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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
6
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.
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.
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.
Magyar Honvédség Egészségügyi Központ, Podmaniczky utcai telephely, Onkológiai Osztály
Budapest, Hungary
PRA Magyarország Kft. Fázis I-es Klinikai Farmakológiai Vizsgálóhely
Budapest, Hungary
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).
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
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).
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
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).
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
Period 1: Maximum Observed Plasma Concentration (Cmax) of Berzosertib
Cmax was obtained directly from the plasma concentration versus time curve.
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
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.
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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
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.
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
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.
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
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.
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
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.
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
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.
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
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.
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
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\*\[ng eq/mL\]).
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
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.
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
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.
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
Period 1: Maximum Observed Blood Concentration (Cmax) of Total Radioactivity
Cmax was obtained directly from the blood concentration versus time curve.
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
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.
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
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.
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
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.
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
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).
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
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).
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
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.
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
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.
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
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.
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
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.
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)