Clinical Trial of an Anti-cancer Drug, CA-4948 (Emavusertib), in Combination With Chemotherapy Treatment (FOLFOX Plus Bevacizumab) in Metastatic Colorectal Cancer

Inclusion Criteria:

* Patients must have histologically or cytologically confirmed colorectal adenocarcinoma
* Patients must have unresectable or metastatic measurable disease on imaging for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 determination within 28 days of registration
* For patients enrolling to the expansion cohort, lesions must be amenable to research biopsy
* Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of CA-4948 (emavusertib) and FOLFOX in combination with bevacizumab in patients \< 18 years of age, children are excluded from this study
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (or Karnofsky ≥ 60%)
* Absolute neutrophil count ≥ 1,500/mcL (within 28 days of registration)
* Platelets ≥ 75,000/mcL (within 28 days of registration)
* Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (within 28 days of registration)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 × institutional ULN; for those with liver metastases, 5 × institutional ULN (within 28 days of registration)
* Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m\^2 (within 28 days of registration)
* Creatine phosphokinase (CPK) elevation at screening \< grade 2 (CPK ≤ 2.5 x ULN) (within 28 days of registration)
* Patients on a cholesterol lowering statin must be on a stable dose with no dose changes within 3 weeks prior to study start
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
* Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible, after discussion with the principal investigator (PI) or National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) Investigational Drug Branch (IDB) Monitor, if the treating physician determines that immediate CNS-specific treatment is not required and is unlikely to be required during the first cycle of therapy
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
* Patients must be able to take oral medications
* The effects of CA-4948 (emavusertib) on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Women of childbearing potential must continue contraception for 9 months following the last dose of study drugs. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol and involved with women of childbearing potential must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months following the last dose of study drugs
* Patients must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Patients with high-frequency microsatellite instability (MSI-H) or deficient deoxyribonucleic acid (DNA) mismatch repair (dMMR) colorectal cancer at pre-enrollment screening
* Patients with prolonged QT interval by Fridericia's correction formula (QTcF) (\> 450ms) on screening electrocardiogram (ECG)
* Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1), with the exception of alopecia
* Patients who are receiving any other investigational agents
* Patients who have received prior treatment with any chemotherapy (either in the adjuvant or metastatic setting), including FOLFOX, fluorouracil/leucovorin/irinotecan (FOLFIRI), folinic acid/fluorouracil/oxaliplatin/irinotecan (FOLFOXIRI), or antiangiogenic agents such as bevacizumab and similar agents, are not eligible for this study
* Patients with a known dihydropyrimidine dehydrogenase deficiency
* Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to CA-4948 (emavusertib) or other agents used in the study
* Patients with a gastrointestinal (GI) condition that could impair absorption of CA-4948 (emavusertib) or cause an inability to ingest CA-4948 (emavusertib)
* Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
* Pregnant women are excluded from this study because CA-4948 (emavusertib) is a blood-brain barrier penetrant with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CA-4948 (emavusertib), breastfeeding should be discontinued if the mother is treated with CA-4948 (emavusertib). These potential risks may also apply to other agents used in this study. Women of childbearing potential must have a negative pregnancy test within 7 days of study registration
* Patients with a history of allogeneic organ or stem cell transplantation
* Patients with significant active bleeding or those in whom the treating physician believes bevacizumab would not be safe or appropriate
* Patients who have had palliative radiation to bone metastases within 2 weeks prior to day 1 of the study treatment
* Patients who have had a major surgical procedure within 4 weeks prior to day 1 of the study treatment
* Patients with hypertension not controlled by antihypertensive medication
* Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) within 14 days prior to treatment; however,

  * Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea; or chronic daily treatment with corticosteroids with a dose of ≤ 10 mg/day methylprednisolone equivalent) may be enrolled
  * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
* Severe infections within 28 days prior to treatment, including but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. This includes receipt of oral or IV antibiotics within 14 days prior to registration. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible