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 have spread to other places in 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 tumor biopsy on cycle 1 day 3.
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 tumor biopsy on Cycle 1 day 2.
COHORT III: Patients receive elimusertib PO BID 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 tumor biopsy on Cycle 1 day 3.
After completion of study treatment, patients are followed every 2 months for up to 6 months.
| Condition | 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 |
|---|---|
| Treatment | biopsy, computed tomography, magnetic resonance imaging, topotecan hydrochloride, irinotecan hydrochloride, Elimusertib |
| Clinical Study Identifier | NCT04514497 |
| Sponsor | National Cancer Institute (NCI) |
| Last Modified on | 31 March 2023 |
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