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
Number of Patients on Treatment With Related 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. The safety and tolerability were evaluated using the number of treatment-related adverse events.
Time frame: Adverse events were recorded between the first patient treated (June 2021) and 30 days out from the last patient ending treatment (October 2024) (3 years and 4 months). Adverse events were collected for a median of 88.5 days, ranging 58 - 315 days.
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. The MTD was not reached due to toxicity experienced during cycle 1.
Time frame: The MTD was evaluated during the dose-escalation phase, occurring from the first patient on treatment (Jun '21) through the last patient's last dose (Sep '24) (3 years and 3 months). MTD was evaluated for a median of 58.5 days, ranging 28 - 285 days.
Overall Response Rate (ORR)
Radiological response will be assessed with Response Evaluation Criteria in Solid Tumors 1.1 criteria and will be portrayed as the percentage of subjects with a complete response (CR) and partial response (PR).
Time frame: ORR was assessed from the time of the first patient on study (June 2021) through the last patient off study (October 2024). ORR was calculated for a median of 103 days, ranging from 30 - 312 days.
Duration of Response
Time frame: Duration of response was assessed from the time of the first patient on treatment (June 2021) through the last patient off study (October 2024). Duration of response was calculated for a median of 103 days, ranging from 30 - 312 days.
Progression Free Survival (PFS)
Time frame: PFS was evaluated from the first patient on study (Jun '21) through the last patient's death or date of progressive disease (Sep '24) (3 years and 3 months). PFS was calculated for a median of 90 days, ranging 25 - 286 days.
Overall Survival
Overall survival (OS) was evaluated from the first patient on study (June 2021) through the last patient's death or off study date (October 2024).
Time frame: OS was calculated for a median of 103 days, ranging from 30 - 312 days.
Pharmacokinetic (PK) Profile of Elimusertib in Combination With Gemcitabine
Individual PK parameters will be estimated for the maximum concentration (Cmax), 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 (first patient's day 1, June 2021, to last patient's day 1, December 2023) equaling the total collection time of 2 year and 6 months. PK samples for collected on a single day for each participant.
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 cycle 1 dose-escalation (first patient's day 1, June 2021, to last patient's day 8, December 2023) equaling the total collection time of 2 year and 6 months. Samples were collected on two days for each participant.
Presence or Absence of Homologous Recombination (HR) Repair Proficiency (Dose Expansion)
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 in the dose expansion cohort
Presence or Absence of ATR Activation (Dose Expansion)
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 in the dose expansion cohort
Increase in Deoxyribonucleic Acid (DNA) Damage Level (Dose Expansion)
Changes in immunohistochemical markers of DNA damage, gamma-H2AX and phosphorylated (p)NBS1.
Time frame: Pre-treatment and on-treatment in the dose expansion cohort
Conversion of Cancer With Stable Replication Forks to One With Unstable Replication Forks (Dose Expansion)
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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 in the dose expansion cohort
Presence or Absence of Replication Stress (Dose Expansion)
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 in the dose expansion cohort.
Pharmacokinetic (PK) Profile of Elimusertib in Combination With Gemcitabine
Individual PK parameters will be estimated for the area under the concentration-time curve (AUC), 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 (first patient's day 1, June 2021, to last patient's day 1, December 2023) equaling the total collection time of 2 year and 6 months. PK samples for collected on a single day for each participant.
Pharmacokinetic (PK) Profile of Elimusertib in Combination With Gemcitabine
Individual PK parameters will be estimated for the 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 (first patient's day 1, June 2021, to last patient's day 1, December 2023) equaling the total collection time of 2 year and 6 months. PK samples for collected on a single day for each participant.