Onvansertib in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients With a KRAS Mutation

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.