Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as [14C]Berzosertib, M6620
Berzosertib · 6 trials · 7 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.
DLT: any death not clearly due to underlying disease/extraneous causes/Grade(Gr) \>=3 nonhematologic/Gr\>=4 hematologic toxicity that was probably/definitely related to any of study interventions, individually/combination that occurred during DLT observation period, except for any of following: Gr3 infusion-related reaction; Transient (\<=6hr) Gr3 flu-like symptoms/fever, controlled with medical management; Transient (\<=72hr) Gr3 fatigue, local reactions, headache, nausea/emesis; Gr3 diarrhea, skin toxicity, liver function test increase; Single laboratory values out of normal range and controlled with medical management; Tumor flare phenomenon: local pain, irritation/rash, localized at sites of known/suspected tumor; Neutropenia (Gr3/4) for \<7 days not associated with any infection; Gr3 thrombocytopenia for \<7 days without clinically significant bleeding and not requiring platelet transfusion; Symptomatic thyroid dysfunction manageable with treatment.
To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose, RPTD) administered concomitantly with radiotherapy (RT) only in the palliative treatment of oesophageal cancer.
To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose, RPTD) administered concomitantly with chemotherapy (cisplatin and capecitabine) only in the palliative treatment of solid cancer.
Highest treatment schedule resulting in less than 45% dose limiting toxicity (DLT) rate.
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, regardless of causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment-related AEs: reasonably related to the study intervention.
| 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. |
| Part A: Carboplatin + M6620 + Avelumab | EXPERIMENTAL | - |
| Stage A1, A2 & B | EXPERIMENTAL | The trial is a single arm study. Different populations are recruited to each stage and the stages run independently of each other. Stage A1 \& A2 will commence before Stage B so that safety data can be obtained in the palliative setting prior to Stage B commencing. Stage A1 may be ongoing when Stage B begins. Each Stage has a separate eligibility criteria. Stage A1: M6620 \& palliative radiotherapy Stage A2: M6620 \& palliative chemotherapy (Cisplatin \& Capecitabine) Stage B: M6620 \& definitive chemoradiotherapy |
| Part A1: Berzosertib | EXPERIMENTAL | - |
| Part A | EXPERIMENTAL | This part will be 3 + 3 dose escalation study of M6620 in combination with gemcitabine as well as gemcitabine and cisplatin in participants with advanced solid tumors. |
| Part B | EXPERIMENTAL | This part will be 3 + 3 dose escalation study of M6620 in combination with cisplatin or cisplatin and etoposide in participants with advanced solid tumors. |
| Part B2 | EXPERIMENTAL | This part will be 3 + 3 dose escalation study of M6620 in combination with irinotecan in participants with advanced solid tumors. |
| Part C1 | EXPERIMENTAL | This will be the expansion part of the study in which participants with advanced non-small cell lung cancer (NSCLC) will be administered M6620 in combination with gemcitabine. |
| Part C2 | EXPERIMENTAL | This will be the expansion part of the study in which participants with advanced triple negative breast cancer (TNBC) will be administered M6620 in combination with cisplatin. |
| Part C3 | EXPERIMENTAL | This will be the expansion part of the study in which participants with platinum-resistant advanced small cell lung cancer (SCLC) will be administered M6620 in combination with cisplatin or carboplatin. |
| 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. |
| M6620 | DRUG | Participants received 90 milligrams per square meter (mg/m\^2) of M6620, intravenously (IV) on Day 2 of every 3 weeks (Q3W) cycle for a maximum of 6 cycles in combination treatment with carboplatin and avelumab on Day 1. The M6620 dose may be de-escalated to 60 mg/m\^2, or 40 mg/m\^2. |
| Avelumab | DRUG | Participants received IV infusion of avelumab 1600 mg on Day 1 of each Q3W cycle for maximum of 6 cycles in combination treatment with carboplatin and M6620. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Carboplatin | DRUG | Participants received carboplatin area under the concentration-time curve 5 on Day 1 of each Q3W cycle for a maximum of 6 cycles in combination treatment with avelumab and M6620. |
| Cisplatin | DRUG | Cisplatin is a platinum based chemotherapy drug licensed to treat a number of different types of cancer. Cisplatin use is not considered standard practice in Stage A2 \& B, therefore Cisplatin is considered an investigational medicinal product for the purpose of this trial. |
| Capecitabine | DRUG | Capecitabine is a chemotherapy drug licensed to treat a number of different types of cancer, it is a noncytotoxic pre-cursor of the cytotoxic 5-fluourouracil. Capecitabine use is not considered standard practice in Stage A2 \& B, therefore Capecitabine is considered an investigational medicinal product for the purpose of this trial. |
| Radiotherapy | RADIATION | Stage A1 uses palliative radiotherapy. Stage B uses definitive radiotherapy. |
| Gemcitabine | DRUG | - |
| Etoposide | DRUG | - |
| Irinotecan | DRUG | - |
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 ATR inhibitor being developed by Merck KGaA for oncology. It has been studied in advanced solid tumors and small-cell lung cancer. It is not approved and remains in clinical development.
Berzosertib has been studied in advanced solid tumors and in relapsed platinum-resistant small-cell lung cancer, where it was tested in combination with topotecan. It is investigational and has not been approved for any indication.
Berzosertib targets ATR, a kinase involved in the DNA damage response. As an ATR inhibitor, it blocks this target to interfere with DNA damage repair in tumor cells. It is a small molecule developed for oncology indications.
Berzosertib is developed by Merck KGaA, which trades under the ticker MKGAF. The company has sponsored the clinical trials evaluating the drug in solid tumors and small-cell lung cancer.
Berzosertib is in Phase 1 development overall, with a Phase 2 trial also completed in small-cell lung cancer. It is investigational and has not been approved by the FDA or any other regulator.
Berzosertib has been evaluated in completed trials including NCT05246111, a human mass balance study in advanced solid tumors; NCT04768296, a Phase 2 study with topotecan in relapsed platinum-resistant small-cell lung cancer; and NCT03309150, an ATRi transition rollover study.
Yes, [14C]Berzosertib is an alternative name for Berzosertib. The carbon-14 labeled form was used in the human mass balance study NCT05246111 to track how the drug is absorbed, metabolized, and excreted in the body.