Onvansertib in Combination With FOLFIRI and Bevacizumab f... | NCT03829410

Label	Type	Description	Intervention Names
Onvansertib + FOLFIRI + Bevacizumab	Experimental	Phase 1b: Onvansertib escalating starting dose of 12 mg/m^2 orally Day 1 through Day 5 and Day 15 through Day 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab. This Phase 1b portion of the study has been completed. Phase 2: Onvansertib Recommended Phase 2 Dose (RP2D) of 15 mg/m^2 orally Day 1 through Day 5 and Day 15 through Day 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle.	Drug: Onvansertib Biological: Bevacizumab Drug: FOLFIRI

Name	Type	Description	Arm Group Labels	Other Names
Onvansertib	Drug	Onvansertib orally.	Onvansertib + FOLFIRI + Bevacizumab

Measure	Description	Time Frame
Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)	DLTs were defined as a Grade 4 hematologic adverse events (AEs), Grade ≥ 3 non-hematologic AEs that were considered related to the study drug and that did not resolve within 14 days following presentation with standard management and care, Grade ≥ 3 thrombocytopenia with bleeding, neutropenic fever, any death not clearly due to the underlying disease or extraneous causes, or any change in liver function that met Hy's Law criteria of a DLT.	Up to Day 28
Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	AEs were defined as any untoward medical occurrence associated with the use of a drug in humans. TEAEs are defined as any AE that started on or after the first day of study treatment and within 30 days of the last administration of study treatment, or that worsened on or after the first day of study treatment. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 on a scale from Grade 1 (mild) to Grade 5 (death). An AE was considered "serious" if it resulted in death, life-threatening AE, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or congenital anomaly/birth defect. The Investigator determined relatedness to the use of onvansertib. Clinically significant changes in vital signs, laboratory parameters, electrocardiograms, physical examinations, weight, and Eastern Cooperative Oncology Group (ECOG) performance status were reported as AEs.	Up to a maximum of 81 weeks
All-Treated Analysis Set: Objective Response Rate (ORR)	ORR was defined as the percentage of participants documented to have a confirmed complete response (CR) or partial response (PR) using the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1). Two-sided 95% confidence interval (CI) was calculated using the exact binomial Clopper-Pearson method. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.

Measure	Description	Time Frame
Phase 2: Number of Participants With TEAEs	AEs were defined as any untoward medical occurrence associated with the use of a drug in humans. TEAEs are defined as any AE that started on or after the first day of study treatment and within 30 days of the last administration of study treatment, or that worsened on or after the first day of study treatment. AE severity was graded according to the CTCAE version 5.0 on a scale from Grade 1 (mild) to Grade 5 (death). An AE was considered "serious" if it resulted in death, life-threatening AE, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or congenital anomaly/birth defect. The Investigator determined relatedness to the use of onvansertib. Clinically significant changes in vital signs, laboratory parameters, electrocardiograms, physical examinations, weight, and ECOG performance status were reported as AEs.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologically confirmed metastatic and unresectable colorectal cancer (CRC).
Documentation of a KRAS mutation in exon 2, 3 or 4 in primary tumor or metastasis, assessed by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Participants with concomitant KRAS and BRAF-V600 mutations are excluded from this study. Participants with Microsatellite Instability High/Deficient Mismatch Repair (MSI-H/ddMMR) are also ineligible for enrollment in this study.
Formalin-fixed, paraffin-embedded (FFPE) tumor tissue must be available for submission to a central laboratory in order for a participant to be eligible. If no archival tissue biopsy is available the participant must have a biopsy obtained at screening.
Age ≥ 18 years.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Signed informed consent for participation in the study.
Participant is not receiving any other standard-of-care or experimental cancer therapy. Participants participating in non-interventional surveys or observational studies are allowed.
Has failed treatment or is intolerant of fluoropyrimidine and oxaliplatin with or without bevacizumab.
1. Participants 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.
2. Participants must have received oxaliplatin based chemotherapy with or without bevacizumab (>6 weeks in duration). Participants who received maintenance therapy with fluoropyrimidines are eligible with or without re-challenge with oxaliplatin in combination with fluoropyrimidines.
3. Participants 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.
4. Participants must not have received prior irinotecan.
5. For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen for advanced disease.
6. Participants who discontinued first-line therapy because of toxicity are eligible for as long as progression occurred < 6 months after the last dose of first-line therapy.
Chemotherapy regimen of irinotecan, fluorouracil [5-FU], and leucovorin (FOLFIRI) therapy is appropriate for the participant as determined by the Investigator.
For a woman of child-bearing potential (WOCBP) or a male with a female partner who is a WOCBP: must have a negative serum or urine pregnancy test within 5 days prior to enrollment. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive months); or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device (IUD) or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child-bearing potential.
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 21 days prior to enrollment. Only participant with measurable disease as defined per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) are eligible for enrollment. CT is the preferred imaging modality, but MRI is also accepted.
Must have acceptable organ function.
Participant must consent to provision of, and Investigator(s) must confirm access to and agree to submit a representative, formalin fixed, paraffin block of tumor tissue to be used for correlative marker assays. Submission of the tissue does not have to occur prior to enrollment.
Signed informed consent to provide blood sample(s) for specific correlative assays.

Exclusion Criteria:

Concomitant KRAS and BRAF-V600 mutations or MSI-H/dMMR
Anti-cancer chemotherapy or biologic therapy administered within 28 days prior to the first dose of study drug. The exception is a single dose of radiation up to 8 Gray (equal to 800 RAD) with palliative intent for pain control up to 14 days before randomization.
More than one prior chemotherapy regimen administered in the metastatic setting.
Major surgery within 6 weeks prior to enrollment.
Untreated or symptomatic brain metastasis.
Women who are pregnant or breastfeeding.
Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, would significantly impede the absorption of an oral agent (e.g., intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection).
Unable or unwilling to swallow study drug.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure (CHF) Class II or higher according to the New York Heart Association (NYHA) Functional Classification, unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.
1. Known active infection with Human Immunodeficiency Virus (HIV), with measurable viral titer, and/or active infection with hepatitis B or C (participants who have had a hepatitis B virus [HBV] immunization are eligible).
2. Known active infection with SARS-CoV-2.
3. Clinically significant ascites or pleural effusions.
Known hypersensitivity to 5-FU/leucovorin.
Known hypersensitivity to irinotecan.
Abnormal glucuronidation of bilirubin: known Gilbert's syndrome.
Participants with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix or prostate, or other solid tumors curatively treated with no evidence of disease for > 2 years.
Any active disease condition that would render the protocol treatment dangerous or impair the ability of the participant to receive study drug.
Planned concomitant use of medications known to prolong the QT/QTc interval according to institutional guidelines.
Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia.
The following are exclusion criteria for bevacizumab:
1. History of cardiac disease: CHF Class II or higher according to the New York Heart Association (NYHA); active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or cardiac arrhythmias requiring anti arrhythmic therapy (beta blockers or digoxin are permitted).
2. Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management) and prior history of hypertensive crisis or hypertensive encephalopathy.
3. History of arterial thrombotic or embolic events (within 6 months prior to study entry).
4. Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease).
5. Evidence of bleeding diathesis or clinically significant coagulopathy.
6. Major surgical procedure (including open biopsy, significant traumatic injury, etc.) within 28 days, or anticipation of the need for major surgical procedure during the study, and minor surgical procedure (excluding placement of a vascular access device) within 7 days prior to study enrollment.
7. Proteinuria at Screening as demonstrated by urinalysis with proteinuria ≥ 2+ (participants discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
8. Abdominal fistula, GI perforation, peptic ulcer, or intra-abdominal abscess within the past 6 months.
9. Ongoing serious, non-healing wound, ulcer, or bone fracture.
10. Known hypersensitivity to any component of bevacizumab.
11. History of reversible posterior leukoencephalopathy syndrome (RPLS).
Use of strong CYP3A4 or UGT1A1 inhibitors or strong CYP3A4 inducers. Participants 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.

Facility	Status	City	State	ZIP	Country	Contacts
Mayo Clinic Cancer Center		Phoenix	Arizona	85054	United States
CARTI Cancer Center

PubMed Identifier	Type	Citation	Retractions
38231047	Result	Ahn DH, Barzi A, Ridinger M, Samuelsz E, Subramanian RA, Wu CC, Croucher PJP, Smeal T, Kabbinavar FF, Lenz HJ. Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Phase Ib Clinical Study. Clin Cancer Res. 2024 May 15;30(10):2039-2047. doi: 10.1158/1078-0432.CCR-23-3053.
39475591

ID	Title	Description
FG000	Phase 1b: Onvansertib 12 mg/m^2	Oral onvansertib 12 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
FG001

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 27, 2021	Jan 14, 2025

ID	Title	Description
BG000	Phase 1b: Onvansertib 12 mg/m^2	Oral onvansertib 12 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
BG001	Phase 1b: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
BG002	Phase 1b: Onvansertib 18 mg/m^2	Oral onvansertib 18 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
BG003	Phase 2: Onvansertib 15 mg/m^2	Oral onvansertib RP2D of 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle.
BG004	Total	Total of all reporting groups

Units	Counts
Participants	BG0009 BG0017 BG0026 BG00346 BG00468

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)

DLTs were defined as a Grade 4 hematologic adverse events (AEs), Grade ≥ 3 non-hematologic AEs that were considered related to the study drug and that did not resolve within 14 days following presentation with standard management and care, Grade ≥ 3 thrombocytopenia with bleeding, neutropenic fever, any death not clearly due to the underlying disease or extraneous causes, or any change in liver function that met Hy's Law criteria of a DLT.

Safety Analysis Set: defined as participants who received at least one dose of onvansertib in any cycle. Three participants enrolled in 15 mg/m^2 (2 in Phase 2 and 1 in Phase 1b) were inadvertently dosed at 12 mg/m^2 and are represented under Phase 1b 12 mg/m^2, as pre-specified in SAP section 9.4.

Posted

Count of Participants

Participants

Up to Day 28

ID	Title	Description
OG000	Phase 1b: Onvansertib 12 mg/m^2	Oral onvansertib 12 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
OG001	Phase 1b: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
OG002	Phase 1b: Onvansertib 18 mg/m^2	Oral onvansertib 18 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.

Units	Counts
Participants	OG0009 OG0017 OG0026

Title

Denominators

Categories

Title	Measurements
	OG0001 OG0011 OG0023

Primary

Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

AEs were defined as any untoward medical occurrence associated with the use of a drug in humans. TEAEs are defined as any AE that started on or after the first day of study treatment and within 30 days of the last administration of study treatment, or that worsened on or after the first day of study treatment. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 on a scale from Grade 1 (mild) to Grade 5 (death). An AE was considered "serious" if it resulted in death, life-threatening AE, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or congenital anomaly/birth defect. The Investigator determined relatedness to the use of onvansertib.

Clinically significant changes in vital signs, laboratory parameters, electrocardiograms, physical examinations, weight, and Eastern Cooperative Oncology Group (ECOG) performance status were reported as AEs.

Posted

Count of Participants

Participants

Up to a maximum of 81 weeks

ID	Title	Description
OG000	Phase 1b: Onvansertib 12 mg/m^2	Oral onvansertib 12 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.

Primary

All-Treated Analysis Set: Objective Response Rate (ORR)

ORR was defined as the percentage of participants documented to have a confirmed complete response (CR) or partial response (PR) using the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1). Two-sided 95% confidence interval (CI) was calculated using the exact binomial Clopper-Pearson method.

CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis).

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.

All-Treated Analysis Set: defined as participants who received at least 1 dose of assigned onvansertib in Cycle 1. Inclusive of the group of participants who were enrolled at 15 mg/m^2 in Phase 1b and Phase 2 (Part 1 and Part 2) as pre-specified in SAP section 9.4.2.

Posted

Number

95% Confidence Interval

percentage of participants

Up to a maximum of 131 weeks

ID	Title	Description
OG000	Phase 1b: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
OG001	Phase 2 Part 1: Onvansertib 15 mg/m^2

Secondary

Phase 2: Number of Participants With TEAEs

AEs were defined as any untoward medical occurrence associated with the use of a drug in humans. TEAEs are defined as any AE that started on or after the first day of study treatment and within 30 days of the last administration of study treatment, or that worsened on or after the first day of study treatment. AE severity was graded according to the CTCAE version 5.0 on a scale from Grade 1 (mild) to Grade 5 (death). An AE was considered "serious" if it resulted in death, life-threatening AE, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or congenital anomaly/birth defect. The Investigator determined relatedness to the use of onvansertib.

Clinically significant changes in vital signs, laboratory parameters, electrocardiograms, physical examinations, weight, and ECOG performance status were reported as AEs.

Safety Analysis Set: defined as participants who received at least one dose of onvansertib in any cycle. Two participants from Phase 2 15 mg/m^2 were inadvertently dosed at 12 mg/m^2 dose level, as pre-specified in SAP section 9.4.

Posted

Count of Participants

Participants

Up to a maximum of 131 weeks

ID	Title	Description
OG000	Phase 2: Onvansertib 15 mg/m^2	Oral onvansertib RP2D of 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle.

Secondary

All-Treated Analysis Set: Disease Control Rate (DCR)

DCR was defined as the percentage of participants documented to have a confirmed CR, PR or stable disease (SD) using the RECIST v1.1. Two-sided 95% CI was calculated using the exact binomial Clopper-Pearson method.

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.

SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).

PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.

Posted

Number

95% Confidence Interval

percentage of participants

Up to a maximum of 131 weeks

ID	Title	Description
OG000	Phase 1b: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.

Secondary

All-Treated Analysis Set: Progression-free Survival (PFS)

PFS was defined as the time in months from the date of first administration of study treatment until the first observation of PD or death due to any cause, whichever occurs first, i.e.: (date of first PD or death date of first administration of study treatment +1)/30.4375. Median and 95% CI were calculated using the Kaplan-Meier method. Participants who did not have an observed documented PD or death from any cause were censored at the latest tumor response assessment date.

PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.

Posted

Median

95% Confidence Interval

months

Up to a maximum of 131 weeks

ID	Title	Description
OG000	Phase 1b: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
OG001	Phase 2 Part 1: Onvansertib 15 mg/m^2

Secondary

All-Treated Analysis Set: Duration of Response (DoR)

DoR was calculated as the (date of first documented tumor progression or death due to any cause minus date of first documentation of a subsequently confirmed objective response plus 1)/30.4375. Participants who did not have an observed documented PD or death from any cause were censored at the latest tumor response assessment date.

Posted

Median

95% Confidence Interval

months

Up to a maximum of 131 weeks

ID	Title	Description
OG000	Phase 1b: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
OG001	Phase 2 Part 1: Onvansertib 15 mg/m^2	Oral onvansertib RP2D of 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle. Participants enrolled in Phase 2 before protocol v2 were categorized under Part 1 due to change in the Inclusion/Exclusion criteria.

Secondary

All-Treated Analysis Set: Overall Survival (OS)

OS was defined as the time in months from the date of first administration of study treatment until death due to any cause, i.e.: (Date of death date of first administration of study treatment +1)/30.4375. Participants who did not have documented death from any cause were censored at the date they were last known to be alive. OS was added as an endpoint with Protocol Amendment #1, therefore, OS data was only collected from then onward.

Posted

Median

95% Confidence Interval

months

Up to a maximum of 131 weeks

ID	Title	Description
OG000	Phase 1b: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
OG001	Phase 2 Part 1: Onvansertib 15 mg/m^2	Oral onvansertib RP2D of 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle. Participants enrolled in Phase 2 before protocol v2 were categorized under Part 1 due to change in the Inclusion/Exclusion criteria.

Secondary

All-Treated Analysis Set: Percentage Change in KRAS-mutant Allelic Fraction (MAF)

Blood samples were analyzed for the presence of circulating tumor DNA (ctDNA [including KRAS mutations]). KRAS-mutant allelic burden was based on liquid biopsies.

Posted

Mean

Standard Deviation

percentage change in MAF

Cycle 1 Day 1 and Cycle 2 Day 1 (28-day cycle length)

ID	Title	Description
OG000	Phase 1b: Onvansertib 15 mg/m^2	Oral onvansertib of 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
OG001	Phase 2 Part 1: Onvansertib 15 mg/m^2	Oral onvansertib RP2D of 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle. Participants enrolled in Phase 2 before protocol v2 were categorized under Part 1 due to change in the Inclusion/Exclusion criteria.

Secondary

Phase 2: Observed Plasma Concentration at the End of Each Dosing Interval (Ctrough) of Onvansertib

Plasma pharmacokinetic (PK) parameters for onvansertib were estimated using non-compartmental methods.

PK Analysis Set: defined as all participants in the safety analysis set who had at least one evaluable plasma concentration of onvansertib.

Posted

Mean

Standard Deviation

ng/mL

Pre-dose on Day 1 of Cycles 1 and 3 (28-day cycle length)

ID	Title	Description
OG000	Phase 2: Onvansertib 15 mg/m^2	Oral onvansertib RP2D of 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle.

Units	Counts
Participants	OG000

Post-Hoc

All-Treated Analysis Set: ORR by Bevacizumab Used in First-line Treatment

ORR was defined as the percentage of participants documented to have a confirmed CR or PR using the RECIST v1.1. Two-sided 95% CI was calculated using the exact binomial Clopper-Pearson method. Data are presented by bevacizumab used in first-line treatment yes versus no.

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.

Posted

Number

95% Confidence Interval

percentage of participants

Up to a maximum of 131 weeks

ID	Title	Description
OG000	Phase 1b; Bevacizumab Used in First-line Treatment: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
OG001	Phase 1b; Bevacizumab Not Used in First-line Treatment: Onvansertib 15 mg/m^2

Post-Hoc

All-Treated Analysis Set: PFS by Bevacizumab Used in First-line Treatment

PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.

Posted

Number

95% Confidence Interval

percentage of participants

Up to a maximum of 131 weeks

ID	Title	Description
OG000	Phase 1b; Bevacizumab Used in First-line Treatment: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.
OG001

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0009 events6 affected9 at risk EG00114 events6 affected7 at risk EG0029 events5 affected6 at risk EG00353 events29 affected46 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0009 events6 affected9 at risk EG00113 events6 affected7 at risk EG0025 events3 affected6 at risk EG003
Stomatitis	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0004 events4 affected9 at risk EG0018 events6 affected7 at risk EG0021 events1 affected6 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0003 events2 affected9 at risk EG00111 events4 affected7 at risk EG0025 events3 affected6 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG00011 events3 affected9 at risk EG0017 events4 affected7 at risk EG0022 events2 affected6 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0003 events3 affected9 at risk EG0012 events1 affected7 at risk EG0021 events1 affected6 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0002 events2 affected9 at risk EG0011 events1 affected7 at risk EG0022 events2 affected6 at risk EG003
Haemorrhoids	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0006 events3 affected9 at risk EG0010 events0 affected7 at risk EG0023 events1 affected6 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0003 events2 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Proctalgia	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Rectal haemorrhage	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0021 events1 affected6 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0002 events2 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Flatulence	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Abdominal discomfort	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Abdominal tenderness	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Dysphagia	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Gingival pain	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0012 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Gingival recession	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Haematochezia	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Oral dysaesthesia	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Oral pain	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Periodontal disease	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Toothache	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Anal fissure	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0002 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Anal incontinence	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Anorectal discomfort	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Cheilitis	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Eructation	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Gingival bleeding	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Glossodynia	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Haemorrhoidal haemorrhage	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hypoaesthesia oral	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Mouth swelling	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Oesophageal pain	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Oesophageal spasm	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Paraesthesia oral	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Rectal fissure	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Small intestinal obstruction	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Fatigue	General disorders	MedDRA (21.1)	Systematic Assessment	EG00022 events8 affected9 at risk EG0019 events7 affected7 at risk EG0028 events4 affected6 at risk EG003
Pyrexia	General disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0014 events4 affected7 at risk EG0020 events0 affected6 at risk EG003
Non-cardiac chest pain	General disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Oedema peripheral	General disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Asthenia	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Chills	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Chest discomfort	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Chest pain	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Complication associated with device	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Device related thrombosis	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Influenza like illness	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Malaise	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Oedema	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Peripheral swelling	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Neutrophil count decreased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0007 events4 affected9 at risk EG0014 events3 affected7 at risk EG00212 events5 affected6 at risk EG003
White blood cell count decreased	Investigations	MedDRA (21.1)	Systematic Assessment	EG00010 events5 affected9 at risk EG0014 events2 affected7 at risk EG0029 events5 affected6 at risk EG003
Platelet count decreased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0005 events4 affected9 at risk EG0011 events1 affected7 at risk EG0023 events3 affected6 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0003 events3 affected9 at risk EG0011 events1 affected7 at risk EG0023 events1 affected6 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Blood alkaline phosphatase increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0012 events2 affected7 at risk EG0021 events1 affected6 at risk EG003
Lymphocyte count decreased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0003 events2 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Weight decreased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Blood bicarbonate decreased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Electrocardiogram QT prolonged	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Blood bilirubin increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Blood chloride increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Blood creatine increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0002 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Blood lactate dehydrogenase increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Electrocardiogram ST-T segment abnormal	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Electrocardiogram T wave abnormal	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
International normalised ratio increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Wall motion score index abnormal	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Weight increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA (21.1)	Systematic Assessment	EG0006 events5 affected9 at risk EG0012 events2 affected7 at risk EG0026 events4 affected6 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA (21.1)	Systematic Assessment	EG0007 events2 affected9 at risk EG0015 events3 affected7 at risk EG0022 events2 affected6 at risk EG003
Leukopenia	Blood and lymphatic system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0023 events1 affected6 at risk EG003
Leukocytosis	Blood and lymphatic system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Eosinophilia	Blood and lymphatic system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0004 events2 affected9 at risk EG0012 events2 affected7 at risk EG0021 events1 affected6 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0012 events2 affected7 at risk EG0021 events1 affected6 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0013 events1 affected7 at risk EG0021 events1 affected6 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0002 events2 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Hyperphosphataemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0023 events2 affected6 at risk EG003
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0022 events2 affected6 at risk EG003
Hypercalcaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hypernatraemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Hyperalbuminaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Hyperlipidaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hypermagnesaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Vitamin B12 deficiency	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Headache	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0012 events2 affected7 at risk EG0022 events2 affected6 at risk EG003
Peripheral sensory neuropathy	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0021 events1 affected6 at risk EG003
Dizziness	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Neuropathy peripheral	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Peripheral motor neuropathy	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Disturbance in attention	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Dysarthria	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Tremor	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Ageusia	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Amnesia	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Cognitive disorder	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Dystonia	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hypoaesthesia	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Memory impairment	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Muscle contractions involuntary	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Neuralgia	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Neurotoxicity	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Restless legs syndrome	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0002 events2 affected9 at risk EG0013 events3 affected7 at risk EG0021 events1 affected6 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0002 events2 affected9 at risk EG0011 events1 affected7 at risk EG0021 events1 affected6 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0022 events2 affected6 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0002 events1 affected9 at risk EG0012 events2 affected7 at risk EG0020 events0 affected6 at risk EG003
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hiccups	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Sinus congestion	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0012 events2 affected7 at risk EG0020 events0 affected6 at risk EG003
Upper-airway cough syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Laryngospasm	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Productive cough	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Respiratory tract congestion	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Sinus pain	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Sleep apnoea syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Sneezing	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Wheezing	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0005 events5 affected9 at risk EG0013 events3 affected7 at risk EG0023 events3 affected6 at risk EG003
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0012 events2 affected7 at risk EG0020 events0 affected6 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Skin hyperpigmentation	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Acne	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Nail disorder	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Papule	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Pruritus generalised	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Rash generalised	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Skin exfoliation	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Skin fissures	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Skin odour abnormal	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Umbilical discharge	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Umbilical erythema	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Urticaria	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hypertension	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0007 events3 affected9 at risk EG0013 events3 affected7 at risk EG0023 events2 affected6 at risk EG003
Hypotension	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hot flush	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Embolism	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Flushing	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Pelvic venous thrombosis	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Thrombosis	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Corona virus infection	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0012 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Sepsis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Sinusitis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Candida infection	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Cellulitis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Gingivitis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Helicobacter infection	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Herpes dermatitis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Herpes virus infection	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hordeolum	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Influenza	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Liver abscess	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Localised infection	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Oral candidiasis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Pilonidal cyst	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Pneumonia	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Subcutaneous abscess	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Viral upper respiratory tract infection	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0022 events2 affected6 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0012 events2 affected7 at risk EG0020 events0 affected6 at risk EG003
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0012 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Flank pain	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0013 events2 affected7 at risk EG0020 events0 affected6 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0003 events1 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Osteoporosis	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Temporomandibular joint syndrome	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Insomnia	Psychiatric disorders	MedDRA (21.1)	Systematic Assessment	EG0002 events2 affected9 at risk EG0012 events2 affected7 at risk EG0021 events1 affected6 at risk EG003
Anxiety	Psychiatric disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0021 events1 affected6 at risk EG003
Depression	Psychiatric disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Confusional state	Psychiatric disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Personality change	Psychiatric disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Dysuria	Renal and urinary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0013 events2 affected7 at risk EG0021 events1 affected6 at risk EG003
Proteinuria	Renal and urinary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Urinary tract obstruction	Renal and urinary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0012 events2 affected7 at risk EG0020 events0 affected6 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Bladder spasm	Renal and urinary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Chromaturia	Renal and urinary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Haematuria	Renal and urinary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Urine flow decreased	Renal and urinary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Vision blurred	Eye disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Lacrimation increased	Eye disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Dry eye	Eye disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Eye irritation	Eye disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Contusion	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Arthropod bite	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Dental restoration failure	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Gastrostomy tube site complication	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Limb injury	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Reaction to previous exposure to any vaccine	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Skin laceration	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Stoma site inflammation	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Tooth injury	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Wound	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected0 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Sinus tachycardia	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Left ventricular dysfunction	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Palpitations	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Sinus bradycardia	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Tachycardia	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Sinus operation	Surgical and medical procedures	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Ear pain	Ear and labyrinth disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0021 events1 affected6 at risk EG003
Vertigo	Ear and labyrinth disorders	MedDRA (21.1)	Systematic Assessment	EG0001 events1 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Portal vein thrombosis	Hepatobiliary disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0010 events0 affected7 at risk EG0020 events0 affected6 at risk EG003
Multiple allergies	Immune system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003
Pelvic pain	Reproductive system and breast disorders	MedDRA (21.1)	Systematic Assessment	EG0000 events0 affected9 at risk EG0011 events1 affected7 at risk EG0020 events0 affected6 at risk EG003

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D004066	Digestive System Diseases
D005767	Gastrointestinal Diseases
D003108	Colonic Diseases
D007410	Intestinal Diseases
D012002	Rectal Diseases

ID	Term
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Phase 1b: Onvansertib 12 mg/m^2	Oral onvansertib 12 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.	0	9	2	9	9	9
EG001	Phase 1b: Onvansertib 15 mg/m^2	Oral onvansertib 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.	0	7	3	7	7	7
EG002	Phase 1b: Onvansertib 18 mg/m^2	Oral onvansertib 18 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab.	0	6	1	6	6	6
EG003	Phase 2: Onvansertib 15 mg/m^2	Oral onvansertib RP2D of 15 mg/m^2 received on Days 1 through 5 and Days 15 through 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-FU, and 2400 mg/m^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle.	1	46	17	46	46	46

ID	Term
C000706408	onvansertib
D000068258	Bevacizumab
C480833	IFL protocol