Trial Outcomes & Findings for Berzosertib + Topotecan in Relapsed Platinum-Resistant Small-Cell Lung Cancer (DDRiver SCLC 250) (NCT NCT04768296)

Last Updated: 2024-09-26

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

76 participants

Primary outcome timeframe

Time from first administration of study treatment up to 27.7 months

Results posted on

2024-09-26

Participant Flow

Participant milestones

Participant milestones
Measure	Safety run-in Part (Dose Level 1 [DL 1]): Berzosertib 105 mg/m^2 + Topotecan 1.25 mg/m^2 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 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 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Overall Study STARTED	3	73
Overall Study COMPLETED	2	66
Overall Study NOT COMPLETED	1	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Safety run-in Part (Dose Level 1 [DL 1]): Berzosertib 105 mg/m^2 + Topotecan 1.25 mg/m^2 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 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 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Overall Study STOP LONG-TERM FOLLOW-UP AS PER SPONSOR'S DECISION	1	7

Baseline Characteristics

Berzosertib + Topotecan in Relapsed Platinum-Resistant Small-Cell Lung Cancer (DDRiver SCLC 250)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Safety run-in Part (Dose Level 1 [DL 1]): Berzosertib 105 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 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 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 n=73 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.	Total n=76 Participants Total of all reporting groups
Age, Continuous	51 Years STANDARD_DEVIATION 4 • n=5 Participants	63 Years STANDARD_DEVIATION 7.8 • n=7 Participants	62 Years STANDARD_DEVIATION 8 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	16 Participants n=7 Participants	17 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	57 Participants n=7 Participants	59 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	63 Participants n=7 Participants	66 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	9 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	19 Participants n=7 Participants	22 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	42 Participants n=7 Participants	42 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	10 Participants n=7 Participants	10 Participants n=5 Participants

PRIMARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=73 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)	5.5 percentage of participants Interval 1.5 to 13.4	—

PRIMARY outcome

Timeframe: Up to Cycle 1 Day 21 (each cycle is of 21 days)

Population: DLT analysis set: all participants who were administered any dose of any study intervention in Safety Run-in Part in Japan and meet at least one of the following criteria: Received at least 80% of planned cumulative dose of study intervention during the DLT and completed the DLT period. The final decision on evaluability is made by the SMC; Experienced at least 1 DL T during the DLT period, regardless of the administered cumulative dose of study intervention and completion of the DLT period.

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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs)	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.

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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs TEAEs	3 Participants	3 Participants
Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs Treatment Related TEAEs	3 Participants	3 Participants

PRIMARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.

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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.

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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.

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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Hematology	0 Participants	3 Participants
Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Biochemistry	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From first documented objective response to PD or death due to any cause, assessed up to 27.7 months

Population: FAS was used. Due to small number of participants with a response, data was not summarized; however, individual participant data is reported for this outcome measure. Here, "Overall Number of Participants Analyzed" = participants who were evaluable for this outcome measure and "number analyzed" = specific participants evaluated in the arm.

DoR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. 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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=4 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC) Participant 2	2.8 months	—
Main Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC) Participant 3	2.6 months	—
Main Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC) Participant 4	2.1 months	—
Main Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC) Participant 1	8.5 months	—

SECONDARY outcome

Timeframe: Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed up to 27.7 months

Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.

PFS was defined as the time is defined as the time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, whichever occurs first. 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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=73 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)	2.2 months Interval 1.5 to 2.7	—

SECONDARY outcome

Timeframe: Time from first administration of study treatment to the date of death, assessed up to 27.7 months

Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.

Overall survival is defined as the time from first administration of study treatment to the date of death.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=73 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Overall Survival (OS)	6.4 months Interval 4.2 to 7.6	—

SECONDARY outcome

Timeframe: Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days

Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

The EORTC QLQ-C30 is a participant completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. For the physical functioning scale, subjects self-rated levels of difficulty in doing strenuous activities, taking a walk, how much they needed to stay in bed or a chair, or needed help with eating, dressing, bathing, using the toilet. The physical functioning scale had 4 possible scores (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. A positive change from baseline indicates improvement in physical functioning.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=33 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Change From Baseline in Physical Functioning Measured by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	-4.0 score on a scale Standard Deviation 20.67	—

SECONDARY outcome

Timeframe: Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days

EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=33 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Number of Participants Who Improved, Worsened or Remained Stable in European Organization for the Research and Treatment of Cancer Quality of Life and Lung Cancer Specific Questionnaire (EORTC QLQ-LC13) Improvement in Cough	6 Participants	—
Main Part: Number of Participants Who Improved, Worsened or Remained Stable in European Organization for the Research and Treatment of Cancer Quality of Life and Lung Cancer Specific Questionnaire (EORTC QLQ-LC13) Stable in Cough	20 Participants	—
Main Part: Number of Participants Who Improved, Worsened or Remained Stable in European Organization for the Research and Treatment of Cancer Quality of Life and Lung Cancer Specific Questionnaire (EORTC QLQ-LC13) Worsened in Cough	7 Participants	—
Main Part: Number of Participants Who Improved, Worsened or Remained Stable in European Organization for the Research and Treatment of Cancer Quality of Life and Lung Cancer Specific Questionnaire (EORTC QLQ-LC13) Improvement in Chest Pain	7 Participants	—
Main Part: Number of Participants Who Improved, Worsened or Remained Stable in European Organization for the Research and Treatment of Cancer Quality of Life and Lung Cancer Specific Questionnaire (EORTC QLQ-LC13) Stable in Chest Pain	22 Participants	—
Main Part: Number of Participants Who Improved, Worsened or Remained Stable in European Organization for the Research and Treatment of Cancer Quality of Life and Lung Cancer Specific Questionnaire (EORTC QLQ-LC13) Worsened in Chest Pain	4 Participants	—

SECONDARY outcome

Timeframe: Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days

EQ-5D-5L is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100, where 0 is the worst health you can imagine and 100 is the best health you can imagine.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=31 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Change From Baseline in Health State as Measured by Visual Analogue Scale (VAS) Component of European Quality of Life 5-dimensions 5 Level Scale (EQ-5D-5L)	-6.3 score on a scale Standard Deviation 19.67	—

SECONDARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=73 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs TEAEs	73 Participants	—
Main Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs Treatment Related TEAEs	67 Participants	—

SECONDARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=73 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs	0 Participants	—

SECONDARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=73 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings	0 Participants	—

SECONDARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.

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 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. The laboratory assessments were graded according to NCI-CTCAE version 5.0 and data for individual clinically significant abnormalities (Grade \>= 3) was extracted using data source (ADLBHEMA). The data categorized here may not necessarily be considered as TEAE by the investigator during the reporting of TEAEs and there is no correlation between the grade \>=3 treatment related TEAEs hematology parameters and the TEAEs in the AE module.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=73 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Anemia	18 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Lymphocyte count decreased	17 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Neutrophil count decreased	28 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Platelet count decreased	26 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) White blood cell decreased	19 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Alanine aminotransferase increased	2 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Alkaline phosphatase increased	1 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Aspartate transaminase increased	1 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Blood bilirnbin increased	3 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Hypokalemia	8 Participants	—
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) Hyponatremia	4 Participants	—

SECONDARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator	33.3 percentage of participants Interval 0.8 to 90.6	0.0 percentage of participants Interval 0.0 to 70.8

SECONDARY outcome

Timeframe: Time from first administration of study treatment up to 27.7 months

DOR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. 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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=1 Participants 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 DL1 and DL2 of safety run-in part and main 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 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator	7.2 months	—

SECONDARY outcome

Timeframe: Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed up to 27.7 months

Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator	14.3 months Interval 4.0 to 14.3	3.3 months Interval 1.2 to 8.1

SECONDARY outcome

Timeframe: Time from first administration of study treatment to the date of death, assessed up to 27.7 months

Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.

Overall survival is defined as the time from first administration of study treatment to the date of death.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Overall Survival (OS)	NA months Interval 8.0 to Due to small number of events, median and upper limit of 95% Confidence Interval from Kaplan-Meier survival curves could not be derived.	15.3 months Interval 10.0 to Due to small number of events, upper limit of 95% Confidence Interval from Kaplan-Meier survival curves could not be derived.

SECONDARY outcome

Timeframe: Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days

Population: As per changes in planned analysis, the outcome measure related to quality of life for safety run-in part was not assessed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days

Population: As per changes in planned analysis, the outcome measure related to quality of life for safety run-in part was not assessed.

EORTC QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The EORTC QLQ-LC13 module generated one multiple-item score assessing dyspnea and a series of single item scores assessing coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arms or shoulder and pain in other parts. Score range: 0 (no burden of symptom domain or single symptom item) to 100 (highest burden of symptoms for symptom domains and single items).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days

Population: As per changes in planned analysis, the outcome measure related to quality of life for safety run-in part was not assessed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

Population: Pharmacokinetic Analysis Set (PKS) included all participants who were administered at least 1 complete infusion of berzosertib in the Safety Run-in Part in Japan and for whom at least 1 quantifiable post-dose plasma concentration of berzosertib was obtained.

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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast) of Berzosertib	2330 hournanogram per milliliter (hng/mL) Geometric Coefficient of Variation 0.8	4090 hournanogram per milliliter (hng/mL) Geometric Coefficient of Variation 7.1

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose. AUC0-t/dose was measured in hour\*nanogram per milliliter per milligram (h\*ng/mL/mg).

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast/Dose) of Berzosertib	12.2 h*ng/mL/mg Geometric Coefficient of Variation 9.9	11.1 h*ng/mL/mg Geometric Coefficient of Variation 9.8

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Berzosertib	2460 h*ng/mL Geometric Coefficient of Variation 1.4	4310 h*ng/mL Geometric Coefficient of Variation 8.8

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of Berzosertib	12.8 h*ng/mL/mg Geometric Coefficient of Variation 11.0	11.7 h*ng/mL/mg Geometric Coefficient of Variation 11.4

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24 and 48 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

Area under the concentration-time curve from pre-dose (time 0) to 48 hours post-dose calculated using the linear-log trapezoidal rule

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h) of Berzosertib	2160 h*ng/mL Geometric Coefficient of Variation 2.0	3790 h*ng/mL Geometric Coefficient of Variation 5.6

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24 and 48 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

AUC0-48 hour/Dose was defined as AUC from time of dosing to 48 hours divided by dose.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h/Dose) of Berzosertib	11.3 h*ng/mL/mg Geometric Coefficient of Variation 9.7	10.3 h*ng/mL/mg Geometric Coefficient of Variation 8.7

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

Area under the concentration-time curve from pre-dose (time 0) to 72 hours post-dose calculated using the linear-log trapezoidal rule

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h) of Berzosertib	2340 h*ng/mL Geometric Coefficient of Variation 0.8	4110 h*ng/mL Geometric Coefficient of Variation 7.1

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

AUC0-72 hour/Dose was defined as AUC from time of dosing to 72 hours divided by dose.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h/Dose) of Berzosertib	12.2 h*ng/mL/mg Geometric Coefficient of Variation 9.9	11.2 h*ng/mL/mg Geometric Coefficient of Variation 9.9

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

Cmax was obtained directly from the plasma concentration versus time curve.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Berzosertib	259 ng/mL Geometric Coefficient of Variation 23.5	446 ng/mL Geometric Coefficient of Variation 17.7

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg).

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of Berzosertib	1.35 ng/mL/mg Geometric Coefficient of Variation 27.5	1.21 ng/mL/mg Geometric Coefficient of Variation 24.9

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2; Pre-dose, 1 and 1.5 hours after dose on Cycle 1 Day 5 (each cycle is of 21 days)

Ceoi was the observed concentration at the end of the infusion period. This was taken directly from the observed Berzosetib concentration-time data.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib Cycle 1 Day 2	259 ng/mL Geometric Coefficient of Variation 23.5	446 ng/mL Geometric Coefficient of Variation 17.7
Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib Cycle 1 Day 5	341 ng/mL Geometric Coefficient of Variation 23.1	500 ng/mL Geometric Coefficient of Variation 42.7

SECONDARY outcome

Timeframe: Pre-dose on Cycle 1 Day 5 (each cycle is of 21 days)

Ctrough was the plasma concentration observed immediately before next dosing.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Plasma Observed Concentration Immediately Before Next Dosing (Ctrough) of Berzosertib	4.84 ng/mL Geometric Coefficient of Variation 22.3	8.57 ng/mL Geometric Coefficient of Variation 23.6

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

CL was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib	77.8 liter per hour Geometric Coefficient of Variation 11.0	85.4 liter per hour Geometric Coefficient of Variation 11.4

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2; Pre-dose, 1 and 1.5 hours after dose on Cycle 1 Day 5 (each cycle is of 21 days)

Accumulation ratio of Cmax was calculated as Cmax after dosing on Day 5 divided by Cmax after dosing on Day 2 of Cycle 1.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib	1.32 ratio Geometric Coefficient of Variation 16.3	1.12 ratio Geometric Coefficient of Variation 24.9

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

Tmax was obtained directly from the plasma concentration versus time curve.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Berzosertib	1.17 hours Interval 1.13 to 1.2	1.20 hours Interval 1.17 to 1.23

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

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.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib	17.6 hours Geometric Coefficient of Variation 10.1	17.0 hours Geometric Coefficient of Variation 13.5

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

tlast is defined as the last sampling time at which the concentration is at or above the lower limit of quantification.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Last Sampling Time (Tlast) of Berzosertib	70.4 hours Geometric Coefficient of Variation 0.3	70.6 hours Geometric Coefficient of Variation 0.7

SECONDARY outcome

Timeframe: Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

Vz: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

Outcome measures

Outcome measures
Measure	Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 Participants 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 DL1 and DL2 of safety run-in part and main 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 n=3 Participants 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Safety Run-in Part: Apparent Volume of Distribution During Terminal Phase (Vz) of Berzosertib	1980 liters Geometric Coefficient of Variation 4.2	2100 liters Geometric Coefficient of Variation 5.8

Adverse Events

Safety run-in Part (Dose Level 1 [DL 1]): Berzosertib 105 mg/m^2 + Topotecan 1.25 mg/m^2

Serious events: 0 serious events

Other events: 3 other events

Deaths: 1 deaths

Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2

Serious events: 31 serious events

Other events: 70 other events

Deaths: 63 deaths

Serious adverse events

Other adverse events

Additional Information

Communication Center

Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Safety run-in Part (Dose Level 1 [DL 1]): Berzosertib 105 mg/m^2 + Topotecan 1.25 mg/m^2 n=3 participants at risk 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 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 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 n=73 participants at risk 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 DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Blood and lymphatic system disorders Anaemia	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	5.5% 4/73 • Number of events 5 • Time from first administration of study treatment up to 27.7 months
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	5.5% 4/73 • Number of events 4 • Time from first administration of study treatment up to 27.7 months
Blood and lymphatic system disorders Myelosuppression	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Blood and lymphatic system disorders Neutropenia	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	4.1% 3/73 • Number of events 4 • Time from first administration of study treatment up to 27.7 months
Cardiac disorders Acute coronary syndrome	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Ear and labyrinth disorders Vestibular disorder	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	2.7% 2/73 • Number of events 2 • Time from first administration of study treatment up to 27.7 months
General disorders Asthenia	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
General disorders Disease progression	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
General disorders Fatigue	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
General disorders General physical health deterioration	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
General disorders Multiple organ dysfunction syndrome	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 2 • Time from first administration of study treatment up to 27.7 months
General disorders Pyrexia	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Hepatobiliary disorders Liver injury	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	2.7% 2/73 • Number of events 3 • Time from first administration of study treatment up to 27.7 months
Infections and infestations COVID-19	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	5.5% 4/73 • Number of events 4 • Time from first administration of study treatment up to 27.7 months
Infections and infestations COVID-19 pneumonia	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	4.1% 3/73 • Number of events 3 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Enterococcal sepsis	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Lung abscess	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Pneumonia	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Pneumonia bacterial	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Pneumonia pneumococcal	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Sepsis	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	2.7% 2/73 • Number of events 2 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Septic shock	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Serratia sepsis	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Staphylococcal sepsis	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Urinary tract infection	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 3 • Time from first administration of study treatment up to 27.7 months
Infections and infestations Urosepsis	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Investigations Neutrophil count decreased	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	2.7% 2/73 • Number of events 2 • Time from first administration of study treatment up to 27.7 months
Investigations Platelet count decreased	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	2.7% 2/73 • Number of events 3 • Time from first administration of study treatment up to 27.7 months
Investigations White blood cell count decreased	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Nervous system disorders Headache	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Nervous system disorders Seizure	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	8.2% 6/73 • Number of events 7 • Time from first administration of study treatment up to 27.7 months
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/3 • Time from first administration of study treatment up to 27.7 months	1.4% 1/73 • Number of events 1 • Time from first administration of study treatment up to 27.7 months