
• 
If only % reported then calculate absolute from % and total WBC count with the following formula 
 
Absolute differential= % differential * total WBC count 


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10.10 Partial Dates 
For diagnosis and prior therapy dates, if day is missing and month is non-missing, the first day of the month 
with be assumed.  If day and month are missing, the missing day and month will be set to 01 January.   
If a death date is missing month or day, the following imputation method will be used: 
• 
 
If only the death year is known and the last date the subject was known to be alive is in the same 
year, the subject’s last alive date will be used as the death date.  If the last alive date occurs in a 
previous year, the missing death month and day will be imputed as the first day and month of the 
year (01JAN). 
• 
 
If the year and month are known and the last alive date is in the same year and month as the 
death date, then the last alive date will be used.  If the last alive date is in a month prior to the 
death month, then the death day will be imputed as the first day of the month. 
10.10.1 AE and Concomitant Medication Start and Stop Dates 
Start Date: If only ‘day’ is missing, and the month and year are not the same as the month and year of 
the first dose, then day will be imputed with ‘01’. Otherwise, if the month and year are the same as first 
dose date, first dose date will be used. If ‘day’ and ‘month’ are missing, and ‘year’ is not missing, then 
month and day will be imputed with month and day of first dose date (assuming same ‘year’). If the start 
date is completely missing, then the first dose date will be used. If the stop date is complete and the 
imputed start date is after the stop date, then the imputed start date will be set to the stop date. The 
original, non-imputed, dates will be retained in the clinical trial database and will be included in subject 
listings. 
 
Stop Date: If only ‘day’ is missing, day will be imputed with last day of the month. If ‘day’ and ‘month’ are 
missing, and ‘year’ is not missing, then month will be imputed with '12' and day will be imputed with '31' 
(or date of study discontinuation/completion if earlier than Dec-31 and year is the same as the year of 
discontinuation). If the stop date is completely missing, it will be set to the date of study 
discontinuation/completion. A stop date will not be applied to ongoing AEs. If the imputed stop date is 
greater than the last contact date, then the imputed stop date will be set to last contact date. The original, 
non-imputed, dates will be retained in the clinical trial database and will be included in subject listings. 
 
10.11 Missing Data 
10.11.1 Missing Neutrophils 
When a neutrophil value is missing, if values for segmented cells (SEGS) and bands (BANDS) are 
available, neutrophils will be calculated as: 
 
      SEGS+BANDS 
 
If the neutrophil value is missing and either SEGS or BANDS are available, the neutrophil value will be 
the non-missing value of SEGS or BANDS. 
10.11.2 Missing Absolute Differential 
See section 10.10.3 Differential above.  
10.12 Completed Trial  
All subjects who remain on trial through their End of Study Visit and listed as “Subject 
Completed Study” will be considered as having completed the trial. 


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 Analysis Sets 
In all analysis sets, individual subjects will be grouped by dose according to the initial dose assigned. 
11.1 Safety 
The safety analysis set comprises all subjects who receive at least one dose of onvansertib and will be 
used in the analysis of safety variables. 
11.2 Intention-to-Treat  
The Intention to Treat (ITT) analysis set comprises all subjects who received at least one dose of study 
treatment (onvansertib and at least one dose of either low-dose cytarabine or decitabine) These subjects 
will be used in the analysis of efficacy variables. 
11.3 Per Protocol  
Subjects in the ITT analysis set who complete at least one cycle of study treatment, have had ≥1 
evaluable post-baseline tumor assessment (BM)  and have no important protocol deviations that have the 
potential to affect efficacy will be included in the PP analysis set.  
11.4 Pharmacokinetics  
The PK analysis set will consist of all subjects in the safety analysis set who have adequate plasma 
onvansertib concentration data as determined by the PK scientist. 
 Interim Analyses 
Not applicable. There is no formal interim analysis planned for this study. However, the Safety Review 
Committee, consisting of the Principal Investigators and Medical Monitor, will monitor subjects for safety 
and to evaluate efficacy of onvansertib doses to minimize exposure of subjects to a non-efficacious dose 
level. 
 Statistical Methods 
All statistical analyses will be performed using SAS® Version 9.4 or higher. 
 
Summaries will be presented by dose level and total within each combination (onvansertib + decitabine or 
onvansertib + low-dose cytarabine) at each dose enrolled, except for demographic data which will be 
presented by Phase but not individual dose levels.  PK summaries will not include totals combining dose 
levels.  
Subjects who have intra-subject dose escalation will be summarized in their initial dose group.   
Categorical variables will be summarized using counts and percentages. Percentages will be rounded to 
one decimal place except 100% will be displayed without any decimal places and percentages will not be 
displayed for zero counts.  
Continuous variables will be summarized using the number of observations (n), mean, standard deviation, 
median, minimum, maximum, 25th and 75th percentiles. The mean, median, and quantiles will be 
presented to one more and the standard deviation to 2 more decimal places than the precision of the 
original variable, while the minimum and miaximum will be presented at the same precision as the original 
variable. 
13.1 Subject Disposition 
The count and percentage of subjects screened, enrolled and treated in the study will be presented, along 
with the count and percentage of subjects included in each analysis set. The count of subjects who 
discontinue the study along with a breakdown of the corresponding reasons for discontinuation will also 


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be summarized in the safety analysis set. The count and percentage of subjects enrolled at each site will 
also be summarized based on all subjects enrolled. All visits and treatment assignments of the safety set 
will presented in the listings. Discontinuations from study will be presented in listings.  
13.2 Demographic and Baseline Characteristics 
Demographics including age (years), age categories, sex, race, ethnicity, height (cm), weight (kg) and 
BMI (kg/m2) will be summarized at baseline using the safety analysis set. An additional demographics 
table will be generated for the PP analysis set 
The number of weeks from AML diagnosis to the first dose of study drug, prior therapy use (yes/no), 
weeks from last prior AML therapy to the first dose of study drug, relapse status (yes/no), weeks from 
relapse to first dose, weeks from last AML therapy to relapse, and progression status (yes/no) will be 
summarized for the safety analysis set. Additionally, ECOG PS will be summarized. Prior AML therapy 
data will be listed by subject.  
Medical history and physical examination results will be presented in listings in the safety analysis set. 
13.3 Treatments 
13.3.1 Extent of Study Drug Exposure 
Study drug exposure will be summarized descriptively based on the safety analysis set for the following 
variables: 
• 
Duration of exposure (months) 
• 
Number of cycles administered for each study treatment 
• 
Total dose administered (mg/m2) calculated for each study treatment  
• 
Number of dose adjustments (increase and decrease) per subject (onvansertib) with reason for 
dose adjustment 
• 
Number of dose interruptions per subject (decitabine) 
• 
Duration of dose interruptions per subject (minutes) (decitabine) 
• 
Number of missed doses per subject for each study drug.   
 
A listing will present exposure data by subject for onvansertib administration for the safety analysis set. 
Separate listings will present exposure data for low-dose cytarabine and decitabine administration based 
on the safety analysis set. 
13.3.2 Concomitant Medications 
Using the safety analysis set, the count and percentage of subjects using at least one concomitant 
medication overall will be summarized along with the count and percentage of subjects using at least one 
concomitant medication for each PT.  
All medications will also be listed for the safety set.  In the listing, medications will be classified as prior, 
prior and concomitant or concomitant. 
13.4 Important Protocol Deviations 
Protocol deviations will be identified, including, but not limited to, subjects that were enrolled even though 
they did not meet all eligibility criteria, subjects who took concomitant medications specifically prohibited 
by the protocol, and subjects who received the wrong study drug or an incorrect dose. The reason for 
each protocol deviation will also be identified. 
Per PRA processes, important protocol deviations data will be entered into our Clinical Trials 
Management System (CTMS). The study team and the Sponsor will conduct ongoing reviews of the 
deviation data from CTMS and the resulting set of PP subjects throughout the study, adjusting the 
deviation criteria as appropriate. The PP analysis set must be finalized at the post-freeze data review 
meeting (or earlier), prior to database lock. 


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For each study phase, important protocol deviations for subjects in the safety analysis set will be 
summarized by deviation category. Important protocol deviations will also be listed. A Data listing will also 
present all protocol deviations by subject including whether deviation is an important protocol deviation 
resulting in exclusion from PP analysis set.           
13.5 Efficacy Analyses 
Inferential statistical analysis comparing efficacy data among onvansertib dose levels or historical data is 
not planned. 
Subjects from the ITT analysis set will be included in the efficacy analyses.  Similar summaries will also 
be generated for the PP analysis set. 
Primary efficacy summaries will be generated for Phase 2 subjects. Derived efficacy data for Phase 1b 
and Phase 2 subjects will be presented in Subject listings. 
13.5.1 Leukemic Response 
The primary efficacy variable is leukemia response in Phase 2 subjects as evaluated by the Investigator 
at the end of each induction cycle, as indicated by the Investigaor, and at the end of -study visit based on 
BM aspirate and peripheral blood examination results. 
Responders are subjects with a CR or CRi accompanied by MLF state. Subjects without efficacy 
evaluable assessments will be considered non-responders in the ITT analysis population.  
The count and proportion of Phase 2 subjects achieving CR, CRi, MLF state, PR, Stable Disease, or 
Treatment Failure as the best overall leukemic response will be summarized based on the ITT analysis 
set using counts and percentages.  
Rate of complete response (CR+CRi) will be summarized for the ITT analysis set and exact 95% binomial 
confidence intervals generated.  
The count of subjects with MLF state and PR will be summarized based on counts and percentages for 
the ITT analysis set. All efficacy tables will also be presented for the PP analysis set.  Ninety-Five% exact 
CIs will be presented for the percentages. Similar summaries will be generated based on extramedullary 
disease.  
BOR data will be provided in a listing. 
13.5.2 Duration of Response 
DOR will be summarized using Kaplan-Meier (KM; Kaplan and Meier 1958) estimates for the ITT and PP 
analysis set in Phase 2 subjects who have had a response (CR, CRi, MLF state, or PR). The min, max, 
25%, 50%, and 75% quartiles will be calculated and corresponding 95% CIs for the quartiles by the KM 
method. A KM plot for DOR will be presented. The count and percentage of responding subjects who 
have an event or are censored will be summarized.   
DOR data will be provided in a listing.  
13.5.3 Event-Free Survival 
EFS will be summarized using KM estimates for the ITT and PP analysis set in Phase 2 subjects. The 
min, max, 25%, 50%, and 75% quartiles will be calculated and corresponding 95% CIs for the quartiles by 
the KM method. A KM plot of EFS will be presented. The count and percentage of those who have an 
event or are censored will be summarized. The EFS rate at 12 months and corresponding 95% CIs by the 
KM method will be presented.  
 
EFS data will be provided in a listing. 


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13.5.4 Overall Survival 
Overall Survival (OS) will be summarized using KM estimates for the ITT and PP analysis sets in Phase 2 
subjects. The min, max, 25%, 50%, and 75% quartiles will be calculated. A KM plot of OS will be 
presented. The count and percentage of subjects who have an event or are censored will be summarized. 
The OS rate at 12 months and corresponding 95% CIs will be presented  by the KM method.   
 
OS data will be provided in a listing. 
13.5.5 Exploratory Efficacy Analyses 
Select individual components from BM aspirate results, BM aspirate response, and other parameters used 
to assess disease response will be listed for the ITT analysis set and the PP set.  
13.6 Safety Analyses 
Data from all subjects who receive at least one dose of study drug (onvansertib) will be included in the 
safety analysis.   
 
Inferential statistical analysis comparing the safety data among onvansertib dose levels or with historical 
data is not planned.  
13.6.1 Adverse Events 
Safety will be assessed primarily based on AEs.  All summaries of AEs will be based on treatment-
emergent AEs unless otherwise indicated. 
Counting of AEs will be by subject, not by event; subjects will be counted only once within each SOC or 
PT.  
 
The count and percentage of subjects who report AEs will be summarized by phase and dose cohort for 
the safety analysis set as follows: 
• 
AEs that are DLTs 
• 
AEs by SOC and PT 
• 
AEs by SOC, PT, and maximum NCI-CTCAE grade 
• 
NCI-CTCAE Grade ≥ 3 AEs by PT  
• 
Serious AEs by SOC and PT 
• 
AEs related to onvansertib by SOC, PT, and maximum NCI-CTCAE grade 
• 
NCI-CTCAE Grade ≥ 3 AEs related to onvansertib by PT  
• 
Serious AEs related to onvansertib by SOC and PT 
• 
AEs leading to discontinuation of study medication 
• 
AEs with an outcome of death 
 
For grade summaries, subjects with multiple events within a particular SOC or PT will be counted under 
the category of their most severe event within that SOC or PT. Events will be sorted by descending 
frequency of the total across all dose cohorts by SOC, and by PT within SOC for summaries. 
AEs and TEAEs will be listed for individual subjects, including information regarding onset, duration, 
severity, seriousness, outcome and relationship to study drug. 
13.6.2 Deaths  
AEs with an outcome of death will be listed. In addition, death data from the survival status CRF will be 
presented in a listing. Causes of death will be included. 
13.6.3 Laboratory Data 
All laboratory results (hematology, clinical serum chemistry and urinalysis) will be presented in listings. 


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Shift tables for some hematology and chemistry tests will be provided for the maximum post-baseline 
grade including data from any unscheduled post-baseline timepoint, and the last study assessment while 
on study treatment. These tables will compare the NCI-CTCAE grade for the baseline value relative to 
each post-baseline time point value for all non-missing post-baseline data.  
13.6.4 Vital Signs 
 
 
A summary of abnormal vital signs by time point will be presented, where abnormal vital signs are systolic 
blood pressure >140 mmHg, diastolic blood pressure >90 mmHg, heart rate <60 beats/min or >100 
beats/min, or temperature >37.5°C. 
Vital sign results will be provided in data listings. 
13.6.5 Physical Examinations, ECGs, and Other Observations Related to Safety 
Additional safety assessments include physical examinations, ECG measurements, ECOG performance 
status, pregnancy tests and multigated acquisition (MUGA) or echocardiography (ECHO) scans. 
Summaries of the above safety assessments are described below.  Only listings will be generated for 
physical examination and pregnancy test results. 
13.6.5.1 ECG  
A summary of average of triplicate ECG parameters, heart rate, P-R interval, QRS interval, QT interval, 
QTcF interval and RR interval and change from baseline will be presented for each planned visit.    
The count and percentage of subjects who have abnormal QTcF during the study will be summarized by 
the following International Conference on Harmonization (ICH) E14 categories: 
 
Male: 
QTc interval > 450 ms 
QTc interval > 480 ms 
QTc interval > 500 ms 
 
Female: 
QTc interval > 480 ms 
QTc interval > 500 ms 
 
Change from baseline in QTc interval: 
QTc interval increases from baseline > 30 ms 
QTc interval increases from baseline > 60 ms 
  
All triplicate and average ECG data will be provided in data listings. 
13.6.5.2 ECOG Performance Status 
For Phase 1b and Phase 2, shift tables comparing ECOG data from baseline to post-treatment follow 
up/EOS ECOG score will be generated. 
 
All ECOG data will be provided in data listings. 
13.6.5.3 ECHO/MUGA 
ECHO/MUGA results will be summarized based on shifts between screening and post-treatment follow 
up/EOS, with shift tables generated using normal/abnormal categories and normal/abnormal non-clinically 
significant abnormal/abnormal clinically significant categories.  


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ECHO/MUGA results will be presented in a listing. 
13.7 Pharmacokinetic Analyses (PK) 
13.7.1 Pharmacokinetic Variables 
Concentrations of onvansertib will be collected in plasma.  
PK parameters of  onvansertib will be calculated for plasma. 
13.7.2 Plasma Pharmacokinetic Summaries 
13.7.2.1 Plasma Concentrations 
The lower limit of quantification (LLOQ) of onvansertib is 0.100ng/mL. Plasma concentrations onvansertib 
below the quantifiable limit (BQL) will be set to 0 in the computation of mean concentration values. 
Descriptive statistics (number of subjects, mean, geometric mean, standard deviation (SD), coefficient of 
variation [%CV], median, min, and max) will be used to summarize the plasma concentrations by phase, 
cycle, combination drug and dose at each scheduled time point. 
Semi-logarithmic (+SD) plots of the arithmetic mean plasma concentration by scheduled sampling time will 
be provided by phase, cycle, combination drug and dose. These plots will show time in hours. The plots will 
present all calculated means and will include a reference line for LLOQ. 
All individual subject plasma concentration data will be listed by subject, by phase, combination drug and 
dose. 
13.7.2.2 Plasma Pharmacokinetic Parameters 
Plasma PK parameters for onvansertib will be estimated using non-compartmental methods with 
WinNonlin® version 8.1 using Best Fit regression. The PK parameters will be estimated from the 
concentration-time profiles, and AUCs will be calculated using linear up / log down method. In estimating 
the PK parameters, BQL values will be set to zero. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. If the actual time is missing, the scheduled 
time will be substituted and flagged. 
In estimating the PK parameters, BLQ values at the beginning of the profile will be set to 0. BLQ values 
that occur after the first quantifiable point will be considered missing. Values that are embedded between 
BLQs, or quantifiable values occurring after two or more BLQs, will be set to missing at the discretion of the 
PK specialist 
The following flags will be used to include parameters that meet the predefined criteria for summary and 
analysis: 
Criteria 
Name 
Analysis Flag 
Criteria 
Regression 
ANL02FL 
Adj Rsq >= 0.8 
Note: Flags will be applied to parameters prior to derivation of additional parameters in SAS and will be 
used to include derived parameters as well. 
The plasma concentration of onvansertib administered in combination with low-dose cytarabine or 
decitabine will be collected at specified study timepoints measured according to the schedule outlined in 
Tables 9-1, 9-2, and 9-3 of the protocol and reported by timepoint for onvansertib. The following PK 
parameters will be calculated as applicable for each subject: 
Table 3. PK Parameters 


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Parameter 
Description 
Cycle, Day 
SAS Programming Notes 
Cmax 
Maximum plasma concentration. Observed 
peak analyte concentration obtained directly 
from the experimental data without 
interpolation, expressed in concentration units 
Cycle 1, Day 1, 
Cycle 1, Day 5,  
Cycle 2, Day 1, 
Cycle 2, Day 5 
Cmax from WNL 
Ctrough 
Observed plasma concentration at the end of 
each dosing interval 
Cycle 1, Day 5, 
Cycle 1, Day 8, 
Cycle 1 Day 15, 
Cycle 1, Day 22, 
Cycle 2 Day 5, 
Cycle 2 Day 8,  
Cycle 2 Day 15, 
Cycle 2 Day 22 
Pre-dose concentration on for 
Cycle 1 on Day 5, 8, 15 and 
22 and Cycle 2 on Day 5, 8, 
15 and 22  from ADPC.  
Calculated in SAS. 
Tmax 
Time to maximum plasma concentration. First 
observed time to reach peak analyte 
concentration obtained directly from the 
experimental data without interpolation, 
expressed in time units. 
Cycle 1, Day 1, 
Cycle 1, Day 5,  
Cycle 2, Day 1, 
Cycle 2, Day 5 
Tmax from WNL 
AUClast 
Area under the concentration-time curve (time 
0 to time of last quantifiable concentration). 
Cycle 1, Day 5,  
Cycle 2, Day 5 
AUClast from WNL 
AUCtau 
Area under the concentration-time curve over 
the dosing interval (time 0 to 24hr). 
If the nominal 24hr concentration was taken at 
or after 24hr postdose then AUCtau will be 
calculated by WNL to 24hr. 
If the nominal 24hr concentration was taken 
before 24hr post-dose and a valid λz is 
available then the data will be extrapolated to 
24hr. 
If the nominal 24hr concentration was taken 
before 24hr post-dose and a valid λz is not 
available then AUC0-24 calculated to actual 
time will be used for AUCtau. 
Cycle 1, Day 1, 
Cycle 1, Day 5,  
Cycle 2, Day 1, 
Cycle 2, Day 5 
AUClast from WNL for Cycle 
1 Day 1 and Cycle 2 Day 1 
AUCtau from WNL Cycle 1 
Day 5 and Cycle 2 Day 5 
In case when AUCtau might 
not be available in WNL file, 
summary file might be used to 
extract the parameters for 24h 
nominal sampling time 
T-HALF 
Terminal phase half-life expressed in time 
units 
Cycle 1, Day 5 
HL_Lambda_z from WNL  
CLss/F 
Apparent clearance at steady state  
Cycle 1, Day 5 
CLss_F from WNL 
Vss/F 
The apparent volume of distribution during the 
terminal phase is calculated by dividing Dose 
by the product of AUCtau and Lz. 
Cycle 1, Day 5 
Vz_F from WNL 
 
Descriptive statistics (number of subjects, mean, geometric mean, SD, %CV, median, min, and max) will 
be used to summarize the calculated PK parameters by phase, cycle, combination drug and dose. For 
Tmax, only median, min and max will be presented.  
All parameters will be listed by subject, by phase, cycle, combination drug and dose; parameters that meet 
the inclusion criteria will be accompanied by an indication that each is criteria met. 
The following parameters will be used for diagnostics and thus listed but not summarized. 


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Parameter 
Description 
SAS Programming Notes 
Adj Rsq 
Goodness of fit statistic for the log-linear terminal elimination 
phase of the concentration-time profile identified by least-squares 
linear regression and adjusted for the number of points (minimum 
of 3) used in the estimation of Lz. 
Rsq_adjusted from WNL 
 
 
Lz 
Terminal phase rate constant calculated by linear regression of the 
terminal log-linear portion of the concentration vs. time curve. 
Using no weighting factor, the terminal log- linear phase of the 
concentration-time curve is identified by least-square linear 
regression of at least 3 data points that yielded a maximum G 
criteria, which is also referred to as adjusted R2. Lz is the absolute 
value of the slope of the terminal log-linear phase. Note: In 
Phoenix, use Best Fit method to determine regression. 
Lambda_z from WNL 
  
 
 
13.8 Pharmacodynamic and Diagnostic Biomarkers 
Polo-like kinase 1, % blasts (serum and BM), and tumor gene expressions will be measured periodically 
during the study. Results will not be transferred  to PRA and will not be included in the TFL deliveries. 
13.9 Methods for Handling Dropouts and Missing Data 
In Phase 1b, subjects who are discontinued prior to completing the first treatment cycle for any reason 
other than toxicity, or who have not received at least 80% of the intended doses without experiencing a 
DLT will be replaced.  Data for subjects who are replaced will not be included in the summary analyses; 
data for replaced subjects will be presented in separate data listings.  Sensitivity analyses of response 
parameters including all subjects (with replaced subjects analyzed as non-responders) may be generated 
as deemed appropriate per study results. Censoring rules for time to event endpoints are specified in 
Sections 10.6.5 to 10.6.7. Rules for imputation of missing/partial dates and other missing data are 
specified in Sections 10.10 and 10.11.  
13.10 Multiplicity 
There will be no adjustment made for multiplicity. 
 References 
1. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working 
Group for Diagnosis, standardization of response criteria, treatment outcomes, and reporting standards 
for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003; 21:4642-9. 
2. Kaplan, E.L., and Meier P. Nonparametric estimation from incomplete observations.  J Am Stat 
Assoc. 1958; 53:457-481. 
 
 Glossary of Abbreviations 
Glossary of Abbreviations: 
AE 
Adverse event 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 


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AUC 
Area under the plasma concentration-time curve 
AUClast 
Area under the concentration-time curve (time 0 to time of last quantifiable 
concentration) 
AUCtau 
Area under the serum concentration-time curve over the dosing interval 
(time 0 to 24hr) 
BM 
Bone marrow 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BQL 
Below the Limit of Quantification 
CI 
Confidence Interval 
CLss/F 
Apparent clearance at steady state 
Cmax 
Maximum plasma concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CRi 
Complete Response with Incomplete Blood Count Recovery 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trials Management System 
Ctrough 
Observed plasma concentration at the end of each dosing interval 
DLT 
Dose-Limiting Toxicity 
DOR 
Duration of Response 
EDC 
Electronic Data Capture 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG PS 
Easter Cooperative Oncology Group Performance Score 
EFS 
Event-free Survival 
EOS 
End of Study 
EOT 
End of Treatment 
ITT 
Intention-to-Treat 
IV 
Intravenously 
LLOQ 
Lower Limit of Quantification 
KM 
Kaplan-Meier 
MLF 
Morphologic Leukemia-Free 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated acquisition scan 


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NCI 
National Cancer Institute 
OS 
Overall Survival 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
p.o. 
Taken orally 
PP 
Per Protocol 
PR 
Partial Response 
PT 
Preferred Term 
RP2D 
Recommended Phase 2 Dose 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SC 
Subcutaneously 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Table, figure, and listing. 
T-HALF 
Terminal phase half-life expressed in time units 
Tmax 
Time to maximum plasma concentration 
Vss/F 
The apparent volume of distribution