Advanced Solid TumorPhase 1NCT05246111
Berzosertib Human Mass Balance Study (DDRiver Solid Tumors 208)
A Phase 1 study testing [14C]Berzosertib, Berzosertib and Topotecan in people with Advanced Solid Tumor, run by Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany at 2 sites in Hungary.
Trial summary
The study was conducted in two periods, Period 1 (mass balance) and Period 2 (extension). The purpose of Period 1 of this study was to provide a quantitative characterization of the mass balance, rates and routes of elimination, and metabolic pathways after a single intravenous administration of [14C]berzosertib. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Solid Tumor
- What is being tested?
- [14C]Berzosertib, Berzosertib and Topotecan
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 2 sitesHungary
- Study dates
- 15 Feb 2022to 28 Jun 2023
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically proven advanced solid tumors that are considered appropriate for treatment in Period 2 of this study, for which no effective standard therapy exists, or standard therapy has failed or cannot be tolerated
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) =< 1
- Evaluable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Screening
- Participant has adequate renal, hematological and hepatic function
- Other protocol defined inclusion criteria could apply
Who cannot join
- Participants with uncontrolled intercurrent illness including, but not limited to, severe active infection including, acute respiratory syndrome coronavirus-2 infection/coronavirus disease 2019 (Covid 19), immune deficiencies, uncontrolled diabetes, uncontrolled arterial hypertension and symptomatic congestive heart failure
- Concurrent participation in another interventional clinical study is not permitted.
- Known hypersensitivity to the study interventions, a similar structural compound, or to one or more excipients used
- Prior or concurrent treatment with a nonpermitted drug/intervention from the first dose of study intervention administration, as defined per protocol.
- Other protocol defined exclusion criteria could apply
Trial locations and contacts
2 sites in 1 country.
Hungary2 sites
Magyar Honvédség Egészségügyi Központ, Podmaniczky utcai telephely, Onkológiai Osztály
Budapest
PRA Magyarország Kft. Fázis I-es Klinikai Farmakológiai Vizsgálóhely
Budapest
About this study
Official title: Phase I Study to Evaluate the Mass Balance, PK, Metabolism and Excretion of Berzosertib (Intravenous) Containing Microtracer [14C]Berzosertib in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 208)
The study was conducted in two periods, Period 1 (mass balance) and Period 2 (extension). The purpose of Period 1 of this study was to provide a quantitative characterization of the mass balance, rates and routes of elimination, and metabolic pathways after a single intravenous administration of [14C]berzosertib. The purpose of Period 2 was to assess safety and efficacy of berzosertib in combination with topotecan.
- Conditions
- Advanced Solid Tumor
- Being tested
- [14C]Berzosertib, Berzosertib, Topotecan
- Keywords
- Topotecan, Ataxia telangiectasia mutated and Rad3-related (ATR) protein, ATR inhibitor, M6620, Berzosertib, Mass balance
- Medical subject headings
- Hereditary Sensory and Autonomic Neuropathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
[14C]BerzosertibDrug
Also called M6620
Participants received single intravenous infusion of [14C]Berzosertib at a dose of 210 milligrams per square meter (mg/m^2) on Day 1 in Period 1 and stay in clinical research unit (CRU) is required until the discharge criteria are met with a maximum confinement period of 15 days.
BerzosertibDrug
Also called M6620
Participants received single intravenous infusion of Berzosertib at a dose of 210 mg/m^2 on Day 2 and Day 5 in period 2 until disease progression or other criteria for study intervention discontinuation were met.
TopotecanDrug
Participants received topotecan at a dose of 1.25 mg/m^2 intravenously on Days 1 through 5 of each 21-day cycle in period 2 until disease progression or other criteria for study intervention discontinuation were met.
| Study group | Role | What they receive |
|---|---|---|
| [14C]Berzosertib | Experimental | Participants received single intravenous infusion of[14C]Berzosertib at a dose of 210 milligrams per square meter (mg/m^2) on Day 1 in Period 1 and stay in clinical research unit (CRU) is required until the discharge criteria are met with a maximum confinement period of 15 days. Receives: Drug: [14C]Berzosertib |
| Berzosertib + Topotecan | Experimental | Participants received single intravenous infusion of Berzosertib at a dose of 210 mg/m^2 on Day 2 and Day 5 in combination with topotecan at a dose of 1.25 mg/m^2 intravenously on Days 1 through 5 of each 21-day cycle in period 2 until disease progression or other criteria for study intervention discontinuation were met. Receives: Drug: Berzosertib; Drug: Topotecan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Period 1: Percent Urinary Recovery (Feurine) of Total Radioactivity
Feurine, fractions of total radioactivity excreted in urine as percentage of the administered dose between time t1 (= start) and t2 (= end).
Measured: Predose, 0-4, 4-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Percent Fecal Recovery (Fefeces) of Total Radioactivity
Fefeces, fractions of total radioactivity excreted in feces as percentage of the administered dose between time t1 (= start) and t2 (= end).
Measured: Predose, 0-4, 4-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Percent Total Recovery in Urine and Feces (Fetotal) of Total Radioactivity
Fetotal, fractions of total radioactivity excreted in urine and feces as percentage of the administered dose between time t1 (= start) and t2 (= end).
Measured: Predose, 0-4, 4-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Maximum Observed Plasma Concentration (Cmax) of Berzosertib
Cmax was obtained directly from the plasma concentration versus time curve.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Berzosertib
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Berzosertib
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Terminal Elimination Half-Life (T1/2) of Berzosertib
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Total Body Clearance (CL) of Berzosertib From Plasma
CL is a quantitative measure of the rate at which a drug substance is removed from the body, calculated as dose divided by AUC0-infinity.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Apparent Volume of Distribution During the Terminal Phase (Vz) of Berzosertib
Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz = Dose/AUC0-inf multiply Lambda z.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Apparent Volume of Distribution at Steady State (Vss) of Berzosertib
Vss is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Maximum Observed Plasma Concentration (Cmax) of Total Radioactivity
Cmax was obtained directly from the plasma concentration versus time curve. Cmax of total radioactivity was calculated in nanogram equivalents per milliliter (ng eq)/mL.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Total Radioactivity
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. AUC0-t was calculated in hour*nanogram equivalents per milliliter (h*[ng eq/mL]).
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Radioactivity
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Terminal Elimination Half-Life (T1/2) of Total Radioactivity
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Maximum Observed Blood Concentration (Cmax) of Total Radioactivity
Cmax was obtained directly from the blood concentration versus time curve.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Area Under the Blood Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Total Radioactivity
Area under the blood concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Area Under the Blood Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Radioactivity
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Terminal Elimination Half-Life (T1/2) of Total Radioactivity in Blood
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Cumulative Amount of Berzosertib Dose Excreted in Urine (Aeurine)
Aeurine is defined as the amount of Berzosertib excreted in urine over the time interval from t1 (= start) and t2 (= end).
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Percentage of Berzosertib Dose Excreted in Urine (Feurine)
Feurine is defined as the amount of Berzosertib unchanged excreted in urine as percentage of the administered dose over the time interval t1 (= start) and t2 (= end).
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Period 1: Renal Clearance (CLr) of Berzosertib
Renal clearance was calculated as total amount of unchanged drug excreted in the urine between times t1 and t2 (Aeurine) divided by area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Measured: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Secondary outcomes (3)
Period 1 and Period 2: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically significant findings in vital signs were reported. Clinical significance was decided by Investigator.
Measured: Period 1: Baseline up to Day 14; Period 2: From Day 1 of period 2 until disease progression or other criteria for study intervention discontinuation are met (up to a maximum of approximately 16 months)
Period 1 and Period 2: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Measurements
12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semi-supine position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported.
Measured: Period 1: Baseline up to Day 14; Period 2: From Day 1 of period 2 until disease progression or other criteria for study intervention discontinuation are met (up to a maximum of approximately 16 months)
Period 1 and Period 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs. Treatment related AEs: reasonably related to the study drug/study treatment.
Measured: Period 1: Baseline up to Day 14; Period 2: From Day 1 of period 2 until disease progression or other criteria for study intervention discontinuation are met (up to a maximum of approximately 16 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Feb 2022
- Study start15 Feb 2022
- Primary completion28 Jun 2023
- Study completion28 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Advanced Solid TumorStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Responsible, Study director, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05246111
- Sponsor's protocol ID
- MS201923_0008
- Other IDs
- 2021-002226-24
- Status last verified
- Sep 2024
- First submitted
- 13 Jan 2022
- Last updated
- 22 Nov 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html
Publications
Bolleddula J, Scheible H, Huber F, Seithel-Keuth A, Schieferstein H, Vagge DS, Mammasse N, Jaks E, Ferrer J, Moulin C, Dong J, Venkatakrishnan K, Papai Z. Microtracer-Based Assessment of the Mass Balance, Pharmacokinetics, and Excretion of [14C]Berzosertib, an Intravenous ATR Inhibitor, in Patients With Advanced Solid Tumors: A Phase 1 Study. Clin Pharmacol Drug Dev. 2025 Sep;14(9):700-709. doi: 10.1002/cpdd.1554. Epub 2025 May 28.
PubMed 40437704
Study at a glance
From the registry record, last updated by the sponsor on 22 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study to Evaluate the Mass Balance, PK, Metabolism and Excretion of Berzosertib (Intravenous) Containing Microtracer [14C]Berzosertib in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 208)
- ClinicalTrials.gov ID
- NCT05246111
- Acronym / sponsor ID
- MS201923_0008
- Conditions
- Advanced Solid Tumor
- Keywords
- Topotecan, Ataxia telangiectasia mutated and Rad3-related (ATR) protein, ATR inhibitor, M6620, Berzosertib, Mass balance
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, GermanyIndustry (pharma, biotech, devices)
- Study start
- 15 Feb 2022 (actual)
- Primary completion
- 28 Jun 2023 (actual)
- Study completion
- 28 Jun 2023 (actual)
- First posted
- 18 Feb 2022 (actual)
- Results
- Posted 22 Nov 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study was conducted in two periods, Period 1 (mass balance) and Period 2 (extension). The purpose of Period 1 of this study was to provide a quantitative characterization of the mass balance, rates and routes of elimination, and metabolic pathways after a single intravenous administration of [14C]berzosertib. The purpose of Period 2 was to assess safety and efficacy of berzosertib in combination with topotecan.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| [14C]Berzosertib | Experimental | Drug: [14C]BerzosertibParticipants received single intravenous infusion of[14C]Berzosertib at a dose of 210 milligrams per square meter (mg/m^2) on Day 1 in Period 1 and stay in clinical research unit (CRU) is required until the discharge criteria are met with a maximum confinement period of 15 days. |
| Berzosertib + Topotecan | Experimental | Drug: Berzosertib, Drug: TopotecanParticipants received single intravenous infusion of Berzosertib at a dose of 210 mg/m^2 on Day 2 and Day 5 in combination with topotecan at a dose of 1.25 mg/m^2 intravenously on Days 1 through 5 of each 21-day cycle in period 2 until disease progression or other criteria for study intervention discontinuation were met. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Histologically proven advanced solid tumors that are considered appropriate for treatment in Period 2 of this study, for which no effective standard therapy exists, or standard therapy has failed or cannot be tolerated
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) =< 1
- Evaluable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Screening
- Participant has adequate renal, hematological and hepatic function
- Other protocol defined inclusion criteria could apply
Key exclusion criteria (5 listed)
- Participants with uncontrolled intercurrent illness including, but not limited to, severe active infection including, acute respiratory syndrome coronavirus-2 infection/coronavirus disease 2019 (Covid 19), immune deficiencies, uncontrolled diabetes, uncontrolled arterial hypertension and symptomatic congestive heart failure
- Concurrent participation in another interventional clinical study is not permitted.
- Known hypersensitivity to the study interventions, a similar structural compound, or to one or more excipients used
- Prior or concurrent treatment with a nonpermitted drug/intervention from the first dose of study intervention administration, as defined per protocol.
- Other protocol defined exclusion criteria could apply
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| [14C]BerzosertibAlso: M6620Participants received single intravenous infusion of [14C]Berzosertib at a dose of 210 milligrams per square meter (mg/m^2) on Day 1 in Period 1 and stay in clinical research unit (CRU) is required until the discharge criteria are met with a maximum confinement period of 15 days. | Drug | [14C]Berzosertib |
| BerzosertibAlso: M6620Participants received single intravenous infusion of Berzosertib at a dose of 210 mg/m^2 on Day 2 and Day 5 in period 2 until disease progression or other criteria for study intervention discontinuation were met. | Drug | Berzosertib + Topotecan |
| TopotecanParticipants received topotecan at a dose of 1.25 mg/m^2 intravenously on Days 1 through 5 of each 21-day cycle in period 2 until disease progression or other criteria for study intervention discontinuation were met. | Drug | Berzosertib + Topotecan |
Primary outcome
Period 1: Percent Urinary Recovery (Feurine) of Total Radioactivity
Time frame: Predose, 0-4, 4-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Feurine, fractions of total radioactivity excreted in urine as percentage of the administered dose between time t1 (= start) and t2 (= end).
Period 1: Percent Fecal Recovery (Fefeces) of Total Radioactivity
Time frame: Predose, 0-4, 4-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Fefeces, fractions of total radioactivity excreted in feces as percentage of the administered dose between time t1 (= start) and t2 (= end).
Period 1: Percent Total Recovery in Urine and Feces (Fetotal) of Total Radioactivity
Time frame: Predose, 0-4, 4-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Fetotal, fractions of total radioactivity excreted in urine and feces as percentage of the administered dose between time t1 (= start) and t2 (= end).
Period 1: Maximum Observed Plasma Concentration (Cmax) of Berzosertib
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Cmax was obtained directly from the plasma concentration versus time curve.
Period 1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Berzosertib
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Period 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Berzosertib
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Period 1: Terminal Elimination Half-Life (T1/2) of Berzosertib
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Period 1: Total Body Clearance (CL) of Berzosertib From Plasma
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
CL is a quantitative measure of the rate at which a drug substance is removed from the body, calculated as dose divided by AUC0-infinity.
Period 1: Apparent Volume of Distribution During the Terminal Phase (Vz) of Berzosertib
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz = Dose/AUC0-inf multiply Lambda z.
Period 1: Apparent Volume of Distribution at Steady State (Vss) of Berzosertib
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Vss is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state.
Period 1: Maximum Observed Plasma Concentration (Cmax) of Total Radioactivity
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Cmax was obtained directly from the plasma concentration versus time curve. Cmax of total radioactivity was calculated in nanogram equivalents per milliliter (ng eq)/mL.
Period 1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Total Radioactivity
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. AUC0-t was calculated in hour*nanogram equivalents per milliliter (h*[ng eq/mL]).
Period 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Radioactivity
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Period 1: Terminal Elimination Half-Life (T1/2) of Total Radioactivity
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Period 1: Maximum Observed Blood Concentration (Cmax) of Total Radioactivity
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Cmax was obtained directly from the blood concentration versus time curve.
Period 1: Area Under the Blood Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Total Radioactivity
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Area under the blood concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Period 1: Area Under the Blood Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Radioactivity
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Period 1: Terminal Elimination Half-Life (T1/2) of Total Radioactivity in Blood
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Period 1: Cumulative Amount of Berzosertib Dose Excreted in Urine (Aeurine)
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Aeurine is defined as the amount of Berzosertib excreted in urine over the time interval from t1 (= start) and t2 (= end).
Period 1: Percentage of Berzosertib Dose Excreted in Urine (Feurine)
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Feurine is defined as the amount of Berzosertib unchanged excreted in urine as percentage of the administered dose over the time interval t1 (= start) and t2 (= end).
Period 1: Renal Clearance (CLr) of Berzosertib
Time frame: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose
Renal clearance was calculated as total amount of unchanged drug excreted in the urine between times t1 and t2 (Aeurine) divided by area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
3 secondary outcomes
Period 1 and Period 2: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Time frame: Period 1: Baseline up to Day 14; Period 2: From Day 1 of period 2 until disease progression or other criteria for study intervention discontinuation are met (up to a maximum of approximately 16 months)
Period 1 and Period 2: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Measurements
Time frame: Period 1: Baseline up to Day 14; Period 2: From Day 1 of period 2 until disease progression or other criteria for study intervention discontinuation are met (up to a maximum of approximately 16 months)
Period 1 and Period 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs
Time frame: Period 1: Baseline up to Day 14; Period 2: From Day 1 of period 2 until disease progression or other criteria for study intervention discontinuation are met (up to a maximum of approximately 16 months)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Nov 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40437704Bolleddula J, Scheible H, Huber F, Seithel-Keuth A, Schieferstein H, Vagge DS, Mammasse N, Jaks E, Ferrer J, Moulin C, Dong J, Venkatakrishnan K, Papai Z. Microtracer-Based Assessment of the Mass Balance, Pharmacokinetics, and Excretion of [14C]Berzosertib, an Intravenous ATR Inhibitor, in Patients With Advanced Solid Tumors: A Phase 1 Study. Clin Pharmacol Drug Dev. 2025 Sep;14(9):700-709. doi: 10.1002/cpdd.1554. Epub 2025 May 28.
- Trial Awareness and Transparency websiteLink provided by the sponsor.
- Medical Information Location Map - Med Info ContactsLink provided by the sponsor.
- DDRiver websiteLink provided by the sponsor.
- Individual participant dataSharing planned: No. Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Responsible study director
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing [14C]Berzosertib, Berzosertib and Topotecan in people with Advanced Solid Tumor, run by Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany at 2 sites in Hungary.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Hungary. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Nov 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Period 1: Percent Urinary Recovery (Feurine) of Total Radioactivity (time frame: Predose, 0-4, 4-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours after dosing on Day 1, continued in 24-hour intervals, until discharge criteria are met, assessed up to Day 14 post-dose). The study lists 21 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05246111, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Nov 2024.