Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Berzosertib · 2 trials · 2 indications
Objective response rate was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD). CR: Disappearance of all target and non-target lesions. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of their diameters, and no unequivocal progression of non-target lesions. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, or unequivocal progression of non-target lesions, or appearance of any new lesion.
DLT is defined as drug-related: Neutropenia Grade 4 for greater than (\>) 7 days' duration; Febrile neutropenia (that is \[i.e.\] absolute neutrophil count less than (\< ) 1000 per millimeter cube (mm\^3) with single temperature of \> 38.3°degree Celsius or a sustained temperature of greater than or equal to (\>=) 38 degree Celsius for more than 1 hour; Infection (documented clinically or microbiologically) with Grades 3 or 4 neutropenia; Thrombocytopenia \>= Grade 3; Grade \>= 3 non-hematological AEs.
An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically significant changes from baseline in vital signs were reported. Clinical significance was decided by Investigator.
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was decided by investigator. Number of participants with clinically significant changes from baseline in 12-Lead ECGs were reported.
The laboratory measurements included hematology and biochemistry. Number of participants with clinically significant abnormalities with Grade greater than or equals to (\>=) 3 in laboratory values reported as TEAEs as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Clinically Significance was decided by investigator.
Feurine, fractions of total radioactivity excreted in urine as percentage of the administered dose between time t1 (= start) and t2 (= end).
Fefeces, fractions of total radioactivity excreted in feces as percentage of the administered dose between time t1 (= start) and t2 (= end).
Fetotal, fractions of total radioactivity excreted in urine and feces as percentage of the administered dose between time t1 (= start) and t2 (= end).
Cmax was obtained directly from the plasma concentration versus time curve.
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-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.
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.
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.
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.
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.
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.
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\*\[ng eq/mL\]).
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.
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.
Cmax was obtained directly from the blood concentration versus time curve.
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.
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.
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.
Aeurine is defined as the amount of Berzosertib excreted in urine over the time interval from t1 (= start) and t2 (= end).
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).
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.
| Arm | Type | Description |
|---|---|---|
| Safety run-in Part (Dose Level1 [DL 1]): Berzosertib 105 mg/m^2 + Topotecan 1.25 mg/m^2 | EXPERIMENTAL | Participants received Berzosertib at a dose of 105 milligrams per square meter (mg/m\^2 ) intravenously on Day 2 and Day 5 of each 21-daycycle in combination with Topotecan at a dose of 1.25mg/m\^2 intravenously on Days1 through 5 of each 21-day cycle in DL1 of safety run-in part until disease progression or other criteria for study intervention discontinuation are met. |
| Safety run-in Part (DL2) +Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | EXPERIMENTAL | Participants received Berzosertib at a dose of 210 mg/m\^2 intravenously on Day 2 and Day 5 of each 21-day cycle 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 DL 1 and DL 2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met. |
| [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. |
| 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. |
| Name | Type | Description |
|---|---|---|
| Berzosertib | DRUG | Participants received Berzosertib at a dose of 105 milligrams per square meter (mg/m\^2 ) intravenously on Day 2 and Day 5 of each 21-day cycle until disease progression or other criteria for study intervention discontinuation are met. |
| Topotecan | DRUG | Participants received Topotecan at a dose of 1.25 mg/m\^2 intravenously on Days 1 through 5 of each 21-day cycle in DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met. |
| [14C]Berzosertib | DRUG | 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. |
Inclusion Criteria: * Dose level 1 participants with histologically proven advanced solid tumors, for which no effective standard therapy exists, or standard therapy has failed or cannot be tolerated * Dose level 1 participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) le...
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Berzosertib is an investigational small molecule being studied for the treatment of small-cell lung cancer and advanced solid tumors. It is being developed by Merck & Company, Inc. (MRK). The drug is currently in clinical development and is not approved by the FDA.
Berzosertib is a small molecule that targets ATR kinase, a key regulator of the DNA damage response. By inhibiting ATR, it may enhance the effects of DNA-damaging agents like topotecan in cancer cells. This mechanism is being explored in clinical trials for small-cell lung cancer and advanced solid tumors.
Berzosertib is being developed by Merck & Company, Inc., a pharmaceutical company traded on the New York Stock Exchange under the ticker symbol MRK. The company is conducting clinical trials to evaluate the drug's safety and efficacy in oncology indications.
Berzosertib is in Phase 1 clinical development. It has completed a Phase 1 human mass balance study and a Phase 2 trial in small-cell lung cancer. The drug remains investigational and has not received FDA approval for any indication.
Berzosertib has been studied in two completed trials. NCT04768296 evaluated berzosertib plus topotecan in relapsed platinum-resistant small-cell lung cancer with 76 participants. NCT05246111 was a human mass balance study in advanced solid tumors with 6 participants. Both trials are completed.
Berzosertib is the only name provided for this drug. It is not known by any alternative names in the available data. The drug is being developed by Merck & Company, Inc. for oncology indications.