This phase I trial identifies the best dose, possible benefits and/or side effects of gemcitabine in combination with elimusertib (BAY 1895344) in treating patients with pancreatic, ovarian, and other solid tumors that have spread to other places in the body (advanced). Gemcitabine is a chemotherapy drug that blocks the cell from making DNA and may kill tumor cells. elimusertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving gemcitabine and elimusertib in combination may shrink or stabilize cancer.
PRIMARY OBJECTIVES: I. Evaluate the safety and tolerability of gemcitabine in combination with elimusertib (BAY 1895344), as assessed by Common Terminology Criteria for Adverse Events (CTCAE) 5.0. (Dose Escalation and Expansion Cohort) II. Determine the maximum tolerated dose (MTD) of gemcitabine in combination with elimusertib (BAY 1895344). (Dose Escalation Cohort) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. Analyze the pharmacokinetic (PK) profile of the gemcitabine and elimusertib (BAY 1895344) combination. III. Assessing whether immunohistochemical markers of deoxyribonucleic acid (DNA) damage, gamma-H2AX and phosphorylated (p)NBS1, increase in on-treatment biopsies compared to the levels seen in pre-treatment biopsies. EXPLORATORY OBJECTIVES: I. Explore biomarkers that predict response to this combination. II. Evaluate mechanisms of acquired resistance to this combination. OUTLINE: This is a dose-escalation study of gemcitabine followed by a dose expansion study. Patients receive gemcitabine intravenously (IV) over 30 minutes on days 1 and 8 and elimusertib orally (PO) once daily (QD) or twice daily (BID) on days 2-3 and 9-10. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. All patients also undergo medical imaging scans after cycle 2 and then every 9 weeks throughout the trial and collection of blood samples during screening and on days 1, 2, and 9-10 of cycle 1. Patients in the dose-expansion portion of the trial also undergo biopsies during screening and on day 9 of cycle 1. After completion of study treatment, patients are followed up for 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Undergo biopsy (dose expansion cohort only)
Undergo collection of blood samples
Undergo medical imaging scans
Given PO
Given IV
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, United States
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Incidence of adverse events
The toxicity of the combination of gemcitabine plus elimusertib will be assessed with Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0 criteria.
Time frame: Up to 1 year
Maximum tolerated dose (MTD)
A conventional algorithm (3+3 design) will be used to identify the MTD, escalating on zero of three or one of six dose-limiting toxicities (DLTs), and de-escalating if two DLTs are encountered. The MTD will be the highest dose level at which zero of three or one of six subjects experience a DLT.
Time frame: Up to completion of dose-escalation phase
Overall response rate (ORR) (expansion cohort)
Radiological response will be assessed with Response Evaluation Criteria in Solid Tumors 1.1 criteria and will be graded as complete response (CR), partial response (PR), stable disease and progressive disease.
Time frame: Up to 1 year
Duration of response (expansion cohort)
Time frame: Time at which measurement criteria are met for CR or PR (whichever is first recorded) until the first date on which recurrent or progressive disease is objectively documented, assessed up to 1 year
Progression free survival (PFS) (expansion cohort)
Time frame: Time from study enrollment until the identification of disease progression or death, assessed up to 1 year
Overall survival (expansion cohort)
Time frame: Time from study enrollment until death due to any cause, assessed up to 1 year
Pharmacokinetic (PK) profile of elimusertib in combination with gemcitabine
Individual PK parameters will be estimated for the maximum concentration (Cmax), area under the concentration-time curve (AUC), half-life (t1/2), apparent clearance (Cl/F) and apparent volume of distribution (V/F), as feasible with non-compartmental methods. The PK variables will be tabulated, and descriptive statistics (e.g., geometric means and coefficients of variation) will be calculated for each dose level. PK parameters will be reported descriptively.
Time frame: Day 1 of dose-escalation phase
Gemcitabine pharmacokinetics
The CDA phenotype will be correlated with gemcitabine half-life, AUC and the dFdU/gemcitabine metabolic ratio.
Time frame: Days 1 and 8 of dose-escalation
Presence or absence of homologous recombination (HR) repair proficiency
Will be defined according to formation of RAD51 foci. Will also be evaluated in relation to the clinical outcomes of ORR and PFS time.
Time frame: Pre-treatment to time of disease progression, assessed up to 1 year
Presence or absence of replication stress
Will be defined at the gene expression and protein levels for phosphorylated (p)KAP1, pRPA32, cyclin E and MYC. Will also be evaluated in relation to the clinical outcomes of ORR and PFS time.
Time frame: Pre-treatment to time of disease progression, assessed up to 1 year
Presence or absence of ATR activation
Will be defined by the expression of pATR and pCHK1. Will also be evaluated in relation to the clinical outcomes of ORR and PFS time.
Time frame: Pre-treatment to time of disease progression, assessed up to 1 year
Conversion of cancer with stable replication forks to one with unstable replication forks
DNA fiber assays will be used to assess whether gemcitabine/elimusertib treatment converts a cancer with stable replication forks to one with unstable replication forks. Will also be evaluated in relation to the clinical outcomes of ORR and PFS time.
Time frame: Pre-treatment to time of disease progression, assessed up to 1 year
Increase in deoxyribonucleic acid (DNA) damage level (expansion cohort)
Changes in immunohistochemical markers of DNA damage, gamma-H2AX and phosphorylated (p)NBS1.
Time frame: Pre-treatment and on-treatment
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