Testing the Addition of an Anticancer Drug, BAY 1895344, to the Usual Chemotherapy With FOLFIRI in Advanced or Metastatic Cancers of the Stomach and Intestines

Inclusion Criteria:

• For Dose Escalation: Patients must have histologically or cytologically confirmedadvanced or metastatic gastrointestinal (GI) cancers with Response EvaluationCriteria in Solid Tumors 1.1 (RECIST1.1) measurable disease who have progressed onat least one prior treatment for metastatic disease and for whom FOLFIRI isconsidered a reasonable treatment option. Patients with mismatch repair deficiencyshould have progressed on immunotherapy

• For Dose Expansion: Patients must have either:

• Colorectal cancer who have previously progressed on irinotecan and tolerated anirinotecan dose equal to or greater than the recommended phase 2 dose (RP2D).If they have mismatch repair deficiency they should have progressed onimmunotherapy OR

• Gastroesophageal cancer who have progressed on at least one first-line therapyfor metastatic disease. If they have mismatch repair deficiency they shouldhave progressed on immunotherapy

• For Dose Expansion: Patients be willing to undergo biopsies for research purposesonly. The accessible tumor can be the primary or metastatic tumor site. Bothresearch biopsies should be taken from the same tumor site

• Patients must have progressive disease on at least first-line therapy for metastaticdisease. Previous treatment with irinotecan is allowed

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of BAY 1895344 in combination with FOLFIRI in patients <18 years of age,children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN

• Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 using the Chronic KidneyDisease Epidemiology Collaboration (CKD-EPI) equation

• International normalization ratio (INR) =< 1.5 × ULN unless participant is receivinganticoagulant therapy, in which case prothrombin time (PT) or activated partialthromboplastin time (aPTT) should be within expected therapeutic range ofanticoagulants. If patient has a new diagnosis of venous thromboembolism (VTE), thenpatient should be appropriately anticoagulated with low molecular weight heparin (LMWH) or direct acting oral anticoagulants (DOACs) and be clinically stable for atleast 1 week post treatment onset

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy, that does not interact with study therapy, with undetectable viral loadwithin 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy that does not interact withstudy therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load and HCV therapy does notinteract with study therapy

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• The effects of BAY 1895344 on the developing human fetus are unknown. For thisreason and because DNA-damage response inhibitors agents as well as othertherapeutic agents used in this trial, 5-FU and irinotecan, are known to beteratogenic, women of child-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation and for 6 months aftercompletion of BAY 1895344 administration

• Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, she should inform her treatingphysician immediately. Men treated or enrolled on this protocol must also agreeto use adequate contraception prior to the study, for the duration of studyparticipation, and 6 months after completion of study treatment administration

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• Patients with a history of prior treatment with an ATR inhibitor

• Patients with a history of other malignancy that could affect compliance with theprotocol or interpretation of the results

• Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study

• 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

• History of hypersensitivity or allergic reactions attributed to compounds of similarchemical or biologic composition to BAY 1895344, 5-FU, leucovorin, or irinotecan.Patient eligibility can be discussed with the primary investigator (PI) if priorreactions do not seem to warrant excluding the patient

• Patients receiving any medications that are substrates of CYP3A4 with a narrowtherapeutic window or strong inhibitors/inducers of CYP3A4 are ineligible, if theycannot be transferred to alternative medication. Because the lists of these agentsare constantly changing, it is important to regularly consult a frequently-updatedmedical reference. As part of the enrollment/informed consent procedures, thepatient will be counseled on the risk of interactions with other agents, and what todo if new medications need to be prescribed or if the patient is considering a newover-the-counter medicine or herbal product

• Patients with uncontrolled intercurrent illness

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Gastrointestinal pathology or history that adversely impact the ability to take orabsorb oral medication

• Pregnant women are excluded from this study because BAY 1895344 as a DNA-damageresponse inhibitor may have the potential for teratogenic or abortifacient effects.Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with BAY 1895344 breastfeeding should bediscontinued if the mother is treated with BAY 1895344 and for 4 months after end oftreatment. These potential risks may also apply to other agents used in this study

• Patients who were unable to tolerate prior irinotecan treatment are excluded fromthis study

• Patients with a corrected QT (QTc) interval >= 470 msec are excluded from this study