November 4, 2020
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November 5, 2020
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April 9, 2024
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June 1, 2021
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July 1, 2024 (Final data collection date for primary outcome measure)
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- 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.
- 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 ]
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- Incidence of adverse events [ Time Frame: Up to 1 year ]
The toxicity of the combination of gemcitabine plus BAY1895344 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.
- 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 ]
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- Pharmacokinetic (PK) profile of elimusertib in combination with gemcitabine [ Time Frame: Day 1 of dose-escalation phase ]
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.
- Gemcitabine pharmacokinetics [ Time Frame: Days 1 and 8 of dose-escalation ]
The CDA phenotype will be correlated with gemcitabine half-life, AUC and the dFdU/gemcitabine metabolic ratio.
- Presence or absence of homologous recombination (HR) repair proficiency [ Time Frame: Pre-treatment to time of disease progression, assessed up to 1 year ]
Will be defined according to formation of RAD51 foci. Will also be evaluated in relation to the clinical outcomes of ORR and PFS time.
- Presence or absence of replication stress [ Time Frame: Pre-treatment to time of disease progression, assessed up to 1 year ]
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.
- Presence or absence of ATR activation [ Time Frame: Pre-treatment to time of disease progression, assessed up to 1 year ]
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.
- Conversion of cancer with stable replication forks to one with unstable replication forks [ Time Frame: Pre-treatment to time of disease progression, assessed up to 1 year ]
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.
- Increase in deoxyribonucleic acid (DNA) damage level (expansion cohort) [ Time Frame: Pre-treatment and on-treatment ]
Changes in immunohistochemical markers of DNA damage, gamma-H2AX and phosphorylated (p)NBS1.
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- Pharmacokinetic (PK) profile of BAY1895344 in combination with gemcitabine [ Time Frame: Day 1 of dose-escalation phase ]
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.
- Gemcitabine pharmacokinetics [ Time Frame: Days 1 and 8 of dose-escalation ]
The CDA phenotype will be correlated with gemcitabine half-life, AUC and the dFdU/gemcitabine metabolic ratio.
- Presence or absence of homologous recombination (HR) repair proficiency [ Time Frame: Pre-treatment to time of disease progression, assessed up to 1 year ]
Will be defined according to formation of RAD51 foci. Will also be evaluated in relation to the clinical outcomes of ORR and PFS time.
- Presence or absence of replication stress [ Time Frame: Pre-treatment to time of disease progression, assessed up to 1 year ]
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.
- Presence or absence of ATR activation [ Time Frame: Pre-treatment to time of disease progression, assessed up to 1 year ]
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.
- Conversion of cancer with stable replication forks to one with unstable replication forks [ Time Frame: Pre-treatment to time of disease progression, assessed up to 1 year ]
DNA fiber assays will be used to assess whether gemcitabine/BAY1895344 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.
- Changes in immunohistochemical markers of deoxyribonucleic acid (DNA) damage, gamma-H2AX and phosphorylated (p)NBS1 (expansion cohort) [ Time Frame: Pre-treatment and on-treatment ]
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Pharmacodynamic (biological endpoints, toxicity and efficacy) parameters [ Time Frame: Up to 30 days ] Will be analyzed with nonparametric statistics.
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Same as current
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Testing the Addition of an Anti-cancer Drug, Elimusertib (BAY 1895344) ATR Inhibitor, to the Chemotherapy Treatment (Gemcitabine) for Advanced Pancreatic and Ovarian Cancer, and Advanced Solid Tumors
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Phase 1 Trial of Gemcitabine Combined With the Elimusertib (BAY 1895344) ATR Inhibitor With Expansion Cohorts in Advanced Pancreatic and Ovarian Cancer
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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.
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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.
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Interventional
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Phase 1
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Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment
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- Advanced Fallopian Tube Carcinoma
- Advanced Malignant Solid Neoplasm
- Advanced Ovarian Carcinoma
- Advanced Pancreatic Adenocarcinoma
- Advanced Primary Peritoneal Carcinoma
- Fallopian Tube High Grade Serous Adenocarcinoma
- Metastatic Pancreatic Adenocarcinoma
- Ovarian High Grade Serous Adenocarcinoma
- Platinum-Resistant Fallopian Tube Carcinoma
- Platinum-Resistant Ovarian Carcinoma
- Platinum-Resistant Primary Peritoneal Carcinoma
- Primary Peritoneal High Grade Serous Adenocarcinoma
- Stage II Pancreatic Cancer AJCC v8
- Stage III Fallopian Tube Cancer AJCC v8
- Stage III Ovarian Cancer AJCC v8
- Stage III Pancreatic Cancer AJCC v8
- Stage III Primary Peritoneal Cancer AJCC v8
- Stage IV Fallopian Tube Cancer AJCC v8
- Stage IV Ovarian Cancer AJCC v8
- Stage IV Pancreatic Cancer AJCC v8
- Stage IV Primary Peritoneal Cancer AJCC v8
- Unresectable Pancreatic Adenocarcinoma
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- Procedure: Biopsy
Undergo biopsy (dose expansion cohort only)
- Procedure: Biospecimen Collection
Undergo collection of blood samples
Other Names:
- Biological Sample Collection
- Biospecimen Collected
- Specimen Collection
- Procedure: Diagnostic Imaging
Undergo medical imaging scans
Other Name: Medical Imaging
- Drug: Elimusertib
Given PO
Other Names:
- ATR Inhibitor BAY1895344
- ATR Kinase Inhibitor BAY1895344
- BAY 1895344
- BAY-1895344
- BAY1895344
- Drug: Gemcitabine
Given IV
Other Names:
- dFdC
- dFdCyd
- Difluorodeoxycytidine
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Experimental: 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.
Interventions:
- Procedure: Biopsy
- Procedure: Biospecimen Collection
- Procedure: Diagnostic Imaging
- Drug: Elimusertib
- Drug: Gemcitabine
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Not Provided
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Active, not recruiting
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64
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54
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July 1, 2024
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July 1, 2024 (Final data collection date for primary outcome measure)
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Inclusion Criteria:
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
- Patients who have successfully undergone treatment for another, unrelated clinically relevant cancer, >= 3 years post final treatment, are eligible to participate in this study
- Patients cannot have received radiation to more than 25% of their hematopoietically active bone marrow. Pelvic radiation is considered to affect 25% of the haematopoietically active bone marrow, and only one prior course of pelvic radiation is allowed (Hayman et al., 2011)
- Patients previously treated with an ATR inhibitor are excluded
- Participants who have undergone major surgery =< 4 weeks before initiating protocol therapy must have sufficiently recovered from adverse events caused by the procedure, as judged by the treating investigator
- Subjects with a gastrointestinal disorder or malabsorption that could potentially affect the absorption of the study drug are excluded
- Participants with a history of a clinically relevant second primary malignancy within the past 2 years are excluded. Exceptions include resected basal and squamous cell carcinomas of the skin and completely resected carcinoma in situ of any type
- Patients not able to swallow tablets
- For the Dose Expansion Cohort, patients who cannot safely undergo tumor biopsies are excluded
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Sexes Eligible for Study: |
All |
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18 Years and older (Adult, Older Adult)
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No
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Contact information is only displayed when the study is recruiting subjects
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United States
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NCT04616534
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NCI-2020-08370 NCI-2020-08370 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 10403 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO ) 10403 ( Other Identifier: CTEP ) UM1CA186709 ( U.S. NIH Grant/Contract )
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No
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Studies a U.S. FDA-regulated Drug Product: |
Yes |
Studies a U.S. FDA-regulated Device Product: |
No |
Product Manufactured in and Exported from the U.S.: |
No |
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Plan to Share IPD: |
Yes |
Plan Description: |
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page. |
URL: |
https://grants.nih.gov/policy/sharing.htm |
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National Cancer Institute (NCI)
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Same as current
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National Cancer Institute (NCI)
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Same as current
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Not Provided
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Principal Investigator: |
James M Cleary |
Dana-Farber - Harvard Cancer Center LAO |
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National Cancer Institute (NCI)
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April 2024
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