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

Study Overview

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

This phase I trial tests the safety, 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 be safe and tolerable in treating patients with advanced solid tumors.

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.

Metastatic Lung Small Cell Carcinoma
Metastatic Malignant Solid Neoplasm
Metastatic Neuroendocrine Carcinoma
Metastatic Pancreatic Adenocarcinoma
Stage III Lung Cancer AJCC v8
Stage III Pancreatic Cancer AJCC v8
Stage IV Lung Cancer AJCC v8
Stage IV Pancreatic Cancer AJCC v8
Unresectable Lung Small Cell Carcinoma
Unresectable Malignant Solid Neoplasm
Unresectable Neuroendocrine Carcinoma
Unresectable Pancreatic Adenocarcinoma

PROCEDURE: Biopsy
PROCEDURE: Biospecimen Collection
PROCEDURE: Computed Tomography
DRUG: Elimusertib
DRUG: Irinotecan Hydrochloride
PROCEDURE: Magnetic Resonance Imaging
DRUG: Topotecan Hydrochloride

NCI-2020-05958
NCI-2020-05958 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
10402 (OTHER Identifier) (OTHER: Yale University Cancer Center LAO)
10402 (OTHER Identifier) (OTHER: CTEP)
UM1CA186689 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2020-08-14	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-03-05
First Submitted that Met QC Criteria 2020-08-14	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-03-06
First Posted (ACTUAL) 2020-08-17	Results First Posted N/A	Last Verified 2025-03

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Cohort I (elimusertib, irinotecan) 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,	PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Biospecimen Collection Undergo collection of blood samples PROCEDURE: Computed Tomography Undergo CT DRUG: Elimusertib Given PO DRUG: Irinotecan Hydrochloride Given IV PROCEDURE: Magnetic Resonance Imaging Undergo MRI
EXPERIMENTAL: Cohort II (elimusertib, irinotecan) 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 cy	PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Biospecimen Collection Undergo collection of blood samples PROCEDURE: Computed Tomography Undergo CT DRUG: Elimusertib Given PO DRUG: Irinotecan Hydrochloride Given IV PROCEDURE: Magnetic Resonance Imaging Undergo MRI
EXPERIMENTAL: Cohort III (elimusertib, topotecan) 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,	PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Biospecimen Collection Undergo collection of blood samples PROCEDURE: Computed Tomography Undergo CT DRUG: Elimusertib Given PO PROCEDURE: Magnetic Resonance Imaging Undergo MRI DRUG: Topotecan Hydrochloride Given IV

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Cohort I (elimusertib, irinotecan)

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,

PROCEDURE: Biopsy

Undergo tumor biopsy

PROCEDURE: Biospecimen Collection

Undergo collection of blood samples

PROCEDURE: Computed Tomography

Undergo CT

DRUG: Elimusertib

Given PO

DRUG: Irinotecan Hydrochloride

Given IV

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

EXPERIMENTAL: Cohort II (elimusertib, irinotecan)

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 cy

PROCEDURE: Biopsy

Undergo tumor biopsy

PROCEDURE: Biospecimen Collection

Undergo collection of blood samples

PROCEDURE: Computed Tomography

Undergo CT

DRUG: Elimusertib

Given PO

DRUG: Irinotecan Hydrochloride

Given IV

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

EXPERIMENTAL: Cohort III (elimusertib, topotecan)

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,

PROCEDURE: Biopsy

Undergo tumor biopsy

PROCEDURE: Biospecimen Collection

Undergo collection of blood samples

PROCEDURE: Computed Tomography

Undergo CT

DRUG: Elimusertib

Given PO

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

DRUG: Topotecan Hydrochloride

Given IV

Primary Outcome Measures	Measure Description	Time Frame
Maximum tolerated dose (MTD) (Dose Escalation Phase)	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.	Up to 21 days
Occurrence of grade 4 hematologic AEs (Dose Expansion Phase)	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.	Up to 6 months post-treatment

Secondary Outcome Measures	Measure Description	Time Frame
Objective response rate (ORR)	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.	Up to 12 weeks
Duration of response (DOR)	DOR will be estimated by the Kaplan-Meier method.	From when a patient achieves disease control (complete response, partial response, stable disease) on a restaging scan to the time of radiographic progression, assessed up to 6 months post-treatment
Progression-free survival (PFS)	PFS will be estimated by the Kaplan-Meier method.	From when a patient starts treatment to when they demonstrate radiographic progression or succumb to the disease, assessed up to 6 months post-treatment
Overall survival (OS)	OS will be estimated by the Kaplan-Meier method.	From when a patient starts treatment to the date they succumb to the disease, assessed up to 6 months post-treatment
Maximum concentration (Cmax)	Will be estimated for each study drug based upon plasma collections from cycle 1 in all study patients.	Cycle 1, days 1, 2, 3, and 4
Area under the concentration-time curve (AUC)	Will be estimated for each study drug based upon plasma collections from cycle 1 in all study patients.	Cycle 1, days 1, 2, 3, and 4
Changes in tumor expression patterns of gamma-H2AX	Will be estimated for expansion cohort only study patients.	Baseline up to cycle 1, day 6
Changes in tumor expression patterns of pS343-NBS1	Will be estimated for expansion cohort only study patients.	Baseline up to cycle 1, day 6

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

DOSE ESCALATION COHORTS: Patients must have a biopsy-proven solid tumor that is metastatic or unresectable and has progressed on at least one line of standard therapy
DOSE ESCALATION COHORTS: Patients must have a solid tumor for which irinotecan or topotecan is considered standard of care
DOSE EXPANSION COHORTS: Patients must have biopsy proven metastatic or unresectable small cell lung cancer (SCLC), poorly differentiated neuroendocrine carcinoma (PD-NEC) (any extrapulmonary neuroendocrine carcinoma with small cell or large cell histology) or pancreatic adenocarcinoma (PDA) and have progressed on at least one line of standard therapy
DOSE EXPANSION COHORTS: Patients must have at least one measurable lesion outside of the lesion to be biopsied
Patients must be able to swallow pills
Age >= 18 years. Because no dosing or adverse event data are currently available on the use of BAY 1895344 in combination with irinotecan or topotecan in patients < 18 years of age, children are excluded from this study
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Hemoglobin > 9 g/dL
Absolute neutrophil count >= 1,500/mcL
Platelets >= 100,000/mcL
Total bilirubin =< 2 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 (=< 5 x institutional ULN if liver metastases present)
Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2
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. Furthermore, these patients must be asymptomatic from previously treated brain metastases (e.g. not on steroids for neurologic symptoms within 30 days of study enrollment)
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 as well as other therapeutic agents used in this trial 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 BAY 1895344 administration
Patient must have the 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

Patients who have previously been treated with irinotecan will not be eligible to participate in the irinotecan arm and patients who have previously been treated with topotecan will not be eligible to participate in the topotecan arm. However, patients who previously received irinotecan may be treated with topotecan (and vice versa) should the other agent be considered a possible standard of care for their disease. Patients who have previously been treated with BAY 1895344 will be excluded from the study
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 and endocrinopathies from prior immunotherapy
Patients who are receiving any other investigational agents
The investigator(s) must state a medical or scientific reason if patients who have brain metastases will be excluded from the study
History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 1895344 or other agents used in study
Patients receiving any medications or substances 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
Pregnant women are excluded from this study because BAY 1895344 is agent 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 BAY 1895344, breastfeeding should be discontinued if the mother is treated with BAY 1895344. These potential risks may also apply to other agents used in this study
Patients with an uncontrolled infection requiring IV antibiotics will not be eligible to participate in the study
Patients on strong CYP3A4 inhibitors must discontinue them at least 1 week prior to starting irinotecan therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Thatcher Heumann, Yale University Cancer Center LAO

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