Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Carcinoma

Small Cell Lung Carcinoma

Carcinoma, Neuroendocrine

Adenocarcinoma

Pancreatic Neoplasms

Carcinoma, Small Cell

Lung Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Carcinoma, Bronchogenic

Bronchial Neoplasms

Small Cell Lung Cancer

Pancreatic Cancer

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Irinotecan

Topotecan

Camptothecin

Topoisomerase I Inhibitors

Enzyme Inhibitors

Patients receive elimusertib PO BID on days 1 and 2 and irinotecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

Patients receive elimusertib PO QD on days 2, 3, 9, 10, 16, and 17 of cycle 1 and 2, and on days 2, 3, 9, and 10 of each cycle thereafter. Patients receive irinotecan IV over 90 minutes on days 1, 8, and 15 of cycle 1 and 2, and on days 1 and 8 of each cycle thereafter. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

Patients receive elimusertib PO QD on days 2 and 5 and topotecan IV over 30 minutes on days 1-5 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

Biopsy

Biospecimen Collection

Computed Tomography

Elimusertib

Irinotecan Hydrochloride

Magnetic Resonance Imaging

Topotecan Hydrochloride

Thatcher Heumann

This phase I trial investigates the side effects and best dose of BAY 1895344 when given together with usual chemotherapy (irinotecan or topotecan) in treating patients with solid tumors that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced), with a specific focus on small cell lung cancer, poorly differentiated neuroendocrine cancer, and pancreatic cancer. BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as irinotecan and topotecan, 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. Adding BAY 1895344 to irinotecan or topotecan may help to slow the growth of tumors for longer than seen with those drugs alone.

PRIMARY OBJECTIVES:

I. To assess safety and tolerability of each of the elimusertib (BAY 1895344) plus topoisomerase 1 (top1) inhibitor (irinotecan hydrochloride \[irinotecan\] or topotecan hydrochloride \[topotecan\]) combinations.

II. To estimate maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of each of the combinations.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To estimate objective response rate (ORR), progression free survival (PFS), overall survival (OS) and duration of response (DOR) in patients treated with each combination.

III. To estimate plasma pharmacokinetic (PK) characteristics of BAY 1895344 plus each top1 inhibitor (irinotecan or topotecan) when used in combination.

IV. To estimate changes in pharmacodynamic (PD) markers of deoxyribonucleic acid (DNA) damage (gamma-H2AX, phosphorylated \[p\]S343-NBS1) elicited by each combination from on-treatment tumor biopsies (in dose expansion cohorts only).

EXPLORATORY OBJECTIVES:

I. To estimate response outcomes (ORR, PFS, OS, DOR) in study patients by tumor ataxia telangiectasia mutated (ATM) expression loss (assessed by immunohistochemistry \[IHC\]).

II. To estimate response outcomes (ORR, PFS, OS, DOR) in study patients with tumor DNA damage response (DDR) mutations (assessed by whole exome sequencing \[WES\], ribonucleic acid \[RNA\] sequencing \[RNA Seq\], and circulating tumor DNA \[ctDNA\] analysis).

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 3 cohorts.

COHORT I: Patients receive elimusertib orally (PO) twice daily (BID) on days 1 and 2 and irinotecan intravenously (IV) over 90 minutes on day 1 of each cycle. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

COHORT II: Patients receive elimusertib PO once daily (QD) on days 2, 3, 9, 10, 16, and 17 of cycle 1 and 2, and on days 2, 3, 9, and 10 of each cycle thereafter. Patients receive irinotecan IV over 90 minutes on days 1, 8, and 15 of cycle 1 and 2, and on days 1 and 8 of each cycle thereafter. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

COHORT III: Patients receive elimusertib PO QD on days 2 and 5 and topotecan IV over 30 minutes on days 1-5 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

After completion of study treatment, patients are followed every 2 months for up to 6 months.

Testing the Addition of an Anti-cancer Drug, BAY 1895344, to Usual Chemotherapy for Advanced Stage Solid Tumors, With a Specific Focus on Patients With Small Cell Lung Cancer, Poorly Differentiated Neuroendocrine Cancer, and Pancreatic Cancer

BAY 1895344 Plus Topoisomerase-1 (Top1) Inhibitors in Patients With Advanced Solid Tumors, Phase I Studies With Expansion Cohorts in Small Cell Lung Carcinoma (SCLC), Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) and Pancreatic Adenocarcinoma (PDA)

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Will assess the prevalence of tumor ATM expression loss in all patients. Will also estimate response outcomes (ORR, PFS, OS, DOR) in study patients by tumor ATM expression loss.

Will assess the specific tumor DDR gene mutations present in study patients. Will also estimate response outcomes (ORR, PFS, OS, DOR) in study patients with tumors with DDR gene mutations.

Defined by occurrence of \>= 2 dose limiting toxicities (DLTs) defined as grade 4 neutropenia lasting \>= 7 days, grade 4 thrombocytopenia, grade 4 anemia, grade 3 neutropenia with fever, grade 3 thrombocytopenia with bleeding, any grade 3 hematologic toxicity lasting \>= 7 days (counting from first day of toxicity grade recognition) or any non-hematologic grade \>= 2 adverse events (AEs) lasting \>= 7 days (with the exception of grade 2 \[G2\] fatigue, G2 nausea or G2 diarrhea) (counting from first day of toxicity grade recognition) in any dose level during cycle 1 of treatment. DLTs will be graded by Common Terminology Criteria for Adverse Events version 5.0.

Grade 4 hematologic toxicity will be monitored using the Bayesian approach of Thall, Simon, Estey as extended by Thall and Sung. Clinical safety data (e.g. AEs) will be tabulated and summarized using descriptive statistics as requested by the sponsor investigator, executive committee, medical monitor or Data Safety Monitoring Board using methods described in the Data Safety Monitoring Plan.

Will be estimated by measuring the number of patients who achieve complete response or partial response by Response Evaluation Criteria in Solid Tumors 1.1 criteria on 12-week restaging computed tomography scans from the total number of patients who received the study treatment.

DOR will be estimated by the Kaplan-Meier method.

PFS will be estimated by the Kaplan-Meier method.

OS will be estimated by the Kaplan-Meier method.

Will be estimated for each study drug based upon plasma collections from cycle 1 in all study patients.

Will be estimated for expansion cohort only study patients.

Spots Global Cancer Trial Database for unresectable neuroendocrine carcinoma