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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
28
Undergo tumor biopsy
Undergo collection of blood samples
Undergo CT
Given PO
Given IV
Undergo MRI
Given IV
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
Yale University
New Haven, Connecticut, United States
Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, United States
Mayo Clinic in Florida
Jacksonville, Florida, United States
University of Kansas Clinical Research Center
Fairway, Kansas, United States
University of Kansas Cancer Center
Kansas City, Kansas, United States
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, United States
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, United States
...and 13 more locations
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.
Time frame: 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.
Time frame: Up to 6 months post-treatment
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.
Time frame: Up to 12 weeks
Duration of response (DOR)
DOR will be estimated by the Kaplan-Meier method.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline up to cycle 1, day 6
Changes in tumor expression patterns of pS343-NBS1
Will be estimated for expansion cohort only study patients.
Time frame: Baseline up to cycle 1, day 6
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