Inclusion Criteria:

• Histologically confirmed metastatic and unresectable CRC. 
• Kras mutation in exon 2, 3 or 4 in primary tumor or metastasis, assessed by a CLIA-certified lab. Subjects with concomitant Kras and BRAF-V600 utations are excluded from this study. Subjects with MSI-H/ddMMR (Microsatellite Instability High/Deficient Mismatch Repair) are also ineligible for enrollment in this study. 
• Age ≥ 18 years old. 
• ECOG Performance Status of 0 or 1. 
• Subject is not receiving any other cancer therapy. Patients participating in surveys or observational studies are allowed. 
• Has failed treatment or is intolerant of fluoropyrimidine and oxaliplatin with or without bevacizumab.
  • 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 radiologic progression during or < 6 months after the last dose of first-line therapy.
  • 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.
  • 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. 
  • For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen. 
  • 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.
• FOLFIRI therapy is appropriate for the patient as determined by the Investigator. 
• 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. 
• Must have acceptable organ function. 
• 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.
• Patient 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 (Microsatellite Instability High/Deficient Mismatch Repair).
• Anti-cancer chemotherapy or biologic therapy administered within 4 weeks 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 randomization. 
• Untreated 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.
  • Known active infection with Human Immunodeficiency Virus (HIV), with measurable viral titer, and/or active infection with hepatitis B or C (patients who have had a hepatitis B virus [HBV] immunization are eligible).
  • Clinically significant ascites or pleural effusions.
• Known hypersensitivity to 5-fluorouracil/leucovorin.
• Known hypersensitivity to irinotecan.
• Abnormal glucuronidation of bilirubin, known Gilbert’s syndrome.
• Patients with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, 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 patient to receive study drug.
• Any condition (e.g., psychological, geographical, etc.) that does not permit compliance with the protocol.
• QT interval with Fridericia’s correction (QTcF) > 470 milliseconds (Vandenberk 2016). The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT prolongation, (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during Screening and that result may be used to determine eligibility.
• Planned concomitant use of medications known to prolong the QT/QTc interval. 
• 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:
  • History of cardiac disease: congestive heart failure (CHF) > NYHA Class II; 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, with the exception of subjects who have been receiving therapy and are deemed by the investigator to have stable/controlled disease;
  • 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;
  • History of arterial thrombotic or embolic events (within 6 months prior to study entry);
  • Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease);
  • Evidence of bleeding diathesis or clinically significant coagulopathy;
  • 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;
  • Proteinuria at Screening as demonstrated by urinalysis with proteinuria ≥ 2+ (patients 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);
  • History of abdominal fistula, GI perforation, peptic ulcer, or intra-abdominal abscess within 6 months;
  • Ongoing serious, non-healing wound, ulcer, or bone fracture;
  • Known hypersensitivity to any component of bevacizumab;
  • History of reversible posterior leukoencephalopathy syndrome (RPLS).