Inclusion Criteria:

• Histologically confirmed metastatic and/or unresectable colorectal cancer (CRC).
• Documentation of a kirsten rat sarcoma virus gene (KRAS) or neuroblastoma-RAS (NRAS) mutation in exon 2, 3, or 4 in primary tumor or metastasis, assessed by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
• Age ≥ 18 years.
• Participants with tumors that have progressed on an oxaliplatin/fluoropyrimidine--based regimen with or without bevacizumab.
• Participants must have had systemic therapy within 180 days of the screening visit.
• Participants must have, at any time previously, received oxaliplatin-based chemotherapy with or without bevacizumab (≥ 6 weeks in duration).
• Participants who received oxaliplatin/fluoropyrimidine-based neoadjuvant, adjuvant, and/or fluoropyrimidine maintenance or adjuvant therapy and have disease recurrence or progression > 6 months from their last dose of oxaliplatin will be required to have received oxaliplatin/fluoropyrimidine-based therapy with or without bevacizumab as first-line treatment for metastatic disease.
• Participants who received an oxaliplatin-based regimen in the first-line setting and discontinued oxaliplatin because of toxicity or who received oxaliplatin for maintenance therapy are eligible as long as progression occurred < 6 months after the last dose of oxaliplatin therapy for advanced metastatic disease. It is recommended that these participants be re-challenged (if feasible) with oxaliplatin/fluoropyrimidine therapy and subsequently progress prior to eligibility. Participants with oxaliplatin-related neuropathy or oxaliplatin infusion-related hypersensitivity that cannot be rechallenged with oxaliplatin are eligible.
• Participants must not have received prior treatment with irinotecan.
• FOLFIRI therapy is appropriate for the participant as determined by the Investigator.
• Imaging computed tomography (CT) or 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 participants 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. All subsequent scans must consistently use the same imaging modality for comparison with the Screening scan throughout the study.
• Must have acceptable organ function.
• Signed informed consent to provide blood sample(s) for specific correlative assays.

Exclusion Criteria:

• Concomitant KRAS or NRAS and BRAF-V600 mutation or Microsatellite Instability High/Deficient Mismatch Repair (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 enrollment, provided it is not the target lesion.
• More than 1 prior chemotherapy regimen administered in the metastatic setting.
• Major surgery within 6 weeks prior to enrollment.
• Untreated or symptomatic brain metastasis.
• 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.
• Known hypersensitivity to fluoropyrimidine or leucovorin.
• Known hypersensitivity to irinotecan.
• Abnormal glucuronidation of bilirubin; known Gilbert's syndrome.
• QT interval:
  • Fridericia's correction (QTcF) > 470 milliseconds. The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate electrocardiograms (ECGs). In the case of potentially correctible causes of QT prolongation that are readily corrected (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 according to institutional guidelines;
  • Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia.
• Use of strong cytochrome P450 3A4 (CYP3A4) or cytochrome P450 2C19 (CYP2C19) inhibitors or strong CYP3A4 inducers. Participants currently receiving these agents who can be switched 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.
• The following are exclusion criteria for bevacizumab:
  • History of cardiac disease: Congestive heart failure (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, with the exception of participants who have been receiving therapy and are deemed by the Investigator to have stable/controlled disease;
  • Current uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic blood 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 (eg, 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+ (participants discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours to be eligible);
  • Abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within the past 6 months;
  • Ongoing serious, non-healing wound, ulcer, or bone fracture;
  • Known hypersensitivity to any component of bevacizumab;
  • History of reversible posterior leukoencephalopathy syndrome.

Eligibility last updated 3/17/23. Questions regarding updates should be directed to the study team contact.