A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer in Patients With a KRAS Mutation
Phase: PHASE1
Conditions: Metastatic Colorectal Cancer, KRAS Gene Mutation
Sponsor: Cardiff Oncology

Protocol Number: TROV-054 
 
Official Title: A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with FOLFIRI and 
Bevacizumab for Second-Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS 
Mutation 
 
NCT Number: NCT03829410 
 
Document Date: 27 October 2021 

Clinical Study Report 
Confidential 
Sponsor Name: Cardiff Oncology, Inc. 
 
Study Number: TROV-054 
 
 
  
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
 
Protocol Amendment 1, dated 26 Oct 2021 
Summary of Changes with Protocol Amendment 1, dated 26 Oct 2021 

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SUMMARY OF CHANGES: PROTOCOL AMENDMENT v2.0 
 
Version 2.0 Date: 26 Oct 2021 
 
SUMMARY AND RATIONALE 
Key reasons for the protocol amendment included: 
• 
The completion of Phase 1b, with the determination of the RP2D and MTD of 15 mg/m2, which are identical. 
• Sample size for Phase 2 increased from 26 to approximately 80 patients. 
• 
Primary, secondary, and exploratory statistical endpoints and analyses were revised. Safety analyses revised. 
• 
Inclusion and Exclusion Criteria were revised. 
• 
Confirmation by liquid biopsy of KRAS mutation status is not required for study eligibility. Already established requirement for 
documentation of KRAS mutation in exon 2, 3, or 4 in primary tumor or metastasis, assessed by a CLIA-certified laboratory, is still required. 
• 
Patients must have FFPE tumor tissue (newly acquired or archival) for study eligibility. 
• 
PK sampling times revised and new food effect substudy added with sampling times. 
• 
Revised schedule for collection of circulating tumor DNA (ctDNA) and deleted collection of circulating tumor cells (CTCs). 
• 
Disease assessment (radiographic imaging) and re-staging revised and clarified. 
• 
Made end of study (EOS) visit an end of treatment (EOT) visit instead. 
• 
Study visit following last dose of onvansertib, previously referred to as the end of study (EOS) visit, now renamed end of treatment (EOT) 
visit. 
• 
Definition of EOS (completion of study) consistently revised to once patients have been followed for 1 year after EOT rather than after last 
dose. 
• 
Added additional information regarding follow-up (e.g., radiographic scanning, collection of new-anti-cancer treatment, defined patients to 
be followed as any ongoing from Phase 1b and all from Phase 2, etc). 
• 
Deleted requirement that all AEs must be attributed to study drug unless there is a reasonably acceptable alternate cause for the AEs. 
• 
In the event of defined toxicities, both the 5-FU bolus and/or leucovorin may be eliminated in subsequent cycles at the Investigator’s 
discretion. Guidance was also provided if intolerance of individual drugs from the FOLFIRI + bevacizumab regimen is observed. 
• 
Dose reductions for onvansertib were added. Dose delays for onvansertib were revised, including from patients who experience any Grade 2 
or higher AE to any Grade 3 or higher AE considered related to the study drug will have their next dose of onvansertib withheld. 
• 
Concomitant medications and treatments were clarified and new prohibited medications added and others deleted. 
A detailed table summarizing each revision (previous wording and changes to wording) incorporated into Protocol TROV-054, Version 2.0, dated 
11 Oct 2021, and the rationale for each change follows. Corresponding changes have been made to the Protocol Synopsis and List of Abbreviations 

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and are not listed separately. This table does not contain minor administrative adjustments or corrections that do not have an impact on study conduct 
or subject safety (e.g., corrections of grammar or spelling). 
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Rationale 
1. 
 
Title Page 
--Trovagene, Inc. 
--
 
 
--Version number 1.4 
--Cardiff Oncology, Inc. 
--
 
 
--Version number 2.0 
Change in Sponsor name and 
contact information, version 
number 
2. 
 
Protocol 
Approvals 
--
 
 
--
 
 
--
 
 
--
 
 
Change to signatories/titles 
3. 
 
Synopsis 
--Number of study sites approximately 3 
--Principal Investigator: 
 
 
--Number of study sites approximately 7 
--Principal Investigator: 
 
 
Increased number of sites and 
changed Principal Investigator 
4. 
 
Study 
Administrative 
Structure 
--Investigator: 
 
--Contract Research Organization: 
 
--Medical Monitor: 
 
 
--Principal Investigator: 
 
 
--Contract Research Organization: 
 
--Medical Monitor: 
 
 
Edited to reflect administrative 
updates. 
5. 
 
Section 1.1  
N/A 
Section 1.1 (Background) Colorectal 
Cancer 
Although an agent specifically targeting 
mutated KRAS has been approved for the 
treatment of cancer, this agent (sotorasib, 
Lumakras) is approved only for the 
treatment of non-small cell lung cancer 
(NSCLC) harboring a single specific KRAS 
mutation (G12C). In clinical trials, the 
activity of sotorasib in G12C-mutated CRC 
was substantially lower than that of G12C-
mutated NSCLC: ORR of 7.1% and 32.2%, 
respectively, in a Phase 1 study of sotorasib 
in patients with solid tumors with the 
KRAS G12C mutation (Hong 2020). Thus, 
additional treatments are needed for patients 
Background information 
updated about treatments for 
cancers with KRAS mutation. 

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with KRAS-mutated CRC. 
6. 
 
Section 1.2 
Section 1.2 (Background) Onvansertib 
--Two additional clinical studies… 
Section 1.2 (Background) Onvansertib 
--Three additional clinical studies…and 
Study CRDF-001 (A Phase 2 clinical study 
of onvansertib in combination with 
nanoliposomal irinotecan, leucovorin, and 
5-FU for the second-line treatment of 
patients with metastatic pancreatic ductal 
adenocarcinoma). 
Background information 
updated for onvansertib from 
two to three studies. 
7. 
 
Section 2.1 
Section 2.1 Objectives 
Section 2.1.1 Phase1b 
--To evaluate the DLTs and MTD or RP2D 
of onvansertib… 
 
Section 2.1.2 Phase 2 
--To assess the preliminary efficacy of  
onvansertib… 
In the Phase 2 segment of the trial, 
confirmation of a KRAS mutation will be 
obtained by liquid biopsy during screening 
to confirm eligibility. 
Section 2.1 Objectives 
Section 2.1.1 Phase1b 
--To evaluate the DLTs and MTD of the 
recommended Phase 2 dose (RP2D) of 
onvansertib… 
Section 2.1.2 Phase 2 
--To assess the efficacy and safety of 
onvansertib … 
--Revisions to objectives reflect 
completion of Phase 1b and 
need to select RP2D and to 
fully evaluate both efficacy and 
safety.  
--Deleted Phase 2 objective for 
confirmation of a KRAS 
mutation by liquid biopsy 
during screening to confirm 
eligibility. 
8. 
 
Section 2.2.1 
Section 2.2 Endpoints 
Section 2.2.1 Primary 
The primary endpoint of Phase 2 is the 
objective response rate (ORR) by Response 
Evaluation Criteria In Solid Tumors 
Version 1.1 (RECIST v1.1) criteria in 
patients who receive at least 1 cycle 
(2 courses) of onvansertib… 
Section 2.2 Endpoints 
Section 2.2.1 Endpoints for the 
Completed Phase 1b Portion of the Study 
Primary 
The primary endpoint of Phase 2 is the 
objective response rate (ORR) by Response 
Evaluation Criteria In Solid Tumors 
Version 1.1 (RECIST v1.1) in patients who 
receive at least 1 cycle (28 days/4 weeks of 
treatment) of onvansertib… 
--Primary endpoint of Phase 2 
clarified from 1 cycle (2 
courses) to 1 cycle 
(28 days/4 weeks of treatment) 
of onvansertib.  
--Added population for analysis 
(treated-patient).. 

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9. 
 
Section 2.2.2 
Section 2.2 Endpoints 
Section 2.2.2 Secondary 
The following secondary endpoints will be 
explored in the study population: 
• 
Preliminary efficacy defined as 
complete response (CR) plus 
partial response (PR) plus SD 
• 
AEs, according to the NCI-
CTCAE version 5.0  
• 
Progression-free survival (PFS) 
defined from the date of first drug 
administration to progression or 
death, whichever occurs first 
• 
Reduction in KRAS allelic burden 
on liquid biopsies 
Section 2.2 Endpoints 
Section 2.2.2 Endpoints for the Phase 2 
Portion of the Study 
Secondary 
The following secondary endpoints will be 
explored. All efficacy evaluations will be 
conducted in the treated-patient population: 
• 
Disease Control Rate (DCR) 
defined as complete response (CR) 
plus partial response (PR) plus 
stable disease (SD) 
• 
Safety as assessed primarily by 
AEs, according to the NCI-
CTCAE version 5.0 (conducted in 
the safety population consisting of 
all enrolled patients) 
• 
Progression-free survival (PFS) 
defined from the date of first drug 
administration to progression or 
death, whichever occurs first 
• 
Duration of response (DOR) 
defined from the date of first 
response (CR or PR) to PD or 
death, whichever occurs first 
• 
Overall survival (OS)  
• 
Reduction in KRAS allelic burden 
on liquid biopsies 
• 
PK of onvansertib in combination 
with FOLFIRI and bevacizumab  
--Secondary endpoints of 
Phase 2 revised to clarify 
population for efficacy 
analyses (treated-patient). 
--Clarified preliminary efficacy 
endpoint to be a DCR endpoint. 
--Added endpoints of DOR, 
OS, and PK of onvansertib in 
combination with FOLFIRI and 
bevacizumab 

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10.  
Section 2.2.2 
Section 2.2 Endpoints 
Section 2.2.3 Exploratory 
• 
Target inhibition of PLK1 based 
on circulating tumor cells (CTCs)  
• 
Use of circulating tumor cells and 
circulating tumor 
deoxyribonucleic acid (DNA) to 
evaluate relevant biomarkers 
correlated with patient response 
• 
Use of archival tumor tissue (if 
available) to evaluate genomic 
profiles (DNA/ribonucleic acid 
[RNA]) associated with patient 
response 
Section 2.2 Endpoints 
Section 2.2.2 Endpoints for the Phase 2 
Portion of the Study 
Exploratory 
• 
Use of circulating tumor DNA 
(ctDNA) and carcinoembryonic 
antigen (CEA) to evaluate relevant 
biomarkers correlated with patient 
response 
• 
Use of formalin-fixed, paraffin-
embedded (FFPE) tumor tissue to 
evaluate baseline genomic profiles 
(DNA/RNA) associated with 
patient response 
• 
Preliminary assessment of food 
effect 
Revised exploratory endpoints, 
including addition pertaining to 
food effect 
11.  
Section 3.1 
3.1 Overall Study Design and Plan 
This study will consist of a Screening 
Period, a Treatment Period conducted in 
28-day cycles (there are two 14-day 
courses of treatment in each 28-day cycle), 
End-of-Study (EOS) assessments, and a 
Follow-Up Period. 
Subjects will continue treatment in the 
study (Cycle 1, Cycle 2, Cycle 3, etc.) until 
disease progression (PD) or death, 
unacceptable toxicity, withdrawal of 
consent, or discontinuation based on 
Investigator discretion. 
3.1 Overall Study Design and Plan 
This study will consist of a Screening 
Period, a Treatment Period conducted in 28-
day cycles, End of Treatment (EOT) 
assessments, and a Follow-up Period for up 
to 1 year after EOT. Completion of 1 year 
of follow-up constitutes completion of the 
study (EOS). 
Patients will continue treatment in the study 
(Cycle 1, Cycle 2, Cycle 3, etc.) until 
disease progression (PD) or death, 
unacceptable toxicity, withdrawal of 
consent, or discontinuation based on 
Investigator discretion. Patients will 
continue in follow up until study 
completion (defined as 1 year of follow-up 
after EOT), death, or withdrawal of consent 
for further follow-up. Patients may continue 
on treatment after radiographic progression 
if, in the judgment of the treating physician: 
the patient is benefitting from treatment; the 
--Revised two 14-day courses 
of treatment in each 28-day 
cycle to 28 day-cycle, added 
EOT assessments, and defined 
EOS.  
--Defined study completion and 
added criteria for continuing on 
treatment after radiographic 
progression 
--Added a preliminary food 
effect study in a subgroup of 
patients. 

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patient has no ongoing Grade 2 or greater 
AEs that are attributed to study drugs; and 
there are no other therapies available for 
treatment of the patient’s cancer.  
A subgroup of patients (at least 12 patients) 
enrolled in the Phase 2 portion of the study 
will participate in a preliminary food effect 
study. See Section 6.2.11.4 for more details. 
12.  
Section 3.1.1 
3.1 Overall Study Design and Plan 
Section 3.1.1 Screening Period 
In the Phase 2 segment of the trial, 
confirmation of a KRAS mutation will be 
obtained by liquid biopsy during screening 
to confirm eligibility. 
3.1 Overall Study Design and Plan 
Section 3.1.1 Screening Period 
In the Phase 2 segment of the study, under 
protocol version 2.0, FFPE tumor tissue 
must be available for submission. If 
archival tissue is not available, patients 
must undergo a biopsy at screening to 
obtain tissue for eligibility. 
--Deleted requirement for 
confirmation of a KRAS 
mutation by liquid biopsy 
during screening to confirm 
eligibility. 
--Added that patient must have 
FFPE tumor tissue (newly 
acquired or archival) in order to 
be enrolled. 
13.  
Section 3.1.2 
3.1 Overall Study Design and Plan 
Section 3.1.2 Treatment: Phase 1 
The starting dose level of onvansertib will 
be 12 mg/m2/day for Days 1 to 5 of each 
14-day treatment course (there are two 
14-day treatment courses in each 28-day 
cycle). 
3.1 Overall Study Design and Plan 
Section 3.1.2 Treatment Period for the 
Completed Phase 1b Portion of the Study 
The starting dose level of onvansertib was 
12 mg/m2/day for Days 1 to 5 and 15 to 
19 of each 28-day treatment cycle. 
Dosing and days used were 
clarified. 
14.  
Section 3.1.2.1 
3.1 Overall Study Design and Plan 
Section 3.1.2.1 Dose Escalation and 
Dose-limiting Toxicity 
• 
If 2 or more DLTs are observed in a 
3-patient or 6-patient cohort at a 
given dose level, the MTD has been 
exceeded, dose escalation will be 
stopped, and up to 3 additional 
patients will be enrolled at the next 
lower dose, if it exists, unless 6 
patients have already been treated at 
that prior dose. 
3.1 Overall Study Design and Plan 
Section 3.1.2.1 Dose Escalation and Dose-
limiting Toxicity 
• 
If 2 or more DLTs were observed in 
a 3-patient or 6-patient cohort at a 
given dose level, the MTD was 
deemed to have been exceeded, dose 
escalation was stopped, and up to 3 
additional patients were enrolled at 
the next lower dose. 
Deleted the part about unless 
6 patients have already been 
treated at that prior dose as this 
did not occur. 

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15.  
Section 3.1.3 
3.1 Overall Study Design and Plan 
Section 3.1.3 Treatment: Phase 2 
Phase 2 will start once the RP2D is 
identified. Final determination of the RP2D 
will be based on evaluating all available 
data from the dose escalation Phase 1b 
portion of the trial, including low-grade, 
but chronic toxicities, dose reductions 
and/or missed doses of onvansertib. In the 
Phase 2 segment of the trial, confirmation 
of a KRAS mutation will be obtained by 
liquid biopsy during screening to confirm 
eligibility. 
3.1 Overall Study Design and Plan 
Section 3.1.3 Treatment Period for the 
Phase 2 Portion of the Study 
Phase 2 commenced once 15 mg/m2 was 
selected as the RP2D (is also the MTD). 
The sample size of the Phase 2 portion of 
the study has been increased from 26 
patients to approximately 80 patients in 
order to further evaluate the safety and 
efficacy of the onvansertib 15 mg/m2 dose. 
--Revised to show that 
15 mg/m2 was selected as the 
RP2D (is also the MTD). 
--Sample size for Phase 2 
increased from 26 to 
approximately 80 patients. 
--Deleted requirement for 
confirmation of a KRAS 
mutation by liquid biopsy 
during screening to confirm 
eligibility. 
16.  
Section 3.1.3.1 
3.1 Overall Study Design and Plan 
Section 3.1.3.1 Recommended Phase 2 
Dose 
The RP2D is the highest dose at which 1 or 
fewer of 6 patients experience a DLT 
during Cycle 1 of therapy (the definition of 
DLT is provided in Section 7.1.4). If 2 or 
more DLTs are observed at the next highest 
dose, this dose is also referred to as the 
MTD. If no higher dose level has been 
studied, the RP2D is also referred to as the 
highest treatment dose (HTD). 
3.1 Overall Study Design and Plan 
Section 3.1.3.1 Recommended Phase 2 
Dose 
The RP2D is the highest dose at which 1 or 
fewer of 6 patients experienced a DLT 
during Cycle 1 of therapy in the Phase 1b 
portion of the study (the definition of DLT 
is provided in Section 7.1.4). Determination 
of the RP2D was based on evaluating all 
available data from the dose escalation 
Phase 1b portion of the study, including 
low-grade, but chronic toxicities, dose 
reductions, and/or missed doses of 
onvansertib. Based on results of the 
Phase 1b portion of this study, 
15 mg/m2/day was selected as the RP2D 
(and is also the MTD).  
Revised to reflect RP2D 
(15 mg/m2/day and is also the 
MTD) with completion of 
Phase 1b. 
17.  
3.1.3.2 
3.1 Overall Study Design and Plan 
Section 3.1.3.2 Dose Modifications 
In Phase 1b and 2, should a subject 
experience a Grade ≥2 neutropenia or 
neutropenic fever during treatment, a dose 
modification will be allowed for the 
treatment component(s) deemed probable 
3.1 Overall Study Design and Plan 
Section 3.1.3.2 Dose Modification 
Guidelines 
For those patients enrolled in the Phase 2 
portion of the study who receive the 
optional (at Investigator’s discretion) 5-FU 
bolus and leucovorin, occurrence of a 
--Revised so that in the event 
of defined toxicities, both the 
5-FU bolus and/or leucovorin 
may be eliminated in 
subsequent cycles at the 
Investigator’s discretion. 
--Guidance was provided if 

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for the etiology of the toxicity. In the case 
of the 5-FU component, in subsequent 
cycles and according to institutional 
guidelines, dose modification including 
elimination of the 5-FU bolus infusion will 
be allowed. 
Dose modifications for onvansertib are 
allowed in accordance with Section 5.3.1. 
Dose adjustments for FOLFIRI and 
bevacizumab are allowed in accordance 
with Section 5.3.2 and will be based on 
dose modification guidelines provided in 
Table 5-4; additional details are provided in 
the relevant package insert(s) (Leucovorin 
Prescribing Information; Fluorouracil 
Prescribing Information; Camptosar 
Prescribing Information; (Avastin 
Prescribing Information). Any necessary 
dose level reductions for onvansertib or for 
FOLFIRI and bevacizumab should follow 
the dose levels outlined in Table 5-1 and 
Table 5-3. 
Grade ≥ 2 neutropenia or neutropenic fever 
that is determined to be caused or 
exacerbated by the administration of the 
5-FU bolus and/or leucovorin may have the 
5-FU bolus and/or leucovorin eliminated in 
subsequent cycles, at the Investigator’s 
discretion. If individual drugs from the 
FOLFIRI + bevacizumab regimen are 
discontinued because of patient intolerance, 
patients may remain on onvansertib and the 
remaining drugs from the FOLFIRI + 
bevacizumab regimen, provided that either 
5-FU or irinotecan (or both) is continued. 
Onvansertib may not be administered as a 
single agent or with bevacizumab alone, as 
there are no data to support either of these 
treatment scenarios. 
Dose modifications for onvansertib are 
allowed in accordance with Section 5.3.1. 
Dose adjustments for FOLFIRI and 
bevacizumab are allowed in accordance 
with Section 5.3.2; additional details are 
provided in the relevant package insert(s) 
(Leucovorin Prescribing Information; 
Fluorouracil Prescribing Information; 
Camptosar Prescribing Information; 
Avastin Prescribing Information). 
intolerance of individual drugs 
from the 
FOLFIRI + bevacizumab 
regimen is observed. 
18.  
Section 3.1.4 
Section 3.1.4 End of Study 
The EOS visit should occur within 28 days 
(± 5 days) after the last dose of onvansertib 
is administered, and should include the 
assessments outlined in the Schedule of 
Assessments (Table 6 1). The EOS visit is 
described further in Section 6.2.12. 
Section 3.1.4 End of Treatment 
The EOT visit should occur within 28 days 
(± 5 days) after the last dose of onvansertib 
is administered, and should include the 
assessments outlined in the Schedule of 
Assessments (Table 6-1). The EOT visit is 
described further in Section 6.2.13. 
Study visit following last dose 
of onvansertib, previously 
referred to as the end of study 
(EOS) visit, now renamed end 
of treatment (EOT) visit.   
19.  
Section 3.1.5 
Section 3.1.4 End of Study 
The EOS visit should occur within 28 days 
(± 5 days) after the last dose of onvansertib 
Section 3.1.5 Follow-up and End of Study 
Patients (any ongoing from Phase 1b and 
those from Phase 2) will be followed for 
Added additional information 
regarding follow-up (e.g., who 
will be followed, radiographic 

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is administered, and should include the 
assessments outlined in the Schedule of 
Assessments (Table 6-1). The EOS visit is 
described further in Section 6.2.12. 
overall survival for 1 year after EOT (alive 
versus deceased with dates). Patients who 
are taken off onvansertib, but remain on 
FOLFIRI + bevacizumab or any 
component(s) of the FOLFIRI + 
bevacizumab regimen will also continue 
follow-up for radiographic disease 
progression via CT/MRI scans every 
8 weeks. Follow-up information regarding 
new anti-cancer treatment, such as type of 
treatment and duration of treatment, will be 
collected approximately every 8 weeks 
during the 1 year follow-up period. Once 
patients have been followed for 1 year after 
EOT, they will be considered to have 
completed the study (EOS). 
scanning, collection of new-
anti-cancer treatment, 
definition of completion of 
study [EOS] as once patients 
have been followed for 1 year 
after EOT). 
20.  
Section 3.2 
Section 3.2 Study Duration 
The Screening Period will be up to 28 days 
prior to the first dose of onvansertib. 
Patients will continue treatment in the 
study (Cycle 1, Cycle 2, Cycle 3, etc.) until 
PD or death, unacceptable toxicity, 
withdrawal of consent, or discontinuation 
based on Investigator discretion. 
Section 3.2 Study Duration 
The Screening Period will be up to 28 days 
prior to the first dose of onvansertib. 
Patients will continue treatment in the study 
(Cycle 1, Cycle 2, Cycle 3, etc.) until PD or 
death, unacceptable toxicity, withdrawal of 
consent, or discontinuation based on 
Investigator discretion. Patients (any 
ongoing from Phase 1b and all from 
Phase 2) will be followed for overall 
survival for 1 year after EOT (alive versus 
deceased with dates). Patients who are 
taken off onvansertib, but remain on 
FOLFIRI + bevacizumab or any 
component(s) of the FOLFIRI + 
bevacizumab regimen will also continue 
follow-up for radiographic disease 
progression via CT/MRI scans every 
8 weeks. Follow-up information regarding 
new anti-cancer treatment, such as type of 
treatment and duration of treatment, will be 
collected approximately every 8 weeks 
Added additional information 
regarding follow-up, 
radiographic scanning during 
follow-up, collection of new-
anti-cancer treatment, and 
definition of completion of 
study (EOS) as being once 
patients have been followed for 
1 year after EOT. 

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during the 1 year follow-up period. Once 
patients have been followed for 1 year after 
EOT, they will be considered to have 
completed the study (EOS). 
21.  
Section 4.1.1 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #2: In the Phase 2 
segment of the trial, confirmation of a 
KRAS mutation will be obtained by liquid 
biopsy during screening to confirm 
eligibility. 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #2: N/A 
Removed part of Criterion #2 
during Phase 2 for 
confirmation of a KRAS 
mutation by liquid biopsy 
during screening to confirm 
eligibility. 
22.  
Section 4.1.1 
Section 4.1.1 Inclusion Criteria 
Inclusion Criteria #13: If archival tumor 
tissue is available, the subject must give 
consent to having it used for future 
correlative marker assays. Confirmation of 
the availability and consent for use of 
archival tumor tissue does not have to 
occur prior to enrollment. Refer to Section 
6.2.10 for guidelines regarding provision of 
archival tumor tissue samples. 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #3: FFPE tumor tissue 
must be available for submission to a 
central laboratory in order for a patient to 
be eligible. If no archival tissue biopsy is 
available the patient must have a biopsy 
obtained at screening. Refer to Section 6.2.4 
for guidelines regarding provision of tumor 
tissue samples. 
Deleted Inclusion Criteria #13 
and replaced with Inclusion 
Criteria #3. Patient must have 
FFPE tumor tissue (newly 
acquired or archival) in order to 
be eligible. 
23.  
Section 4.1.1 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #6: Subject is not 
receiving any other cancer therapy. Patients 
participating in surveys or observational 
studies are allowed. 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #7: Subject is not 
receiving any other standard-of-care or 
experimental cancer therapy. Patients 
participating in non-interventional surveys 
or observational studies are allowed. 
Clarification 
24.  
Section 4.1.1 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #7: Has failed treatment 
or is intolerant of fluoropyrimidine and 
oxaliplatin with or without bevacizumab. 
a. 
All patients must have received a 
minimum of 6 weeks of the first-line 
regimen that included oxaliplatin and a 
fluoropyrimidine with or without 
bevacizumab in the same cycle. 
Treatment failure is defined as 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #8: Has failed treatment 
or is intolerant of fluoropyrimidine and 
oxaliplatin with or without bevacizumab. 
a. 
Patients must have had systemic 
therapy within 180 days of the 
screening visit, but can have no anti-
cancer therapy within 28 days of the 
planned first day of treatment on study. 
Inclusion subcriteria were 
revised and clarified, including 
new additions. 

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radiologic progression during or 
< 6 months after the last dose of first-
line therapy. 
b. Patients who show tumor progression 
while on maintenance therapy with a 
fluoropyrimidine with or without 
bevacizumab after prior 
fluoropyrimidine-oxaliplatin with or 
without bevacizumab induction 
therapy are eligible. Rechallenge with 
oxaliplatin is permitted and will be 
considered part of the first-line 
regimen for metastatic disease, with 
both initial oxaliplatin treatment and 
subsequent rechallenge being 
considered as one regimen. 
c. 
Patients who received 
oxaliplatin/fluoropyrimidine-based 
neoadjuvant or adjuvant therapy and 
have disease recurrence or progression 
> 6 months from their last dose of 
neoadjuvant or adjuvant treatment (or 
> 6 months from surgery if no 
adjuvant therapy was administered) 
will be required to receive 
fluoropyrimidine/oxaliplatin-based 
therapy with or without bevacizumab 
for metastatic disease. 
d. For patients with rectal cancer, 
sequential neoadjuvant and adjuvant 
therapy will count as a single systemic 
regimen. 
e. Patients who discontinued first-line 
therapy because of toxicity may be 
enrolled for as long as progression 
occurred < 6 months after the last dose 
of first-line therapy. 
b. Patients must have received oxaliplatin 
based chemotherapy with or without 
bevacizumab (≥ 6 weeks in duration). 
Patients who received maintenance 
therapy with fluoropyrimidines are 
eligible with or without rechallenge 
with oxaliplatin in combination with 
fluoropyrimidines. 
c. 
Patients who received 
oxaliplatin/fluoropyrimidine-based 
neoadjuvant or adjuvant therapy and 
have disease recurrence or progression 
> 6 months from their last dose of 
neoadjuvant or adjuvant treatment (or 
> 6 months from surgery if no adjuvant 
therapy was administered) will be 
required to have received 
fluoropyrimidine/oxaliplatin-based 
therapy with or without bevacizumab 
as first-line treatment for metastatic 
disease. 
d. Patients must not have received prior 
irinotecan. 
e. 
For patients with rectal cancer, 
sequential neoadjuvant and adjuvant 
therapy will count as a single systemic 
regimen for advanced disease. 
f. 
Patients who discontinued first-line 
therapy because of toxicity are eligible 
as long as progression occurred < 
6 months after the last dose of first-line 
therapy. 

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25.  
Section 4.1.1 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #9: For a male or a 
woman of child-bearing potential 
(WOCBP): Must agree to use 
contraception… 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #10: For a woman of 
child-bearing potential (WOCBP) or a male 
with a female partner who is a WOCBP: 
Must agree to use contraception… 
Revised males to males with a 
female partner who is a 
WOCBP. 
26.  
Section 4.1.1 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #11: Imaging computed 
tomography (CT)/magnetic resonance 
imaging (MRI) of chest/abdomen/pelvis or 
other scans as necessary to document all 
sites of disease performed within 28 days 
prior to the first dose of onvansertib. Only 
patients with measurable disease are 
eligible for enrollment. 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #12: Imaging computed 
tomography (CT)/magnetic resonance 
imaging (MRI) of chest/abdomen/pelvis or 
other scans as necessary to document all 
sites of disease performed within 28 days 
prior to the first dose of onvansertib. Only 
patients with measurable disease as defined 
per RECIST v1.1 are eligible for 
enrollment. CT is the preferred imaging 
modality, but MRI is also accepted. 
Revised to specify measurable 
disease as per RECIST v 1.1 
and that CT is the preferred 
imaging modality, but MRI is 
accepted. 
27.  
Section 4.1.1 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #12, Table 4-1 
Acceptable Organ Function: 
--Bilirubin: ≤ 1.5 ULN OR ≤ 2.0 ULN in 
presence of liver metastases 
Section 4.1.1 Inclusion Criteria 
Inclusion Criterion #13, Table 4-1 
Acceptable Organ Function:  
--Bilirubin: ≤ 1.5 ULN OR ≤ 2.0 mg/dL in 
presence of liver metastases 
Revised bilirubin criterion. 
28.  
Section 4.1.2 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #2: Anti-cancer 
chemotherapy or biologic therapy 
administered within 4 weeks prior to the 
first dose of study drug. 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #2: Anti-cancer 
chemotherapy or biologic therapy 
administered within 28 days prior to the 
first dose of study drug. 
Revised from 4 weeks to 
28 days 
29.  
Section 4.1.2 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #4: Major surgery 
within 6 weeks prior to randomization. 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #4: Major surgery 
within 6 weeks prior to enrollment. 
Revised from randomization to 
enrollment. 
30.  
Section 4.1.2 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #5: Untreated brain 
metastasis. 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #5: Untreated or 
symptomatic brain metastasis. 
Added symptomatic brain 
metastasis. 

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31. 
Section 4.1.2 
Section 4.1.2 Exclusion Criteria 
N/A 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #9b: Known active 
infection with SARS-CoV-2 
Added known active infection 
with SARS- CoV-2. 
32. 
Section 4.1.2 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #13: Patients with a 
history of other malignancies except: 
adequately treated non-melanoma skin 
cancer, curatively treated in-situ cancer of 
the cervix,… 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #13: Patients with a 
history of other malignancies except: 
adequately treated non-melanoma skin 
cancer, curatively treated in-situ cancer of 
the cervix or prostate,… 
Added that curatively treated 
in-situ cancer of the prostate is 
an exception to exclusion of 
other malignancies. 
33. 
Section 4.1.2 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #17: In the case of 
potentially correctible causes of QT 
prolongation, (e.g., medications, 
hypokalemia),… 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #17: In the case of 
potentially correctible causes of QT 
prolongation that are readily corrected (e.g., 
medications, hypokalemia),… 
Clarification 
34. 
Section 4.1.2 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #18: Planned 
concomitant use of medications known to 
prolong the QT/QTc interval. 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #18: Planned 
concomitant use of medications known to 
prolong the QT/QTc interval according to 
institutional guidelines. 
Clarification 
35. 
Section 4.1.2 
Section 4.1.2 Exclusion Criteria 
N/A 
Section 4.1.2 Exclusion Criteria 
Exclusion Criterion #21: Use of strong 
CYP3A4 or UGT1A1 inhibitors or strong 
CYP3A4 inducers. Patients currently 
receiving these agents who are able to 
switch to alternate therapy are not excluded. 
Inhibitors should be stopped at least 1 week 
prior to the first dose of protocol therapy 
and inducers should be stopped at least 2 
weeks prior to initiation of protocol therapy. 
Added exclusion criteria for 
use of strong CYP3A4 or 
UGT1A1 inhibitors or strong 
CYP3A4 inducers. 
36. 
Section 4.2 
4.2 Removal of Patients From Therapy 
or Assessment 
•
Entry into another investigational
clinical study or start of additional
anticancer therapy
4.2 Removal of Patients From Therapy 
or Assessment 
•
Entry into another investigational
clinical study or start of additional
anticancer therapy (participation in
--Clarifications 
--Revised EOS to EOT 
--Guidance was provided if 
intolerance of individual drugs 
from the FOLFIRI + 
bevacizumab regimen is 

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•
In the event that a patient is withdrawn
from the study,…
•
An EOS reason must be recorded
If a patient is discontinued from the study 
for any reason, every effort must be made 
to perform all EOS assessments 
(Section 6.1)… 
N/A 
non-interventional surveys or 
observational studies are allowed) 
•
In the event that a patient is withdrawn
from treatment and/or the study,…
•
An EOT reason must be recorded
If a patient is discontinued from treatment 
or the study for any reason, every effort 
must be made to perform all EOT 
assessments (Section 6.1)… 
If individual drugs from the FOLFIRI + 
bevacizumab regimen are discontinued 
because of patient intolerance, patients may 
remain on onvansertib and the remaining 
drugs from the FOLFIRI + bevacizumab 
regimen, provided that either 5-FU or 
irinotecan (or both) is continued. 
Onvansertib may not be administered as a 
single agent or with bevacizumab alone, as 
there are no data to support either of these 
treatment scenarios. See also 
Sections 3.1.3.2 and 5.3. 
observed. 
37. 
Section 5.2.1 
5.2.1 
Onvansertib Administration 
The starting dose of onvansertib will be 
12 mg/m2 administered PO on Day 1 
through Day 5 every 14 days (there are two 
14-day courses of treatment in each 28 day
cycle).
Table 5-1 Dose Levels of Onvansertib, all
rows under Frequency said Days 1 to 5 of
each 14-day course.
5.2.1 
Onvansertib Administration 
Completed Phase 1b Portion of the Study 
The starting dose of onvansertib was 
12 mg/m2 administered PO on Day 1 
through Day 5 and Day 15 through Day 19 
of each 28-day treatment cycle. 
Table 5-1 Dose Levels of Onvansertib in 
the Completed Phase 1b Portion of the 
Study, all rows under Frequency say Days 1 
to 5 and 15 to 19 of each 28-day cycle. 
Clarification 
38. 
Section 5.2.1 
5.2.1 
Onvansertib Administration 
N/A 
5.2.1 
Onvansertib Administration 
Phase 2 Portion of the Study 
Subdivided into completed 
Phase 1b and Phase 2 sections. 

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Based on results of the Phase 1b portion of 
this study, 15 mg/m2/day was selected as 
the RP2D (also the MTD). The RP2D and 
dose modifications for onvansertib for the 
Phase 2 portion of the study are shown in 
Table 5-2. 
Note: Table 5-2 is not reproduced in this 
Summary of Changes, but shows RP2D of 
15 mg/m2 with dose reductions to 12 mg/m2 
QD and 6 mg/m2 QD with all frequency as 
Days 1 to 5 and 15 to 19 of each 28-day 
cycle. 
New subsection added for 
Phase 2 dosing, along with 
corresponding table. 
39.  
Section 5.2.1.1 
Section 5.2.1.1 Food Restrictions 
N/A 
Section 5.2.1.1 Food Restrictions 
See Section 6.2.11.4 for information on PK 
food effect substudy. 
Added cross-reference to 
section on food effect substudy  
40.  
Section 5.2.1.2 
5.2.1.2 Dose Rounding 
Dose rounding is to the nearest 5 mg, 
rounded up for dose calculations ending in 
0.5 to 0.9. (For example, if 18 mg/m2 dose 
is calculated at 32.4 mg, the dose would be 
rounded down to 30 mg, provided as one 
20 mg capsule and two 5 mg capsules of 
onvansertib). 
5.2.1.2 Dose Rounding 
Dose rounding is to the nearest 5 mg, 
rounded up for dose calculations ending in 
0.5 to 0.9. For example, at the RP2D of 
15 mg/m2 the daily dose is calculated at 
27 mg and would be rounded up to 30 mg, 
provided as one 20 mg capsule and two 
5 mg capsules of onvansertib. 
Dose rounding revised to 
reflect RP2D dose of 15 mg/m2 
41.  
Section 5.2.2 
5.2.2 FOLFIRI and Bevacizumab 
Administration 
Note: Table 5-2, Dose Levels of FOLFIRI 
and Bevacizumab, is not reproduced in this 
Summary of Changes, but shows frequency 
of bevacizumab, irinotecan, leucovorin, 
and 5-FU (bolus) as being given on Day 1 
of each 14-day course and 5-FU infusion as 
beginning on Day 1 of each 14-day course. 
A Note to table said: One cycle is 28 days. 
There are two 14-day courses of treatment 
in each 28 day cycle. 
5.2.2 FOLFIRI and Bevacizumab 
Administration 
Completed Phase 1b Portion of the Study 
Note: Table 5-3 (revised from Table 5-2), 
Doses of FOLFIRI and Bevacizumab in the 
Completed Phase 1b Portion of the Study, is 
not reproduced in this Summary of 
Changes, but shows frequency of 
bevacizumab, irinotecan, leucovorin, and 
5-FU (bolus) as being given on Days 1 and 
15 of each 28-day cycle and 5-FU infusion 
--Clarifications 
--Subdivided into completed 
Phase 1b and Phase 2 sections. 
For Phase 1b, clarified dosing 
in FOLFIRI and Bevacizumab 
Administration section for 
Completed Phase1b Portion of 
the Study. 

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as beginning on Days 1 and 15 of each 
28-day cycle.
--Deleted Note: One cycle is 28 days. There
are two 14-day courses of treatment in each
28 day cycle.
--Footnote “a” was added to 5-FU bolus
that dose modifications including
elimination of the 5-FU bolus infusion were
allowed.
42. 
Section 5.2.2 
5.2.2 FOLFIRI and Bevacizumab 
Administration 
N/A 
5.2.2 FOLFIRI and Bevacizumab 
Administration 
Phase 2 Portion of the Study 
After evaluation of safety data from the 
Phase 1b portion of the study, the 5-FU 
bolus and leucovorin will be optional, at the 
investigator’s discretion, for any patients in 
the Phase 2 portion of the study enrolled 
under version 2.0 of the protocol. All 
patients in the Phase 2 portion will receive 
the 46-hour 5-FU continuous infusion.  
Note: Table 5-4, Doses of FOLFIRI and 
Bevacizumab in the Phase 2 Portion of the 
Study, is not reproduced in this Summary of 
Changes, but provides dosing guidelines for 
drugs in FOLFIRI and bevacizumab 
Subdivided into completed 
Phase 1b and Phase 2 sections. 
For Phase 2, added new text 
and dosing table in FOLFIRI 
and bevacizumab 
administration section. 
43. 
Section 5.3 
Section 5.3 Dose Modifications 
In Phase 1b and 2, should a subject 
experience a Grade ≥2 neutropenia or 
neutropenic fever during treatment, a dose 
modification will be allowed for the 
treatment component(s) deemed probable 
for the etiology of the toxicity. In the case 
of the 5-FU component, in subsequent 
cycles and according to institutional 
guidelines, dose modification including 
elimination of the 5-FU bolus infusion will 
be allowed. 
Section 5.3 Dose Modifications 
For those patients enrolled in the Phase 2 
portion of the study (this was also applied 
to patients enrolled in the Phase 1b portion 
of the study) who receive the 5-FU bolus 
and leucovorin, occurrence of a Grade ≥ 2 
neutropenia or neutropenic fever that is 
determined to be caused or exacerbated by 
the administration of the 5-FU bolus and/or 
leucovorin may have the 5-FU bolus and/or 
leucovorin eliminated in subsequent cycles, 
at the Investigator’s discretion. 
--Clarification to dose 
modifications, including that 
leucovorin was added to 5-FU 
bolus, both of which may be 
eliminated in subsequent 
cycles.  
--Info on DLTs was deleted as 
not applicable to Phase 2. 

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Dose modifications for onvansertib are 
allowed in accordance with Section 5.3.1. 
Dose adjustments for FOLFIRI and 
bevacizumab are allowed in accordance 
with Section 5.3.2 and will be based on 
dose modification guidelines provided in 
Table 5 4; additional details are provided in 
the relevant package insert (Leucovorin 
Prescribing Information; Fluorouracil 
Prescribing Information; Camptosar 
Prescribing Information; (Avastin 
Prescribing Information). Any necessary 
dose level reductions for onvansertib or for 
FOLFIRI and bevacizumab should follow 
the dose levels outlined in Table 5-1 and 
Table 5-3. 
For any Grade 1 and 2 nausea or vomiting, 
maximize the antiemetic regimen 
prescribed to the subject. For Grade 3 
nausea or vomiting, reduce irinotecan for 
the next cycle. For each subsequent cycle, 
the subject may continue irinotecan at the 
previous dose level, provided nausea has 
resolved to Grade 2 or 1. For Grade 4 
nausea or vomiting, discontinue 5-FU bolus 
and continue 5-FU infusion and irinotecan 
at one lower dose level. If one of the drugs 
(onvansertib or FOLFIRI or bevacizumab) 
must be discontinued based on Investigator 
discretion or due to toxicity, patients may 
continue to receive the other drug(s) alone. 
If 2 or more DLTs are observed in a 
3-patient or 6-patient cohort at a given dose
level and no lower dose for de-escalation
exists, the study will be stopped and
subjects and investigators will be notified
of termination of the study.
Dose modifications for onvansertib are 
allowed in accordance with Section 5.3.1. 
Dose adjustments for FOLFIRI and 
bevacizumab are allowed in accordance 
with Section 5.3.2 and will be based on 
dose modification guidelines provided in 
Table 5-6 and Table 5-7; additional details 
for FOLFIRI and bevacizumab are provided 
in the relevant package insert (PI). 
As per Table 5-7, for any Grade 1 and 2 
nausea or vomiting, maximize the 
antiemetic regimen prescribed to the 
patient. For Grade 3 nausea or vomiting, 
reduce irinotecan for the next cycle. For 
each subsequent cycle, the patient may 
continue irinotecan at the previous dose 
level, provided nausea has resolved to 
Grade 2 or 1. For Grade 4 nausea or 
vomiting, discontinue 5-FU bolus (if using) 
and continue 5-FU infusion and irinotecan 
at one lower dose level. These dose 
reductions for vomiting and/or nausea 
should be made only if they persist/occur 
despite 2 treatments with adequate 
(combination) antiemetic therapy. 
As per Sections 3.1.3.2 and 4.2, if 
individual drugs from the FOLFIRI + 
bevacizumab regimen are discontinued 
because of patient intolerance, patients may 
remain on onvansertib and the remaining 
drugs from the FOLFIRI + bevacizumab 
regimen, provided that either 5-FU or 
irinotecan (or both) is continued. 
Onvansertib may not be administered as a 
single agent or with bevacizumab alone, as 
there are no data to support either of these 
treatment scenarios. 

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44.  
Section 5.3.1.1 
Section 5.3.1 Onvansertib 
5.3.1.1 Dose Delays 
Patients who experience any Grade 2 or 
higher AE considered related to the study 
drug (i.e., adverse reaction or suspected 
adverse reaction according to the criteria in 
Section 7.1.2) will have their next dose of 
onvansertib held until all study drug-related 
toxicities have improved to Grade 1 or to 
Baseline. If the AE does not resolve to 
Grade 1 or less or to Baseline within 2 
weeks, the patient will be discontinued 
from study treatment. Dose delays do not 
alter the Schedule of Assessments. If 
pharmacokinetic or pharmacodynamic 
studies are scheduled at the time of a dose 
delay, these will be delayed, and should be 
rescheduled by the Investigator and 
Sponsor.  
If a patient forgets to take their dose of 
study drug on any day during Days 1 to 5 
of the cycle, they will have the opportunity 
to take the scheduled dose within 4 to 
6 hours of the original scheduled time on 
that same day. If a patient misses a dose of 
study drug on any day during Days 1 to 5 
of the cycle, they will not be able to make 
up the missed dose on the next day or move 
the Day 1 to 5 dosing schedule out to 
additional consecutive days (e.g., Day 6, 
etc.). If onvansertib is vomited, participants 
should not retake drug, but should take it 
instead at the next scheduled time. 
Section 5.3.1 Onvansertib Dose 
Modifications 
5.3.1.1 Dose Delays 
Patients who experience any Grade 3 or 
higher AE considered related to onvansertib 
(i.e., adverse reaction or suspected adverse 
reaction according to the criteria in Section 
7.3) will have their next dose of onvansertib 
held until all study drug-related toxicities 
have improved to Grade 1 or to Baseline. If 
the AE does not resolve to Grade 1 or less 
or to Baseline within 2 weeks, the patient 
will be discontinued from treatment, unless 
the investigator believes it is in the patient’s 
best interest to delay more than 2 weeks and 
has discussed the case and obtained 
approval of the Medical Monitor to restart 
the treatment after a delay longer than 
2 weeks. In the Phase 2 portion of the trial, 
if a patient experiences recurrent Grade 3 or 
higher toxicity related to onvansertib at the 
lowest allowed onvansertib dose (6 mg/m2), 
treatment with onvansertib must be 
discontinued as no further dose reductions 
are allowed. Dose delays do not alter the 
Schedule of Assessments. If 
pharmacokinetic or pharmacodynamic 
studies are scheduled at the time of a dose 
delay, these will be delayed, and should be 
rescheduled by the Investigator and 
Sponsor.  
If treatment is delayed for 7 days, e.g., 
Cycle 1 Day 15 must be delayed to Day 22, 
then the numbering of the subsequent dose 
will not change, e.g., the treatment given on 
Day 22 will be considered the Cycle 1 Day 
15 dose. However, if treatment is delayed 
for 14 days or greater, then the next 
--Clarifications 
--Revised from patients who 
experience any Grade 2 or 
higher AE to any Grade 3 or 
higher AE considered related to 
the study drug will have their 
next dose of onvansertib 
withheld.  
--Deleted consideration of 
restarting onvansertib after AE 
resolution must be discussed 
with the Medical Monitor. 
--Changed cross-reference to 
relationship of adverse events 
to the study drug section 
instead of unexpected adverse 
events section.  
--Added allowance for 
continuing treatment per 
investigator discretion if AE 
does not resolve to Grade 1 or 
less or to Baseline within 
2 weeks.  
--Rules for numbering of dose 
cycles were clarified. 

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treatment will be considered Day 1 of the 
subsequent cycle. Examples: if Cycle 1 
Day 15 is delayed by 14 days, the next 
treatment will be considered the Cycle 2 
Day 1 treatment. If Cycle 2 Day 1 is 
delayed by 14 days, the next treatment will 
still be considered the Cycle 2 Day 1 
treatment. 
If a patient forgets to take their dose of 
study drug on any day during Days 1 to 5 or 
15 to 19 of the cycle, they will have the 
opportunity to take the scheduled dose 
within 4 to 6 hours of the original scheduled 
time on that same day. If a patient misses a 
dose of study drug on any day during 
Days 1 to 5 or Days 15 to 19 of the cycle, 
they will not be able to make up the missed 
dose on the next day or move the Day 1 to 5 
or Day 15 to 19 dosing schedule out to 
additional consecutive days (e.g., Day 6, 
Day 20, etc.). If onvansertib is vomited, 
participants should not retake drug, but 
should take it instead at the next scheduled 
time. 
45.  
Section 5.3.1.2 
Section 5.3.1 Onvansertib 
5.3.1.2 Dose Reduction 
If a DLT resolves to Grade 1 or less, the 
dose of onvansertib will be reduced to the 
next lower dose level in subsequent cycles 
based on Investigator discretion. 
Section 5.3.1 Onvansertib 
5.3.1.2 Dose Reduction 
Completed Phase 1b Portion of the Study 
If a DLT resolved to Grade 1 or less, the 
dose of onvansertib was reduced to the next 
lower dose level in subsequent cycles based 
on Investigator discretion (see 
Section 5.2.1, Table 5-1). 
Phase 2 Portion of the Study 
Dose reduction levels for onvansertib in the 
Phase 2 portion of the study are outlined in 
Section 5.2.1, Table 5-2. 
Onvansertib-related hematologic AEs 
--Revised to show separate 
completed Phase 1b and 
Phase 2 dose reduction 
guidance. 
--Added table for dose 
reduction for onvansertib-
related hematologic adverse 
events. 

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require modifications to the onvansertib 
dose per Table 5-5: 
 
HEMATOLOGIC TOXICITIES: Dose 
modifications recommended for the next 
treatment cycle based on toxicity 
experienced during a previous cycle (i.e., 
after Days 1-5  or 15-19 of any cycle): 
--Grade 3 or 4 neutropenia or 
thrombocytopenia: 1st occurrence, 
Continue onvansertib at current dose level, 
2nd occurrence, Continue onvansertib at one 
lower dose level 
Febrile neutropenia (defined as ANC 
< 1000/μL and T ≥ 38.5°C): 1st 
occurrence, Continue onvansertib at current 
dose level, 2nd occurrence, Continue 
onvansertib at one lower dose level 
46.  
Section 5.3.1.3 
Section 5.3.1 Onvansertib 
5.3.1.3 Dose Escalation 
Once a dose level of onvansertib has 
cleared the DLT safety window, patients 
continuing on treatment may have their 
dose increased to that next higher dose 
level at the discretion of the investigator. 
For example, if the onvansertib 15 mg/m2 
dose level has been cleared for safety, 
patients on treatment at onvansertib 
12 mg/m2 may have their dose of 
onvansertib increased to 15 mg/m2. 
Section 5.3.1 Onvansertib 
5.3.1.3 Dose Escalation 
Completed Phase 1b Portion of the Study 
In the completed Phase 1b portion of the 
study, once a dose level of onvansertib had 
cleared the DLT safety window, patients 
continuing on treatment were allowed to 
have their dose increased to that next higher 
dose level at the discretion of the 
Investigator. For example, if the 
onvansertib 15 mg/m2 dose level had been 
cleared for safety, patients on treatment at 
onvansertib 12 mg/m2 were permitted to 
have their dose of onvansertib increased to 
15 mg/m2. 
Revised to reflect completion 
of Phase 1b. 
47.  
Section 5.3.2 
5.3.2 FOLFIRI and Bevacizumab Dose 
Modifications 
Should a subject experience a Grade ≥ 2 
5.3.2 FOLFIRI and Bevacizumab Dose 
Modifications 
Should a patient experience a Grade ≥ 2 
--Revised to allow for 
continuation of all other study 
drugs if irinotecan is 

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neutropenia or neutropenic fever during 
treatment, a dose modification will be 
allowed for the treatment component(s) 
deemed probable for the etiology of the 
toxicity. In the case of the 5-FU 
component, in subsequent cycles and 
according to institutional guidelines, dose 
modification including elimination of the 
5-FU bolus infusion will be allowed. 
Dose adjustments for FOLFIRI and 
bevacizumab are allowed and should be in 
accordance with the Dose Modification 
Guidelines (Table 5-4). Any necessary dose 
reductions for FOLFIRI should follow the 
dose levels outlined in Error! Reference 
source not found.. Additional details for 
FOLFIRI and bevacizumab are provided in 
the relevant package insert (PI) 
(Leucovorin Prescribing Information; 
Fluorouracil Prescribing Information; 
Camptosar Prescribing Information; 
Avastin Prescribing Information).  
Note: Table 5-3, Dose Reduction Levels of 
FOLFIRI, is not reproduced in this 
Summary of Changes, but had only 2 dose 
reduction columns and no footnotes. 
neutropenia or neutropenic fever during 
treatment, a dose modification will be 
allowed for the treatment component(s) 
deemed probable for the etiology of the 
toxicity.  
Any necessary dose reductions for 
FOLFIRI should follow the dose levels 
outlined in Table 5-6, and should be in 
accordance with the dose modification 
guidelines presented in Table 5-7. 
Additional details for FOLFIRI and 
bevacizumab are provided in the relevant 
package insert (Leucovorin Prescribing 
Information; Fluorouracil Prescribing 
Information; Camptosar Prescribing 
Information; Avastin Prescribing 
Information). Note: if irinotecan is 
discontinued due to toxicity, all other study 
drugs may be continued (5-FU, 
bevacizumab, and onvansertib). 
Note: Table 5-6, Dose Reduction Levels of 
FOLFIRI, is not reproduced in this 
Summary of Changes, but revisions 
included adding a third dose reduction as an 
option for irinotecan and 5-FU infusion. 
Footnotes were added to this table 
pertaining to 5-FU and leucovorin. 
discontinued.  
--Dosing table was revised to 
add a third dose reduction as an 
option for irinotecan and 5-FU 
infusion. Footnotes were added 
to this table pertaining to 5-FU 
and leucovorin. 
48.  
Section 5.3.2, 
Table 5-7 
5.3.2 FOLFIRI and Bevacizumab Dose 
Modifications 
Table 5-4, Dose Modification Guidelines 
for FOLFIRI and Bevacizumab: 
--HEMATOLOGIC TOXICITIES: Dose 
modifications recommended for the next 
treatment cycle based on unresolved 
toxicity experienced during a previous 
cycle (i.e., after Day 1 of any cycle): 
5.3.2 FOLFIRI and Bevacizumab Dose 
Modifications 
Table 5-7, Dose Modification Guidelines 
for FOLFIRI and Bevacizumab: 
--HEMATOLOGIC TOXICITIES: Dose 
modifications recommended for the next 
treatment cycle based on unresolved 
toxicity experienced during a previous 
cycle (i.e., after Day 1 or 15 of any cycle): 
Clarifications made to dosing 
modification guidelines for 
certain toxicities. 

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Grade 3 or 4 neutropenia or 
thrombocytopenia 
--Continue onvansertib at one lower dose 
level 
 
--Febrile neutropenia (defined as ANC 
< 1000/μL and T ≥ 38.5°C):  
--If fever resolves, and counts recover to 
ANC ≥ 1000/μL and platelets ≥ 
75,000/mm3 within (sic, missing 
parameters) 
--Continue onvansertib at one lower dose 
level 
 
--Grade 2 diarrhea: Discontinue 5-FU 
bolus. Reduce 5-FU infusion and irinotecan 
one dose level for the next cycle. For each 
subsequent cycle, … 
--Grade 2 mucositis: May discontinue 
5-FU bolus. Reduce 5-FU infusion and 
irinotecan one dose level for the next 
cycle…. 
--Grade 3 nausea or vomiting: Reduce 
irinotecan one dose level for the next 
cycle…. 
--Grade 4 nausea or vomiting: 
Discontinue 5-FU bolus and continue 5-FU 
infusion and irinotecan at one lower dose 
level. These dose reductions for vomiting 
and/or nausea should be made only if they 
persist/occur despite two treatments with 
adequate (combination) antiemetic therapy. 
The use of aprepitant is prohibited for those 
patients receiving FOLFIRI. 
Grade 3 or 4 neutropenia or 
thrombocytopenia 
--N/A (deleted) 
 
--Febrile neutropenia (defined as ANC 
< 1000/μL and T ≥ 38.5°C):  
--If fever resolves, and counts recover to 
ANC ≥ 1000/μL and platelets ≥ 
75,000/mm3 within 4 weeks, resume 
protocol therapy with dose reductions as 
follows:… 
-- N/A (deleted) 
 
 
--Grade 2 diarrhea: Discontinue 5-FU 
bolus. Reduce 5-FU infusion and irinotecan 
one dose level for the next dose. For each 
subsequent dose, … 
--Grade 2 mucositis: May discontinue 
5-FU bolus (if using). Reduce 5-FU 
infusion and irinotecan one dose level for 
the next dose…. 
--Grade 3 nausea or vomiting: Reduce 
irinotecan one dose level for the next 
dose…. 
--Grade 4 nausea or vomiting: 
Discontinue 5-FU bolus (if using) and 
continue 5-FU infusion and irinotecan at 
one lower dose level. These dose reductions 
for vomiting and/or nausea should be made 
only if they persist/occur despite 2 
treatments with adequate (combination) 
antiemetic therapy. 
49.  
Section 5.6 
Section 5.6 Concomitant Medications 
and Treatments 
Section 5.6 Concomitant Medications and 
Treatments 
--Clarifications 
--New prohibited medications 

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 The following medications are prohibited 
during the study: 
• 
Investigational agents  
• 
Other antineoplastic agents  
• 
Radiotherapy  
• 
Chemotherapy  
• 
Immunotherapy  
• 
Digoxin, digitoxin, and other digitalis 
drugs 
• 
Fludrocortisone acetate (Florinef) 
The following medications are prohibited 
during the study: 
• 
Investigational agents  
• 
Other antineoplastic agents, including 
radiotherapy, chemotherapy, and 
immunotherapy 
• 
Strong inducers or inhibitors of 
CYP3A4 or strong UGT1A1 inhibitors, 
as identified per institutional 
guidelines. Comprehensive lists can be 
found at: https://drug-
interactions.medicine.iu.edu/  
• 
Drugs known to prolong the QT 
interval and with a known or potential 
risk of Torsades de Pointes, as 
identified per institutional guidelines. 
Comprehensive lists can be found at: 
https://www.crediblemeds.org/ 
added and others deleted. 
50.  
Table 6-1  
Table 6-1 Schedule of Assessments 
--Column headers for both Cycles 1 and 2: 
Treatment Course (two courses per cycle) 
--Column headers for Day 1 (first day of 
first course) and Day 15 ± 3 days (first day 
of second course) 
--Column header: End of Study with 
corresponding footnote “j” about 
radiographic imaging and footnote “m” that 
read: EOS assessments should be 
conducted within 28 days (± 5 days) after 
the last dose of onvansertib is administered. 
Table 6-1 Schedule of Assessments 
--Column headers for both Cycles 1 and 2: 
Treatment Course (two courses per cycle) 
were deleted. 
--Column headers for Day 1 and Day 15 ± 
3 days had parenthetical information 
deleted 
--Column header: End of Treatment, cross-
reference to previous footnote “j” about 
radiographic imaging was deleted and 
cross-reference to footnote ”m” was revised 
to footnote “j” which reads: EOT 
assessments should be conducted within 
28 days (± 5 days) after the last dose of 
onvansertib is administered. Patients (any 
ongoing from Phase 1b and all from 
Phase 2) will be followed for overall 
survival for 1 year after EOT, at which 
--Clarifications 
--End of Study procedures 
became End of Treatment 
instead.  

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point they will be considered to have 
completed the study (EOS). 
51.  
Table 6-1 
Table 6-1 Schedule of Assessments 
N/A 
Table 6-1 Schedule of Assessments 
--New footnote “a” added to existing row of 
Confirmation of all Eligibility criteria: 
Eligibility will be confirmed by submission 
of an eligibility checklist including de-
identified supporting source documents to 
the CRO Medical Monitor for review and 
approval. Documentation of a KRAS 
mutation in exon 2, 3, or 4 as determined by 
an assay performed in a CLIA-certified 
laboratory must be provided for inclusion in 
the study. 
Updates to procedures for 
confirmation of eligibility 
criteria. Note that already 
established requirement for 
documentation of KRAS 
mutation in exon 2, 3, or 4 in 
primary tumor or metastasis, 
assessed by a CLIA-certified 
laboratory was also added as a 
clarification to this footnote. 
52.  
Table 6-1 
Table 6-1 Schedule of Assessments 
--Row of Liquid biopsy for KRAS test and 
corresponding footnote “a”: Blood for 
KRAS liquid biopsy will be obtained at 
screening for Phase 2 only. Blood will be 
collected in two 10-mL CEE-Sure tubes 
(for overnight delivery to 
 
Table 6-1 Schedule of Assessments 
N/A 
Deleted as liquid biopsies for 
KRAS mutation will not be 
performed and confirmation by 
liquid biopsy of KRAS 
mutation status is not required 
for study eligibility 
53.  
Table 6-1 
Table 6-1 Schedule of Assessments 
--Row of Triplicate 12-lead ECG at 
screening and Day 1 of Cycles 2 and 
beyond 
Table 6-1 Schedule of Assessments 
--Moved triplicate ECG assessments during 
study from Table 6-1 to new Table 6-2 
Schedule of Assessments for PK 
Sampling and schedule revised to Days 1 
and 5 for Cycles 1, 3, and 5, to coincide 
with PK sampling times with associated 
footnote “b” that reads as follows: 12-lead 
ECGs will be obtained to coincide with PK 
sampling times. All ECGs should be 
performed in triplicate. ECG will also be 
performed at Screening (see Table 6-1). 
--Moved during treatment ECG 
assessments from Table 6-1 to 
new Table 6-2. Note that ECG 
at screening was retained in 
Table 6-1. 
54.  
Table 6-1 
Table 6-1 Schedule of Assessments 
Footnote “e” for blood chemistry and CEA 
row and CBC with differential row: Blood 
Table 6-1 Schedule of Assessments 
Footnote “f” for blood chemistry and CEA 
row and CBC with differential row: Blood 
Added clarification for Day 8 
schedule of assessments 
sampling. 

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chemistry panel includes sodium, 
potassium, chloride, bicarbonate, calcium, 
magnesium, phosphorus, blood urea 
nitrogen, creatinine, glucose, albumin, 
alkaline phosphatase, total bilirubin, AST, 
ALT. CBC and clinical chemistry testing 
(including CEA) may occur up to 48 hours 
prior to Day 1 and Day 15 (CBC) and 
Day 1 (clinical chemistry). 
chemistry panel includes sodium, 
potassium, chloride, bicarbonate, calcium, 
magnesium, phosphorus, blood urea 
nitrogen, creatinine, glucose, albumin, 
alkaline phosphatase, total bilirubin, AST, 
ALT. CBC and clinical chemistry testing 
(including CEA) may occur up to 48 hours 
prior to Day 1 and Day 15 (CBC) and 
Day 1 (clinical chemistry). The Day 8 
sample will be collected in Cycle 1 only 
and may occur up to 24 hours before or 
after Day 8. 
55.  
Table 6-1 and 
Table 6-2 
Table 6-1 Schedule of Assessments 
Had row for blood samples for PK 
assessment at Cycle 1, Days 5, 6, 7, and 8 
with associated footnote “f “ that read: 
Blood samples for PK analysis will be 
obtained during cycle 1, only, on Days 5, 6, 
7, and 8. Samples on Day 5 should be 
collected pre-dose and 1, 2, 3, 4, and 8 
hours post dose; samples on other days 
should be collected 24, 48, and 72 hours 
post-Day 5 dose, respectively. 
Table 6-1 Schedule of Assessments, 
moved PK sampling times to new 
Table 6-2 Schedule of Assessments for 
PK Sampling and schedule revised to 
Days 1 and 5 for Cycles 1, 3, and 5, with 
corresponding footnote “a” that reads as 
follows: Blood samples for PK analysis will 
be obtained during C1D1, C1D5, C3D1, 
C3D5, C5D1 and C5D5. Samples on C1D1, 
C3D1, and C5D1 should be collected pre-
dose, and samples collected on C1D5, 
C3D5, and C5D5 should be collected 2 to 
4 hrs after the patient has taken the dose. 
--New Table 6-2 Schedule of Assessments 
for PK Sampling had food effect substudy 
blood sampling added on C3D5 and C5D5 
with associated footnote “c” that reads as 
follows: See Section 6.2.11.4 for details. 
Note that the PK samples collected for the 
food effect study on C3D5 and C5D5 may 
overlap with those collected for general PK 
analysis (from 2 to 4 hours postdose). One 
blood sample can be used to satisfy both 
blood draw requirements. 
PK sampling times revised and 
moved from Table 6-1 to new 
Table 6-2; new food effect 
substudy sampling times newly 
added to this table. 

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56.  
Table 6-1 
Table 6-1 Schedule of Assessments 
--Row for archival tumor tissue at 
screening if available (not required) and 
corresponding footnote “g”: Availability 
and access to archival tissue does not need 
to occur prior to enrollment. Archival 
tumor tissue can be obtained after accrual 
and stored for future analysis, with patient 
consent. 
--N/A for tumor tissue sample submission 
Table 6-1 Schedule of Assessments 
--Row for archival tumor tissue and 
corresponding previous footnote “g” 
deleted. 
--New row added of Tumor tissue sample 
submission at Screening with new 
footnote “b”: Tumor tissue (FFPE) will be 
collected at study entry for central 
confirmation of KRAS mutation status and 
future correlated biomarker studies. If 
archival FFPE tissue is not available, the 
patient must undergo a biopsy at screening 
to obtain tissue for eligibility. Confirmation 
of KRAS mutation in tumor samples is not 
required for study eligibility. 
Patients must have FFPE tumor 
tissue (newly acquired or 
archival) in order to be eligible. 
57.  
Table 6-1 
Table 6-1 Schedule of Assessments 
-Row for blood samples for ctDNA had 
blood collected at Days 1 and 7 of Cycle 1 
and Day 1 of Cycles 2 and beyond.   
--Corresponding footnote “h”: Blood for 
ctDNA assessment should be collected on 
Days 1 (pre-dose) and 7 of Cycle 1; on 
Day 1 of Cycles 2 to 9, and at EOS. Blood 
will be collected in three 10-mL Streck 
tubes (for overnight delivery to 
Trovagene). 
Table 6-1 Schedule of Assessments 
--Row for blood samples for ctDNA has 
blood collected at Day 1 of Cycle 1 and 
again at Day 1 of Cycles 2 and 3 and every 
other Cycle after Cycle 3. 
--Corresponding footnote “g”: Blood for 
ctDNA assessment should be collected 
predose on Day 1 of Cycles 1, 2, 3, and 
every other Cycle after Cycle 3 (Cycle 5, 
Cycle 7, Cycle 9, etc), and at EOT. Blood 
will be collected in three 10-mL Streck 
tubes (for overnight delivery to Cardiff 
Oncology). 
Changed frequency of ctDNA 
collection and where delivered. 
58.  
Table 6-1 
Table 6-1 Schedule of Assessments 
-Row for blood samples for circulating 
tumor cells (CTCs) at Day 1 and EOS. 
--Corresponding footnote” i”:  Blood for 
CTC assessment should be collected on 
Day 1 of Cycle 1 (pre-dose), and at EOS. 
At each time point, blood will be collected 
Table 6-1 Schedule of Assessments 
N/A 
Deleted collection of CTCs. 

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in one 10-mL Streck tube (for delivery 
overnight to 
). 
59.  
Table 6-1 
Table 6-1 Schedule of Assessments 
--Row for Disease assessment 
(radiographic imaging) 
--Corresponding footnote “j”: Radiographic 
imaging will be obtained during screening, 
prior to the start of Cycles 3, 5, 7 etc., until 
EOS, and at EOS. Radiographic imaging 
should include CT of the 
chest/abdomen/pelvis with contrast (or 
MRI if contraindication to intravenous 
contrast). Radiographic imaging may occur 
up to 28 days prior to the first dose of 
onvansertib (study drug). 
--Row for re-staging at Screening and at 
Cycles 2 and Beyond and corresponding 
footnote “l” that said Restaging with CT or 
MRI should be done at screening within 
28 days of administering the first dose of 
onvansertib and prior to the start of 
Cycles 3, 5, 7 etc., until EOS. 
Table 6-1 Schedule of Assessments 
--Revised Row to say Disease assessment 
(radiographic imaging) and re-staging 
--Corresponding footnote “h”: Radiographic 
imaging will be obtained during screening, 
prior to the start of Cycle 3 and at all 
subsequent odd-numbered cycles (Cycles 5, 
7, 9 etc.), at EOT, and every 8 weeks 
thereafter until PD, start of a new anti-
cancer therapy, or EOS. Patients who are 
taken off onvansertib, but remain on 
FOLFIRI + bevacizumab or any 
component(s) of the FOLFIRI + 
bevacizumab regimen will also continue 
follow-up for radiographic disease 
progression via CT/MRI scans every 
8 weeks. Radiographic imaging should 
include CT of the chest/abdomen/pelvis 
with contrast (or MRI if contraindication to 
intravenous contrast). Radiographic 
imaging may occur up to 28 days prior to 
the first dose of onvansertib (study drug). 
--Previous row for re-staging and 
corresponding prior footnote “l” was 
deleted. 
Requirements for radiographic 
imaging were revised and 
clarified. 
60.  
Table 6-1 
Table 6-1 Schedule of Assessments 
Onvansertib footnote “k”: Patients will take 
onvansertib on Days 1 through 5 of each 
14-day treatment course. Onvansertib will 
be dosed in the clinic on Day 1 of each 
cycle, but otherwise may be taken at home 
for patient convenience. 
Table 6-1 Schedule of Assessments 
Onvansertib footnote” i”: Patients will take 
onvansertib on Days 1 to 5 and Days 15 to 
19 of each 28-day treatment course. 
Onvansertib will be dosed in the clinic on 
Day 1 of each cycle, and Day 5 of Cycles 1, 
3, and 5 but otherwise may be taken at 
home for patient convenience. 
Clarification 
61.  
Section 6.2.3 
Section 6.2.3 Liquid Biopsy for KRAS 
Test 
6.2.3 Confirmation of KRAS Mutation 
Status 
--Liquid biopsies for KRAS 
mutation will not be performed 

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In the Phase 2 segment of the trial, 
confirmation of a KRAS mutation will be 
obtained by liquid biopsy during screening 
to confirm eligibility.  
Documentation of a KRAS mutation in 
exon 2, 3, or 4  as determined by an assay 
performed in a CLIA-certified laboratory 
must be provided for inclusion in the study. 
and confirmation by liquid 
biopsy of KRAS mutation 
status is not required for study 
eligibility. 
--Note that already established 
requirement for documentation 
of KRAS mutation in exon 2, 
3, or 4 in primary tumor or 
metastasis, assessed by a 
CLIA-certified laboratory 
replaced the prior text. 
62.  
Section 6.2.4 
Section 6.2.10 Archival Tumor Tissue 
Availability and access to archival tumor 
tissue samples does not need to be 
confirmed by the site prior to enrollment in 
accordance with the Schedule of 
Assessments (Table 6 1). If available, 
archival tumor tissue can be obtained after 
accrual for future use. 
Where local center regulations prohibit 
submission of blocks of tumor tissue, two 2 
mm cores of tumor from the block and 10 
to 30 unstained slides of whole sections of 
representative tumor tissue are preferred. 
Where two 2 mm cores of tumor from the 
block are unavailable, 10 to 30 unstained 
slides of whole sections of representative 
tumor tissue alone are acceptable. 
Availability and consent for use of archival 
tumor tissue is not required for study 
eligibility. 
Section 6.2.10 on Archival Tissue Tumor-
deleted and Section 6.2.4 called Tumor 
Sample Submission added: 
For all patients enrolled under version 2.0 
of the protocol, tumor tissue (FFPE) will be 
collected at study entry. If archival FFPE 
tissue is not available, the patient must 
undergo a biopsy to obtain tissue for 
eligibility. Note that confirmation of KRAS 
mutation status in the submitted tumor 
samples is not required for study eligibility. 
FFPE tumor tissue requirements: 
• 
Tumor sample requirements: 
o 
Specimens from the most 
recent biopsy procedure 
should be submitted, and must 
be less than six years old   
o 
Optimal tumor cross sectional 
size = 25 mm2, minimum = 
5 mm2  
o 
Tumor is required to be at 
least 20% of the sample by 
ratio of tumor nuclei to benign 
nuclei 
Patients must have FFPE tumor 
tissue (newly acquired or 
archival) in order to be eligible. 

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• 
FFPE Fixation requirements 
o 
10% formalin fixation (neutral 
buffered) for 6 to 72 hrs, 
paraffin embedded.  
o 
No decalcification of the 
samples (EDTA 
decalcification is accepted) 
• 
Submit either an FFPE block or 
unstained slides: 
o 
If submitting slides: provide a 
minimum of 10 unstained 
slides cut at 5 microns on 
positively charged, unbaked 
slides and 1 stained 
hematoxylin and eosin (H&E) 
slide. If an H&E slide is not 
available, provide 11 
unstained slides. Submit 10 
additional slides if tissue size 
is < 25mm2. 
o 
If submitting an FFPE block: 
choose the block with greatest 
tumor content. At least one 
stained H&E slide is required, 
or an extra unstained slide cut 
from the block will be 
generated if H&E slide is not 
available.  
63.  
Section 6.2.9 
Section 6.2.9 Electrocardiograms 
Twelve-lead ECGs will be performed in 
triplicate in accordance with the Schedule 
of Assessments (Table 6-1). To minimize 
variability, it is important that patients are 
in a resting position for at least 5 minutes 
prior to each ECG evaluation. Body 
position should be consistently maintained 
for each ECG to prevent changes in heart 
rate. Any clinically significant changes in 
Section 6.2.10 Electrocardiograms 
Twelve-lead ECGs will be performed in 
triplicate at Screening (Table 6-1) and in 
accordance with the Schedule of 
Assessments for Pharmacokinetic Sampling 
(Table 6-2). To minimize variability, it is 
important that patients are in a resting 
position for at least 5 minutes prior to each 
ECG evaluation. Body position should be 
consistently maintained for each ECG to 
--Added cross-reference to 
Table 6-2 as ECG assessments 
now appear on both Table 6-1 
(ECG at screening) and 
Table 6-2 (ECG assessments 
during treatment).  

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ECGs that occur during the study should be 
reported as an AE in the eCRF. 
prevent changes in heart rate. Any clinically 
significant changes in ECGs that occur 
during the study should be reported as an 
AE in the eCRF. 
64.  
Section 6.2.11.2 
Section 6.2.11.2 Hematology 
CBC may occur up to 48 hours prior to 
Days 1 and 15.   
Section 6.2.11.2 Hematology 
Hematology testing: CBC may occur up to 
48 hours prior to Days 1 and 15 and 
24 hours prior to, or after, Day 8. 
Revision to frequency of CBC 
testing. 
65.  
Section 6.2.11.3 
Section 6.2.11.3 Samples for 
Pharmacokinetic Analysis 
Blood samples for PK analysis should be 
obtained during Cycle 1 only on Days 5, 6, 
7, and 8 in accordance with the Schedule of 
Assessments (Table 6-1). 
Section 6.2.11.3 Samples for 
Pharmacokinetic Analysis  
Pharmacokinetic samples were obtained 
from patients in the Phase 1b portion of the 
study to better characterize PK and allow 
for population PK and exposure-related 
analyses to facilitate onvansertib dose 
selection for the Phase 2 portion of the trial. 
PK samples will also be collected from all 
patients enrolled on the Phase 2 portion of 
the study under version 2.0 of the protocol 
for further exposure-related analyses of the 
15 mg/m2 dose according to the Schedule of 
Assessments for PK sampling (Table 6-2). 
Triplicate ECGs should be obtained as close 
as possible to the PK blood sampling. 
--Cross-reference to newly 
added Table 6-2, Schedule of 
Assessments for PK Sampling. 
--PK sampling times revised 
and moved from Table 6-1 to 
new Table 6-2; food effect 
substudy sampling times newly 
added to this table. 
--Added that ECGs should be 
obtained as close as possible to 
the PK blood sampling. 
66.  
Section 6.2.11.4 
N/A 
Section 6.2.11.4 Food Effect Substudy 
A subgroup of patients (at least 12 patients) 
enrolled on the Phase 2 portion of the study 
will participate in a preliminary food effect 
study. The food effect study will be 
conducted during Cycles 3 and 5 for the 
participating patients. All patients should 
come to the clinic after an overnight fast, 
and be provided with either water or a fat-
containing meal. This substudy will follow 
a cross-over design, with half of the 
participating patients (at least 6) taking their 
onvansertib dose on C3D5 in clinic in a 
Section added for new food 
effect substudy 

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fasted state, with water only. On C5D5, 
these patients will take their dose 
30 minutes after the consumption of a fat-
containing meal. PK samples will be drawn 
immediately before dosing and at 0.5, 1, 
1.5, 2, 2.5, 3, 4, 8, and 24 hours post-dose 
following both the fasted dose on C3D5 and 
the fed dose on C5D5 (also see Table 6-2). 
The second half of the food effect study 
participants (at least 6 patients) will 
undergo the same testing on Cycles 3 and 5, 
but the order of the fasted and fed states 
will be reversed; ie, the second group will 
take their onvansertib dose in a fed state on 
C3D5 and will take their dose in a fasted 
state on C5D5. 
67.  
N/A 
Section 6.2.11.4 Samples for Circulating 
Tumor Cell Assessment 
Blood for CTC assessment should be 
collected prior to study treatment 
administration on Cycle 1 Day 1 and at 
EOS, as outlined in the Schedule of 
Assessments (Table 6-1). At each time 
point, blood will be collected in one 10-mL 
Streck tube (for overnight delivery to 
 
). 
N/A 
Deleted collection of CTCs. 
68.  
Section 6.2.12 
6.2.12 Disease Assessment: Radiographic 
Imaging 
Radiographic imaging using RECIST v1.1 
will be obtained prior to the start of Cycle 3 
and all subsequent odd numbered cycles  
and at EOS, as outlined in Schedule of 
Assessments (Table 6-1). Radiographic 
imaging may occur up to 28 days prior to 
administration of the first dose of 
onvansertib (study drug). 
6.2.12 Disease Assessment: Radiographic 
Imaging 
Baseline radiographic imaging may occur 
up to 28 days prior to administration of the 
first dose of onvansertib (study drug). CT is 
the preferred modality, but MRI is 
acceptable. The same imaging modality 
should be used throughout the trial.   
Radiographic imaging for disease restaging 
during the treatment period will be obtained 
at screening, prior to the start of Cycle 3 
Requirements for radiographic 
imaging were revised and 
clarified. 

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Restaging with CT or MRI should be done 
within 28 days of the first dose of 
onvansertib and prior to the start of Cycle 3 
and all subsequent odd numbered cycles, 
until EOS. 
and at all subsequent odd-numbered cycles 
(Cycles 5, 7, 9, etc), at EOT, and every 
8 weeks thereafter until PD, start of a new 
anti-cancer therapy, or EOS, as indicated in 
the Schedule of Assessments (Table 6-1). 
Patients who are taken off onvansertib, but 
remain on FOLFIRI + bevacizumab or any 
component(s) of the FOLFIRI + 
bevacizumab regimen are not considered to 
have started a new anti-cancer therapy and 
should continue to undergo scans every 
8 weeks. Radiographic imaging should 
include CT of the chest/abdomen/pelvis 
with contrast (or MRI if the patient has 
contraindication to intravenous contrast). 
69.  
Section 6.2.13 
Section 6.2.13 End-of-Study/Follow-Up 
The EOS visit should occur within 28 days 
after the last dose of onvansertib is 
administered, and should include the 
assessments outlined in the Schedule of 
Assessments (Table 6-1).  
Follow-up information will be collected via 
voice or written contact approximately 
every 8 weeks until PD (from patients with 
SD or better) at the end of treatment 
assessments. 
Section 6.2.13 End of Treatment/Follow-
Up/End of Study 
The EOT visit should occur within 28 days 
(± 5 days) after the last dose of onvansertib 
is administered, and should include the 
assessments outlined in the Schedule of 
Assessments (Table 6-1).  
Patients (any ongoing from Phase 1b and all 
from Phase 2) will be followed for overall 
survival for 1 year after EOT. Follow-up 
information regarding post-study treatment, 
including duration of treatment, will be 
collected approximately every 8 weeks 
during this 1-year period. Once 1 year of 
follow-up after EOT has been completed, 
the patient will be considered to have 
completed the study (EOS). 
--EOS visit changed to EOT 
visit 
--Revised follow-up for 
Phase 2. 
70.  
Section 7.3 
Section 7.3 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. All AEs must be 
Section 7.3 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 
Deleted requirement that all 
AEs must be attributed to study 
drug unless there is a 
reasonably acceptable alternate 
cause for the AEs.  

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attributed to study drug unless there is a 
reasonably acceptable alternate cause for 
the AEs. This relationship should be 
described as follows:… 
onvansertib. This causal relationship should 
be described as follows:… 
71.  
Sections 8, 8.1 
and 8.2 
Section 8: PATIENT 
DISCONTINUATION AND TRIAL 
DISCONTINUATION 
Section 8.1 Patient Discontinuation  
A patient 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 patient 
is otherwise entitled… 
Patients who are discontinued prior to 
completing the first treatment cycle (28 
days; there are two 14-day courses of 
treatment in each 28-day cycle) for any 
reason other than toxicity, or who have not 
received at least 80% of the intended doses, 
will be replaced. 
Section 8.2 Study Discontinuation:  
If 2 or more DLTs are observed in a 3-
patient or 6-patient cohort at a given dose 
level and no lower dose for de-escalation 
exists, the study will be stopped and 
subjects and investigators will be notified 
of termination of the study. 
Section 8: PATIENT TREATMENT 
AND STUDY DISCONTINUATION 
AND SPONSOR TRIAL 
DISCONTINUATION 
Section 8.1 Patient Discontinuation 
A patient may choose to stop treatment 
and/or withdraw from this study at any time 
for any reason without penalty of 
jeopardizing their health care or loss of 
benefits to which the patient is otherwise 
entitled… 
Patients enrolled in the completed Phase 1b 
portion of the study who discontinued from 
treatment prior to completing the first 
treatment cycle (28 days) for any reason 
other than toxicity, or who did not receive 
at least 80% of the intended doses, may 
have been replaced. 
Section 8.2 Study Discontinuation:  
In the completed Phase 1b portion of the 
study, if 2 or more DLTs were observed in 
a 3-patient or 6-patient cohort at a given 
dose level and no lower dose for de-
escalation existed, the study would have 
been stopped and patients and the 
Investigators would have been notified of 
termination of the study. 
--Clarified patient 
discontinuation to also mean 
patient choosing to stop 
treatment.  
--Clarified replacement of 
subjects in Phase 1b.  
--Clarified that DLTs were 
evaluated in the completed 
Phase 1b portion of the study. 
72.  
Section 9.1 
Section 9.1 Determination of Sample Size  
This is a single-arm study that consists of 
determining the MTD and RP2D in the 
Phase 1b segment of the trial, and using the 
RP2D to treat patients in the Phase 2 
continuation segment. 
Section 9.1 Determination of Sample Size 
This is a single-arm study that consists of 
determining the MTD and RP2D in the 
Phase 1b segment of the study, and using 
the RP2D to treat patients in the Phase 2 
continuation segment. The Phase 2 portion 
Sample size revisions for 
Phase 2. 

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of the study has been amended to enroll 
additional patients at 15 mg/m2 to obtain 
additional PK, PD, safety, and efficacy data 
for this dose and schedule of onvansertib 
given in combination with FOLFIRI + 
bevacizumab. The total sample size across 
both segments of the study is approximately 
100 patients (18 patients in Phase 1b and 
approximately 80 patients in Phase 2). 
73.  
Section 9.1.1 
Section 9.1 Determination of Sample Size 
Section 9.1.1 Phase 1 
A standard 3 + 3 dose-escalation design 
will be used (Le Tourneau 2012) as 
described in in Section 3.1.2. The dose 
escalation scheme and DLT evaluation plan 
is outlined in Section 3.1.2.1. Patients will 
be enrolled to one of the series of doses 
levels shown in Table 5-1 (onvansertib) 
and Table 5-2 (FOLFIRI and 
bevacizumab).  
Enrollment in Phase 1b will stop when 6 
patients have been treated at the highest 
dose level at which 1 or fewer patients 
experience a DLT. 
The number of patients to be enrolled in 
Phase 1b depends on the observed safety 
profile, which will determine the number of 
patients enrolled in each cohort. The total 
number of patients is expected to be up to 
18 (up to 6 patients per cohort). 
Section 9.1 Determination of Sample Size 
Section 9.1.1 Phase 1b 
A standard 3 + 3 dose-escalation design was 
used (Le Tourneau 2012) as described in 
Section 3.1.2. The dose escalation scheme 
and DLT evaluation plan used is outlined in 
Section 3.1.2.1.  
The number of patients to be enrolled in 
Phase 1b was dependent on the observed 
safety profile, which determined the 
number of patients enrolled in each cohort. 
The total number of patients was expected 
to be up to 18 (up to 6 patients per cohort). 
Revisions reflect completion of 
Phase 1b. 
74.  
Section 9.1.2 
Section 9.1 Determination of Sample Size 
Section 9.1.2 Phase 2 
In Phase 2, patients will be enrolled and 
treated at the RP2D of onvansertib. The 
definition of the RP2D is provided in 
Section 3.1.3.1. The group of up to 
6 patients who were enrolled at what was 
Section 9.1 Determination of Sample Size 
Section 9.1.2 Phase 2 
In the Phase 2 portion of the study, patients 
will be enrolled and treated with 15 mg/m2 
(the RP2D, also the MTD) of onvansertib 
on Days 1 to 5 and 15 to 19 of a 28 day 
cycle concurrently with FOLFIRI + 
--The group of 6 patients 
enrolled at 15 mg/m2 in 
Phase 1b will not be used in the 
primary analytic cohort for 
Phase 2, but will be used in 
selected analyses.  
--Null hypothesis adjusted.  

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determined to be the the (sic) RP2D in 
Phase 1b will be included in the analytic 
cohort for Phase 2. Final determination of 
the RP2D will be based on evaluating all 
available data from the dose escalation 
Phase 1b portion of the trial, including low-
grade, but chronic toxicities, dose 
reductions and/or missed doses of 
onvansertib. 
Assuming 12 months of accrual during 
Phase 2 at 26 patients per year, resulting in 
26 total patients, and with 6 months follow-
up on the last patient enrolled, and based 
on a one-sided one sample log-rank test 
with 10% Type I error, there will be at least 
90% power to detect an improvement in 
ORR from 5% to 20%. This sample size 
assumes a drop out of 10%. 
The primary endpoint for Phase 2 will be 
ORR. Response rate will be compared with 
an historical baseline of 5% based on based 
on the reported results of bevacizumab 
treatment in second-line setting (Bennouna 
2013). The expected response rate is 20%, 
to reflect a significant improvement over 
other currently approved antiangiogenic 
agents (ziv-aflibercept and ramucirumab), 
with response rates of 12 to 15%.  
Using Southwest Oncology Group’s 
(SWOG’s) one-arm binomial calculator, 
with 10% Type I error and 90% power, 29 
patients are needed for the Phase 2 portion. 
The group of up to 6 patients who were 
enrolled at what is determined to be the 
RP2D in Phase 1b will be included in the 
analytic cohort for Phase 2.  
bevacizumab. The definition of the RP2D is 
provided in Section 3.1.3.1. The group of 
6 patients who were enrolled at 15 mg/m2 in 
Phase 1b will not be included in the primary 
analytic cohort for Phase 2, but will be used 
in selected secondary efficacy analyses. 
Selection of 15 mg/m2 as the RP2D was 
based on evaluating all available data from 
the dose escalation Phase 1b portion of the 
study, including low-grade, but chronic 
toxicities, dose reductions, and/or missed 
doses of onvansertib. 
Based on results of the Phase 1b portion of 
the study, 15 mg/m2 was chosen as the 
RP2D. The initial protocol used a null 
hypothesis of 5% ORR and an experimental 
hypothesis of 20% ORR for the 
onvansertib-containing regimen, and 
determined that only 26 evaluable patients 
in Phase 2 were required to give the trial 
90% power to detect improvement in ORR 
from 5% to 20% with a 10% Type I error 
rate. However, the trial is being expanded to 
include an adjusted null hypothesis of 15% 
against an expected ORR of 30%. 
Based on a one-sided binomial superiority 
one-sample test, assuming approximately 
80 evaluable patients during Phase 2, with 
2.5% Type I error, there will be at least 
85% power to test the threshold ORR of 
15% against the expected ORR of 30%. 
--Plan is to include 
approximately 80 rather than 
26 evaluable patients.  
--Power revised. 

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Assuming a dropout rate of 10%, the plan 
is to include a total of 26 new patients in 
the Phase 2 portion of the study. 
75.  
Section 9.3.1 
Section 9.3 Statistical Analysis 
Section 9.3.1 Statistical Analysis of 
Safety Data 
Data from all patients who receive at least 
1 dose of study drug (onvansertib) will be 
included in the safety analysis… 
Section 9.3 Statistical Analysis 
Section 9.3.1 Statistical Analysis of Safety 
Data 
Data from all patients who receive at least 
1 dose of any study drug will be included in 
the safety analysis…. 
Other safety assessments will include data 
from concomitant medication queries, 
physical examination findings, ECOG 
performance status, weight and vital signs 
measurements, ECG measurements, and 
clinical laboratory testing values. 
Descriptive statistics will be generated as 
appropriate (e.g., mean, median, range, and 
standard deviation for continuous data; and 
frequency for categorical data). 
--Revised analysis of safety 
data to include those who 
receive at least 1 dose of any 
study drug rather than 1 dose of 
onvansertib.  
--Added paragraph on other 
safety assessments for safety 
analysis... 
76.  
Section 9.3.2.1 
Section 9.3.2 Statistical Analysis for 
Phase 2 
Section 9.3.2.1 Primary Analysis 
The primary endpoint for Phase 2 will be 
response rate. Response rate will be 
compared with an historical baseline of 5% 
based on based on the reported results of 
bevacizumab treatment in second-line 
setting (Bennouna 2013). The expected 
response rate is 20%, to reflect a significant 
improvement over other currently approved 
antiangiogenic agents (ziv-aflibercept and 
ramucirumab). 
Response rate is defined as a CR or PR 
according to Investigator’s assessment 
using RECIST v1.1 from the first dose of 
study treatment until PD or death due to 
any cause. Patients with inadequate data for 
Section 9.3.2 Statistical Analysis for 
Phase 2 
Section 9.3.2.1 Primary Analysis 
The primary endpoint for Phase 2 will be 
objective response rate (ORR). Response 
rate will be compared with a historical 
baseline of 15% based on the reported 
results of FOLFIRI-bevacizumab treatment 
in second-line setting (Antoniotti 2020; 
Cremolini 2020). The expected response 
rate is 30% to reflect a clinically 
meaningful endpoint for this population 
with limited treatment options and with 
presumed limited activity of currently 
available regimens. 
Response rate is defined as a CR or PR 
according to Investigator’s assessment of 
radiographic imaging results using RECIST 
Primary analyses revised. 

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tumor assessment (e.g., no baseline 
assessment or no follow-up assessments) 
will be considered as non-responders in the 
assessment of response rate. 
v1.1. Patients with missing or unknown 
response information will be classified as 
non-responders.   
Patients from Phase 2 who receive at least 
1 cycle (28 days/4 weeks of treatment) of 
onvansertib (treated-patient population) will 
be included in the treated-patient population 
for efficacy analysis. Patients who have 
radiographically-confirmed PD prior to the 
completion of the first cycle will be 
excluded from this analysis. 
The percentage of patients who experience 
a CR or PR based on RECIST v1.1 will be 
presented, along with the associated 95% 
confidence interval. 
77.  
Section 9.3.2.2 
Section 9.3.2 Statistical Analysis for 
Phase 2 
Section 9.3.2.2 Analysis of Secondary 
Endpoints 
PFS is defined from the start of treatment 
to the first observation of PD or death, 
whichever comes first. The patients who 
are alive and PD is not observed, PFS will 
be censored at the date of the latest disease 
assessment. 
Section 9.3.2 Statistical Analysis for 
Phase 2 
9.3.2.2 Analysis of Secondary Endpoints 
All secondary efficacy endpoint analysis 
will be carried out in the treated-patient 
population (ie, all patients receiving at least 
1 cycle of onvansertib). Patients who have 
radiographically-confirmed PD prior to the 
completion of the first cycle will be 
excluded from these analyses. 
PFS is defined from the start of treatment to 
the first observation of PD or death, 
whichever comes first. The patients who are 
alive and PD is not observed, PFS will be 
censored at the date of the latest disease 
assessment. 
DOR is defined from the date of first 
response (CR or PR) to PD or death, 
whichever occurs first. This endpoint will 
be evaluated only in patients who have 
objective response of CR or PR.  
Secondary analyses expanded. 

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DCR is defined as the number of patients 
achieving SD, PR, or CR. 
Overall survival will be calculated for 
1 year following EOT, at which point the 
patients will be considered to have 
completed the study (EOS). 
Blood samples obtained at baseline and 
subsequent time points as indicated in the 
Schedule of Assessments (Table 6-1) will 
be analyzed for the presence of ctDNA 
(including KRAS mutations) to assess 
changes in KRAS allelic burden. 
Summary statistics of PK parameters will 
include, but is not necessarily limited to: 
Cmax, Tmax, AUC0-inf, and AUC0-t. Averages, 
standard deviations, and coefficients of 
variation will be provided. Log-
transformation of exposure measurements 
may be conducted as needed. 
78.  
Section 9.3.3 
Section 9.3.2 Statistical Analysis for 
Phase 2 
Section 9.3.2.3: Analysis of Exploratory 
Endpoints 
Section 9.3.2.3.1: Reduction in KRAS 
Allelic Burden on Liquid Biopsies 
Blood samples obtained at baseline and 
subsequent time points as indicated in the 
Schedule of Assessments (Table 6-1) will 
be analyzed for the presence of ctDNA 
(including KRAS mutations). 
 
Section 9.3.3 Statistical Analysis of 
Pharmacodynamic Data 
Circulating tumor cells and circulating 
tumor DNA isolated from blood samples 
will be used to assess inhibition of PLK1 
activity by onvansertib and to evaluate 
Section 9.3.3 Analysis of 
Pharmacodynamic and Pharmacokinetic 
Data (Exploratory Endpoints)  
ctDNA isolated from blood samples will be 
used to monitor changes in KRAS MAF 
and to evaluate relevant biomarkers 
correlated with patient response in the 
treated-patient population. CEA will also be 
collected to evaluate correlation between 
CEA and other biomarkers as well as 
correlation with radiographic response. 
Tumor tissue will be used to evaluate 
baseline genomic profiles (DNA/RNA) 
associated with patient response.  
Exploratory pharmacodynamic analysis will 
include assessments of pharmacodynamic 
biomarkers in both blood and tumor tissue. 
The relationship between onvansertib 
Statistical analysis for 
exploratory endpoints revised 
and expanded, including for 
new food effect substudy. 

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relevant biomarkers correlated with patient 
response. 
If available and consent is given by the 
subject, archival tumor tissue may be used 
to evaluate genomic profiles (DNA/RNA) 
associated with patient response. 
concentration and selected efficacy and 
safety outcomes may be explored. The 
correlation between biomarkers and clinical 
outcomes may be analyzed. In addition, 
exploratory analyses aimed at evaluating 
the relationship between drug concentration 
and changes in ECG parameters will be 
provided. Additional exploratory PK and 
pharmacodynamic analyses may be 
conducted as appropriate. 
To evaluate the impact of concomitant food 
intake, descriptive statistics of PK 
parameters, by fed and fasted state, along 
with the ratio of geometric means between 
fed and fasted states will be provided. 
Summary statistics related to this 
examination will include, but is not 
necessarily limited to: Cmax, Tmax, AUC0-inf, 
and AUC0-t. Averages, standard deviations, 
and coefficients of variation will be 
provided.  
Log-transformation of exposure 
measurements may be conducted as needed 
for PK and pharmacodynamic associated 
analyses. 
79.  
Section 15 
Section 15 References 
N/A 
Section 15 References 
Antoniotti C, Cremolini C, Rossini D, et al. 
TRIBE2 results and toxicity - Authors’ 
reply. Lancet Oncol 2020;21:e300-1. 
Cremolini C, Antoniotti C, Rossini D, et al. 
Upfront FOLFOXIRI plus bevacizumab 
and reintroduction after progression versus 
mFOLFOX6 plus bevacizumab followed by 
FOLFIRI plus bevacizumab in the treatment 
of patients with metastatic colorectal cancer 
(TRIBE2): a multicentre, open-label, phase 
3, randomised, controlled trial. Lancet 
New reference citations added. 

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Oncol 2020;21:497-507. 
Hong DS, Fakih MG, Strickler JH, et al. 
KRAS(G12C) inhibition with sotorasib in 
advanced solid tumors. N Engl J Med. 
2020;383(13):1207-1217.