Phase 1 Trial of Gemcitabine Combined With the Elimusertib (BAY 1895344) ATR Inhibitor With Expansion Cohorts in Advanced Pancreatic and Ovarian Cancer
Overview
- Phase
- Phase 1
- Intervention
- Biopsy Procedure
- Conditions
- Advanced Fallopian Tube Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 14
- Locations
- 3
- Primary Endpoint
- Incidence of adverse events
- Status
- Active, not recruiting
- Last Updated
- 11 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •DOSE ESCALATION COHORT:
- •Patients must have histologically confirmed solid tumor malignancy that is not curable with standard approaches. Gemcitabine must be considered a standard therapy for the participant's malignancy
- •Patients must have a measurable disease, in at least one lesion, for both the dose escalation and expansion cohorts, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
- •Patients must have received one line of treatment for their incurable cancer before enrolling in this trial. Patients with rare malignancies for which there is no accepted standard chemotherapy regimen can enroll without any prior treatments
- •Patients must not have received more than two lines of cytotoxic chemotherapy
- •Patients can have received prior gemcitabine
- •Adjuvant chemotherapy is counted as one line of treatment if patients received it within 6 months of their cancer recurring
- •There is no limit for lines of prior targeted therapies or immunotherapy
- •Patients who received a prior PARP inhibitor must have had progressive disease, or intolerable toxicity, on the PARP inhibitor prior to enrolling on the study
- •DOSE EXPANSION COHORT:
Exclusion Criteria
- •Patients cannot receive chemotherapy, targeted therapy or immunotherapy within 3 weeks of study entry
- •Patients who have had radiotherapy within 4 weeks prior to entering the study
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia and lymphopenia
- •Participants must not have received investigational therapy administered =\< 4 weeks or within a time interval less than at least five half-lives of the investigational agent, whichever is longer, before initiation of protocol therapy
- •Participants with known untreated brain metastases are excluded from this clinical trial
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to elimusertib (BAY 1895344) or gemcitabine
- •Patients receiving any medications that are substrates of CYP3A4 with a narrow therapeutic window, or strong inhibitors/inducers of CYP3A4 are ineligible, if they cannot be transferred to alternative medication. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- •Patients with uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome or psychiatric illness/social situations that would limit compliance with study requirements are excluded
- •Patients with psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant women are excluded from this study because elimusertib (BAY 1895344) as a DNA-damage response inhibitor, and gemcitabine may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with elimusertib (BAY 1895344) breastfeeding should be discontinued if the mother is treated with elimusertib (BAY 1895344) and for 4 months after end of treatment. These potential risks may also apply to other agents used in this study
Arms & Interventions
Treatment (gemcitabine, elimusertib)
Patients receive gemcitabine IV over 30 minutes on days 1 and 8 and elimusertib QD or PO 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.
Intervention: Biopsy Procedure
Treatment (gemcitabine, elimusertib)
Patients receive gemcitabine IV over 30 minutes on days 1 and 8 and elimusertib QD or PO 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.
Intervention: Biospecimen Collection
Treatment (gemcitabine, elimusertib)
Patients receive gemcitabine IV over 30 minutes on days 1 and 8 and elimusertib QD or PO 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.
Intervention: Diagnostic Imaging Testing
Treatment (gemcitabine, elimusertib)
Patients receive gemcitabine IV over 30 minutes on days 1 and 8 and elimusertib QD or PO 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.
Intervention: Elimusertib
Treatment (gemcitabine, elimusertib)
Patients receive gemcitabine IV over 30 minutes on days 1 and 8 and elimusertib QD or PO 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.
Intervention: Gemcitabine
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: Up to 1 year
The toxicity of the combination of gemcitabine plus elimusertib will be assessed with Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0 criteria.
Maximum tolerated dose (MTD)
Time Frame: Up to completion of dose-escalation phase
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.
Overall response rate (ORR) (expansion cohort)
Time Frame: Up to 1 year
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.
Overall survival (expansion cohort)
Time Frame: Time from study enrollment until death due to any cause, assessed 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
Secondary Outcomes
- Presence or absence of replication stress(Pre-treatment to time of disease progression, assessed up to 1 year)
- Increase in deoxyribonucleic acid (DNA) damage level (expansion cohort)(Pre-treatment and on-treatment)
- Presence or absence of homologous recombination (HR) repair proficiency(Pre-treatment to time of disease progression, assessed up to 1 year)
- Pharmacokinetic (PK) profile of elimusertib in combination with gemcitabine(Day 1 of dose-escalation phase)
- Gemcitabine pharmacokinetics(Days 1 and 8 of dose-escalation)
- Presence or absence of ATR activation(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(Pre-treatment to time of disease progression, assessed up to 1 year)