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

Brief summary public domain (ClinicalTrials.gov)

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.

Detailed description public domain (ClinicalTrials.gov)

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.

Intervention public domain (ClinicalTrials.gov)

Procedure: Biopsy Procedure. Undergo tumor biopsy

Intervention public domain (ClinicalTrials.gov)

Procedure: Biospecimen Collection. Undergo collection of blood samples

Intervention public domain (ClinicalTrials.gov)

Procedure: Computed Tomography. Undergo CT

Intervention public domain (ClinicalTrials.gov)

Drug: Elimusertib. Given PO

Intervention public domain (ClinicalTrials.gov)

Drug: Irinotecan Hydrochloride. Given IV

Intervention public domain (ClinicalTrials.gov)

Procedure: Magnetic Resonance Imaging. Undergo MRI

Intervention public domain (ClinicalTrials.gov)

Drug: Topotecan Hydrochloride. Given IV

Arm public domain (ClinicalTrials.gov)

Cohort I (elimusertib, irinotecan) (experimental): 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.

Arm public domain (ClinicalTrials.gov)

Cohort II (elimusertib, irinotecan) (experimental): 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.

Arm public domain (ClinicalTrials.gov)

Cohort III (elimusertib, topotecan) (experimental): 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.

Primary outcome public domain (ClinicalTrials.gov)

Maximum Tolerated Dose (MTD) (Dose Escalation Phase) of Elimursertib. 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. Time frame: Up to 21 days (first treatment cycle).

Primary outcome public domain (ClinicalTrials.gov)

Maximum Tolerated Dose (MTD) (Dose Escalation Phase) of Irinotecan. 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. Time frame: Up to 21 days (first treatment cycle).

Primary outcome public domain (ClinicalTrials.gov)

Maximum Tolerated Dose (MTD) (Dose Escalation Phase) of Topotecan. 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. Time frame: Up to 21 days (first treatment cycle).

Primary outcome public domain (ClinicalTrials.gov)

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. Time frame: Up to 6 months post-treatment.

Secondary outcome public domain (ClinicalTrials.gov)

Objective Response Rate (ORR). Time frame: Tumor response was performed every 6 weeks during treatment and up to 6 months after completing treatment.

Secondary outcome public domain (ClinicalTrials.gov)

Duration of Response (DOR). Time frame: Response was assessed every 6 weeks while the patient was on treatment, and up to 6 months post-treatment..

Secondary outcome public domain (ClinicalTrials.gov)

Progression-free Survival (PFS). Time frame: Disease Progression was assessed every 6 weeks while the patient was on treatment, and up to 6 months post-treatment..

Secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS). Time frame: From date the participant starts treatment until the date of death from any cause, assessed up to 6 months following completion of treatment.

Secondary outcome public domain (ClinicalTrials.gov)

Maximum Concentration (Cmax) of Elimusertib. Time frame: See above as time frames were different fore each dose cohort.

Secondary outcome public domain (ClinicalTrials.gov)

Area Under the Concentration-time Curve (AUC) for Elimusertib. Time frame: See above as time frames are different for each dose cohort.

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: * 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 …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 29 participants (actual).

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Maximum Tolerated Dose (MTD) (Dose Escalation Phase) of Elimursertib [Up to 21 days (first treatment cycle)]. Number, mg. Cohort I (Elimusertib, Irinotecan) (n=9): 10; Cohort II (Elimusertib, Irinotecan) (n=12): 20; Cohort III (Elimusertib, Topotecan) (n=8): 20.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Maximum Tolerated Dose (MTD) (Dose Escalation Phase) of Irinotecan [Up to 21 days (first treatment cycle)]. Number, mg/m^2. Cohort I (Elimusertib, Irinotecan) (n=9): 150; Cohort II (Elimusertib, Irinotecan) (n=12): 25.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Maximum Tolerated Dose (MTD) (Dose Escalation Phase) of Topotecan [Up to 21 days (first treatment cycle)]. Number, mg/m^2. Cohort III (Elimusertib, Topotecan) (n=8): 1.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Occurrence of Grade 4 Hematologic AEs (Dose Expansion Phase) [Up to 6 months post-treatment].

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Objective Response Rate (ORR) [Tumor response was performed every 6 weeks during treatment and up to 6 months after completing treatment]. Count Of Participants, Participants. TAC 1 (Elimusertib, Irinotecan) (n=6): 1; TAC 2 (Elimusertib, Irinotecan) (n=3): 0; TAC 4 (Elimusertib, Irinotecan) (n=6): 0; TAC 5 (Elimusertib, Irinotecan) (n=6): 0; TAC 7 (Elimusertib, Topotecan) (n=2): 0; TAC 14 (Elimusertib, Topotecan) (n=6): 1.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Duration of Response (DOR) [Response was assessed every 6 weeks while the patient was on treatment, and up to 6 months post-treatment.]. Median, months (95% Confidence Interval). TAC 1 (Elimusertib, Irinotecan) (n=4): 2.33 (0.23 to NA) [Upper 95% confidence interval not reached]; TAC 2 (Elimusertib, Irinotecan) (n=1): 1.43 (NA to NA) [Both upper and lower 95% confidence intervals not reached]; TAC 4 (Elimusertib, Irinotecan) (n=4): 1.4 (1.03 to NA) [Upper 95% confidence interval not reached]; TAC 5 (Elimusertib, Irinotecan) (n=2): 1.45 (1.43 to NA) [Upper 95% confidence interval not reached]; TAC 14 (Elimusertib, Topotecan) (n=3): 4.2 (3.13 to NA) [Upper 95% confidence interval not reached].

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Progression-free Survival (PFS) [Disease Progression was assessed every 6 weeks while the patient was on treatment, and up to 6 months post-treatment.]. Median, months (95% Confidence Interval). TAC 1 (Elimusertib, Irinotecan) (n=6): 2.58 (1.37 to 5.53); TAC 2 (Elimusertib, Irinotecan) (n=3): 1.4 (1.33 to NA) [Upper 95% confidence interval not reached]; TAC 4 (Elimusertib, Irinotecan) (n=6): 2.5 (1.53 to 2.8); TAC 5 (Elimusertib, Irinotecan) (n=6): 2.03 (0.67 to 2.8); TAC 7 (Elimusertib, Topotecan) (n=2): 0.87 (0.47 to NA) [Upper 95% confidence interval not reached]; TAC 14 (Elimusertib, Topotecan) (n=6): 3.28 (1.3 to 5.6).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS) [From date the participant starts treatment until the date of death from any cause, assessed up to 6 months following completion of treatment]. Median, months (95% Confidence Interval). TAC 1 (Elimusertib, Irinotecan) (n=6): 9.77 (4.97 to NA) [Upper 95% confidence interval not reached]; TAC 2 (Elimusertib, Irinotecan) (n=3): 2.93 (2.33 to NA) [Upper 95% confidence interval not reached]; TAC 4 (Elimusertib, Irinotecan) (n=6): 6.73 (3.87 to NA) [Upper 95% confidence interval not reached]; TAC 5 (Elimusertib, Irinotecan) (n=6): 4.47 (1.27 to 11.03); TAC 7 (Elimusertib, Topotecan) (n=2): 2.2 (0.47 to NA) [Upper 95% confidence interval not reached]; TAC 14 (Elimusertib, Topotecan) (n=6): 9.4 (9.27 to NA) [Upper 95% confidence interval not reached].

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Maximum Concentration (Cmax) of Elimusertib [See above as time frames were different fore each dose cohort]. Geometric Mean, micrograms per liter (Standard Deviation). TAC1 (10 mg Elimusertib, Biweekly 150 mg/m^2 Irinotecan) (n=6): 246 (1.53); TAC2 (20 mg Elimusertib, Biweekly 150 mg/m^2 Irinotecan) (n=3): 526 (1.71); TAC4 (20 mg Elimusertib, Weekly 25 mg/m^2 Irinotecan) (n=6): 460 (1.53); TAC5 (20 mg Elimusertib, 50 mg/m^2 Weekly Irinotecan) (n=6): 492 (1.63); TAC7 (20 mg Elimusertib, 1 mg/m^2 Topotecan) (n=2): 659 (1.19); TAC14 (20 mg Elimusertib, 1 mg/m^2 Topotecan) (n=6): 247 (2.13).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Area Under the Concentration-time Curve (AUC) for Elimusertib [See above as time frames are different for each dose cohort]. Geometric Mean, mg/L*h (Standard Deviation). TAC1 (10 mg Elimusertib, Biweekly 150 mg/m^2 Irinotecan) (n=6): 2.05 (1.34); TAC2 (20 mg Elimusertib, Biweekly 150 mg/m^2 Irinotecan) (n=3): 3.06 (1.39); TAC4 (20 mg Elimusertib, Weekly 25 mg/m^2 Irinotecan) (n=6): 4.56 (1.49); TAC5 (20 mg Elimusertib, 50 mg/m^2 Weekly Irinotecan) (n=6): 5.53 (1.87); TAC7 (20 mg Elimusertib, 1 mg/m^2 Topotecan) (n=2): 3.69 (1.43); TAC14 (20 mg Elimusertib, 1 mg/m^2 Topotecan) (n=6): 3.90 (2.23).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Maximum Concentration (Cmax) of Irinotecan (Cohorts I and II) [See above as time frames were different for each cohort]. Geometric Mean, micrograms per liter (Standard Deviation). TAC1 (10 mg Elimusertib, Biweekly 150 mg/m^2 Irinotecan) (n=6): 1296 (1.12); TAC2 (20 mg Elimusertib, Biweekly 150 mg/m^2 Irinotecan) (n=3): 1380 (1.35); TAC4 (20 mg Elimusertib, Weekly 25 mg/m^2 Irinotecan) (n=6): 230 (1.30); TAC5 (20 mg Elimusertib, 50 mg/m^2 Weekly Irinotecan) (n=6): 610 (1.78).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Area Under the Concentration-time Curve (AUC) for Irinotecan [See above as time frames were different for each cohort]. Geometric Mean, mg/L*h (Standard Deviation). TAC1 (10 mg Elimusertib, Biweekly 150 mg/m^2 Irinotecan) (n=6): 7.29 (1.13); TAC2 (20 mg Elimusertib, Biweekly 150 mg/m^2 Irinotecan) (n=3): 7.93 (1.31); TAC4 (20 mg Elimusertib, Weekly 25 mg/m^2 Irinotecan) (n=6): 1.18 (1.29); TAC5 (20 mg Elimusertib, 50 mg/m^2 Weekly Irinotecan) (n=6): 3.79 (1.30).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Maximum Concentration (Cmax) of Topotecan (Cohort III, TACs 7 and 14) [Cycle 1 day 1 and 2 before infusion, 5, 15, and 25 min into infusion, and 5, 15, 30 min, 1, 2, 4, 6, and 24 h post end of infusion]. Geometric Mean, micrograms per liter (Standard Deviation). TAC7 (20 mg Elimusertib, 1 mg/m^2 Topotecan) (n=2): 48.6 (1.08); TAC14 (20 mg Elimusertib, 1 mg/m^2 Topotecan) (n=6): 35.4 (1.82).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Area Under the Concentration-time Curve (AUC) for Topotecan [Cycle 1]. Geometric Mean, ug/L*h (Standard Deviation). TAC7 (20 mg Elimusertib, 1 mg/m^2 Topotecan) (n=2): 101 (1.56); TAC14 (20 mg Elimusertib, 1 mg/m^2 Topotecan) (n=6): 116 (1.27).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Changes in Tumor Expression Patterns of Gamma-H2AX [Baseline up to cycle 1, day 6].

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Changes in Tumor Expression Patterns of pS343-NBS1 [Baseline up to cycle 1, day 6].