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Patients receive elimusertib PO QD on days 2, 3, 16, and 17 and irinotecan hydrochloride 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. Patients undergo tumor biopsy during screening and on study and blood sample collection and imaging throughout the study.

Biopsy

Biospecimen Collection

Diagnostic Imaging

Elimusertib

Irinotecan Hydrochloride

Leucovorin Calcium

Liza C Villaruz

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 that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or has spread from where it first started (primary site) to other places in the body (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 elimusertib (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 elimusertib, irinotecan, and fluorouracil with fixed-dose leucovorin followed by a dose-expansion study.

Patients receive elimusertib orally (PO) once daily (QD) on days 2, 3, 16, and 17 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. Patients undergo tumor biopsy during screening and on study and blood sample collection and imaging throughout the study.

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.

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

Phase I/Ib Trial of ATR Inhibitor BAY 1895344 in Combination With FOLFIRI in GI Malignancies With a Focus on Metastatic Colorectal and Gastric/Gastroesophageal Cancers

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Logistic regression and proportional hazards (Cox) regression will be used to assess the relationships between exposure and response and toxicity; exposure-response will be assessed within disease cohorts of sufficient size, while exposure-toxicity will pool all patients. All patients will be used for the E-R analyses. Advanced population PK methods may be employed at a later stage to assess the link between drug exposure and biological effects and efficacy.

Assessed by whole exome sequencing and ribonucleic acid sequencing. The efficacy analyses will be repeated by DDR tumor mutation status, but these analyses will have limited sample sizes and will not be adequately powered for statistical comparisons.

A BOIN - Bayesian Optimal intervals trial design will be used to determine the MTD.

Assessed per Response Evaluation Criteria in Solid Tumors. The probability of clinical response (complete response \[CR\]+partial response \[PR\]) and disease control (CR+PR+stable disease) will be estimated within the disease cohorts, with consideration of previous irinotecan exposure, with exact 95% binomial confidence intervals.

PFS will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions.

OS will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions.

Signaling during the pharmacokinetics (PK) lead-in and in combination with BAY 1895344 will be compared with a non-parametric paired test (e.g. Wilcoxon rank test), at a significance level at p \< 0.05. For tumors, this will be performed only for patients in the dose expansion cohorts.

Signaling during the PK lead-in and in combination with BAY 1895344 will be compared with a non-parametric paired test (e.g. Wilcoxon rank test), at a significance level at p \< 0.05. For tumors, this will be performed only for patients in the dose expansion cohorts.

PK during the PK lead-in and in combination with BAY 1895344 will be compared with a non-parametric paired test, at a significance level at p \< 0.05.

PK of BAY 1895344 in combination with irinotecan and fluorouracil will be compared with historical controls in an exploratory fashion.

Will be assessed by immunohistochemistry (IHC) and PFS. The association between ATM and responses will be described, with a table outlining patients who achieved progressive disease, stable disease, partial or complete responses and whether they exhibited ATM expression by IHC or not.

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT04535401	Advanced Colore... Advanced Digest... Advanced Gastri... Advanced Gastro... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Colo... Metastatic Dige... Metastatic Gast... Metastatic Gast... Stage III Color... Stage IV Colore...	Biopsy Biospecimen Col... Diagnostic Imag... Elimusertib Fluorouracil Irinotecan Hydr... Leucovorin Calc...	18 Years -	National Cancer Institute (NCI)
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	NCT04535401	Advanced Colore... Advanced Digest... Advanced Gastri... Advanced Gastro... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Colo... Metastatic Dige... Metastatic Gast... Metastatic Gast... Stage III Color... Stage IV Colore...	Biopsy Biospecimen Col... Diagnostic Imag... Elimusertib Fluorouracil Irinotecan Hydr... Leucovorin Calc...	18 Years -	National Cancer Institute (NCI)
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	NCT04535401	Advanced Colore... Advanced Digest... Advanced Gastri... Advanced Gastro... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Colo... Metastatic Dige... Metastatic Gast... Metastatic Gast... Stage III Color... Stage IV Colore...	Biopsy Biospecimen Col... Diagnostic Imag... Elimusertib Fluorouracil Irinotecan Hydr... Leucovorin Calc...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for advanced digestive system carcinoma