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

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.

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.

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

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.

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.

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.

An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.

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

ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was decided by investigator. Number of participants with clinically significant changes from baseline in 12-Lead ECGs were reported.

The laboratory measurements included hematology and biochemistry. Number of participants with clinically significant abnormalities with Grade greater than or equals to (>=) 3 in laboratory values reported as TEAEs as per 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.

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.

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.

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.

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

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.

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).

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.

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

AUC0-t/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).

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.

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

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

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

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

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

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

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).

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

Ctrough was the plasma concentration observed immediately before next dosing.

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.

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

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

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.

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

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.