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

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)

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.

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

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)

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.

Time frame: 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

Main Part: Overall Survival (OS)

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

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

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)

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.

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

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)

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.

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

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)

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.

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

Main Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

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.

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

Main Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs

Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically significant changes from baseline in vital signs were reported. Clinical significance was decided by Investigator.

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

Main Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

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.

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

Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)

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.

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

Safety Run-in Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator

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.

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

Safety Run-in Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator

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.

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

Safety Run-in Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator

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.

Time frame: 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

Safety Run-in Part: Overall Survival (OS)

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

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

Safety Run-in 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)

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.

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

Safety Run-in Part: Change From Baseline in Cough, Dyspnea and Chest Pain Measured by European Organization for the Research and Treatment of Cancer Quality of Life and Lung Cancer Specific Questionnaire (EORTC QLQ-LC13)

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).

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

Safety Run-in 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)

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.

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

Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast) of Berzosertib

Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.

Time frame: 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)

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

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).

Time frame: 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)

Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Berzosertib

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.

Time frame: 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)

Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of Berzosertib

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

Time frame: 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)

Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h) of Berzosertib

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

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

Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h/Dose) of Berzosertib

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

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

Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h) of Berzosertib

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

Time frame: 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)

Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h/Dose) of Berzosertib

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

Time frame: 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)

Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Berzosertib

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

Time frame: 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)

Safety Run-in Part: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of Berzosertib

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).

Time frame: 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)

Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib

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

Time frame: 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)

Safety Run-in Part: Plasma Observed Concentration Immediately Before Next Dosing (Ctrough) of Berzosertib

Ctrough was the plasma concentration observed immediately before next dosing.

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

Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib

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.

Time frame: 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)

Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib

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

Time frame: 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)

Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Berzosertib

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

Time frame: 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)

Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib

T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Time frame: 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)

Safety Run-in Part: Last Sampling Time (Tlast) of Berzosertib

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

Time frame: 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)

Safety Run-in Part: Apparent Volume of Distribution During Terminal Phase (Vz) of Berzosertib

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.

Time frame: 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)