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
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
This phase I trial investigates the best dose, possible benefits and/or side effects of BAY
 1895344 in combination with FOLFIRI in treating patients with stomach or intestinal cancer
 that is unlikely to be cured or controlled with treatment or has spread to other places in
 the body (advanced or metastatic). BAY 1895344 may stop the growth of tumor cells by blocking
 some of the enzymes needed for cell growth. Chemotherapy drugs, such as irinotecan,
 fluorouracil, and leucovorin, (called FOLFIRI in short) work in different ways to stop the
 growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
 stopping them from spreading. Giving BAY 1895344 in combination with FOLFIRI may help shrink
 advanced or metastatic stomach and/or intestinal cancer.
PRIMARY OBJECTIVE:

 I. Determine the safety and maximum tolerated dose (MTD) of ATR kinase inhibitor BAY1895344
 (BAY 1895344) with leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI).

 SECONDARY OBJECTIVES:

 I. To observe and record anti-tumor activity by overall response rate (ORR), progression-free
 survival (PFS), and overall survival (OS).

 II. Determine the response and clinical benefit rate (complete response + partial response +
 stable disease) of BAY 1895344 with FOLFIRI in colorectal and gastric/gastroesophageal
 cancers.

 III. Evaluate tumor and peripheral blood mononuclear cell (PBMC) deoxyribonucleic acid (DNA)
 damage signaling in the context of the chemotherapy backbone alone and when combined with BAY
 1895344.

 IV. Evaluate the pharmacokinetics (PK) profile of fluorouracil (5-FU) and irinotecan.

 V. Evaluate the PK profile of BAY 1895344. VI. Evaluate the relationship between ATM status
 by immunohistochemistry (IHC) and clinical efficacy of the BAY 1895344/FOLFIRI combination.

 EXPLORATORY OBJECTIVES:

 I. Evaluate the exposure-response relationship between drug exposures and toxicity and
 response, and UGT1A1 genotype.

 II. Evaluate the relationship between tumor mutations and clinical efficacy of the BAY
 1895344/FOLFIRI combination.

 OUTLINE: This is a dose-escalation study of BAY 1895344, irinotecan, and fluorouracil with
 fixed-dose leucovorin followed by a dose-expansion study.

 Patients receive BAY 1895344 orally (PO) twice daily (BID) on days 1, 2, 15, and 16 and
 irinotecan hydrochloride intravenously (IV) over 90 minutes, fluorouracil IV over 46 hours,
 and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of
 disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up for 30 days and then every 3
 months for up to 1 year or until their disease gets worse or they begin a new treatment for
 their cancer.
Inclusion Criteria:

 -  For Dose Escalation: Patients must have histologically or cytologically confirmed
 advanced or metastatic gastrointestinal (GI) cancers with Response Evaluation Criteria
 in Solid Tumors 1.1 (RECIST1.1) measurable disease who have progressed on at least one
 prior treatment for metastatic disease and for whom FOLFIRI is considered a reasonable
 treatment option

 -  For Dose Expansion: Patients must have either:

 -  Colorectal cancer who have previously progressed on irinotecan and tolerated an
 irinotecan dose equal to or greater than the RP2D OR

 -  Gastroesophageal cancer who have progressed on at least one first-line therapy
 for metastatic disease

 -  For Dose Expansion: Patients be willing to undergo biopsies for research purposes
 only. The accessible tumor can be the primary or metastatic tumor site. Both research
 biopsies should be taken from the same tumor site

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

 -  Patients must be >= 3 weeks since completion of the previous chemotherapy regimen

 -  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 Kidney
 Disease Epidemiology Collaboration (CKD-EPI) equation

 -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
 therapy, that does not interact with study 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 that does not interact with study
 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 and HCV therapy does not interact
 with study therapy

 -  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 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 2B or better

 -  The effects of BAY 1895344 on the developing human fetus are unknown. For this reason
 and because DNA-damage response inhibitors agents as well as other therapeutic agents
 used in this trial, 5-FU and irinotecan, are known to be teratogenic, 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 and for 6 months after completion of BAY 1895344 administration

 -  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. Men treated or enrolled on this protocol must also agree to use
 adequate contraception prior to the study, for the duration of study
 participation, and 6 months after completion of study treatment administration

 -  Ability to understand and the willingness to sign a written informed consent document.
 Participants with impaired decision-making capacity (IDMC) who have a
 legally-authorized representative (LAR) and/or family member available will also be
 eligible

 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 the
 protocol or interpretation of the results

 -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
 nitrosoureas 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 similar
 chemical or biologic composition to BAY 1895344, 5-FU, leucovorin, or irinotecan

 -  Patients receiving any medications that are substrates of CYP3A4 with a narrow
 therapeutic window or strong inhibitors/inducers of CYP3A4 are ineligible, if they
 cannot be transferred to alternative medication. Because the lists of these agents are
 constantly changing, it is important to regularly consult a frequently-updated medical
 reference. As part of the enrollment/informed consent procedures, the patient will be
 counseled on the risk of interactions with other agents, and what to do if new
 medications need to be prescribed or if the patient is considering a new
 over-the-counter medicine or herbal product

 -  Patients with uncontrolled intercurrent illness

 -  Patients with psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Gastrointestinal pathology or history that adversely impact the ability to take or
 absorb oral medication

 -  Pregnant women are excluded from this study because BAY 1895344 as a DNA-damage
 response inhibitor may have 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 BAY 1895344 breastfeeding should be
 discontinued if the mother is treated with BAY 1895344 and for 4 months after end of
 treatment. These potential risks may also apply to other agents used in this study