Small-cell Lung Cancer
Conditions
Keywords
M6620, Berzosertib, Solid Tumor, Topotecan, Ataxia telangiectasia mutated and Rad3-related, Platinum-resistant Small-Cell Lung Cancer, DDRiver
Brief summary
The main purpose of this study is to assess efficacy, safety, tolerability and pharmacokinetics (PK) of Berzosertib in combination with Topotecan in participants with relapsed, platinum-resistant small-cell lung cancer (SCLC). This study will be conducted in two parts: safety run-in part and main part. The safety run-in part will be conducted in Japan.
Interventions
DRUGBerzosertib
Participants received Berzosertib at a dose of 105 milligrams per square meter (mg/m\^2 ) intravenously on Day 2 and Day 5 of each 21-day cycle until disease progression or other criteria for study intervention discontinuation are met.
DRUGTopotecan
Participants received Topotecan at a dose of 1.25 mg/m\^2 intravenously on Days 1 through 5 of each 21-day cycle in DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Dose level 1 participants with histologically proven advanced solid tumors, for which no effective standard therapy exists, or standard therapy has failed or cannot be tolerated * Dose level 1 participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) less than or equal to (\<=) 1 and Karnofsky Scale greater than or equal to (\>=) 70 percent (%) * Dose level 2 and main part participants with ECOG PS \<= 2 and Karnofsky Scale \>= 60% * Dose level 2 and main part participants with histologically confirmed SCLC * Dose level 2 and main part participants with radiologically confirmed progression after first-line or chemoradiation platinum-based treatment (carboplatin or cisplatin), with or without immunotherapy, for treatment of limited or extensive stage SCLC, with a Platinum-free interval (PFI) less than (\<) 90 days. The PFI is measured by the elapsed time from the last day of the regimen of a platinum-based treatment until the first day of documented disease progression * Dose level 2 and main part participants with measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (RECISTv1.1) at Screening. Evidence of measurable disease must be confirmed by the IRC prior to start of treatment * Tumor tissue provision: archival (collected within 12 months before date of informed consent form \[ICF\]) signature for Screening) or fresh biopsy specimen, if medically feasible * Have adequate hematologic and renal function * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Clinically relevant (that is \[i.e.\], active), uncontrolled intercurrent illness including, but not limited to, severe active infection including, severe acute respiratory syndrome coronavirus-2 infection/coronavirus disease 2019, immune deficiencies, uncontrolled diabetes, uncontrolled arterial hypertension, symptomatic congestive heart failure (New York Heart Association Classification greater than or equal to \[\>=\] Class III), unstable angina pectoris, myocardial infarction, uncontrolled cardiac arrhythmia, cerebral vascular accident/stroke. Calculated corrected QT interval (QTc) average (using the Fridericia correction calculation) of greater than \[\>\] 450 millisecond (msec) for males and \> 470 msec for females. Any psychiatric illness/social situations that would limit compliance with study requirements * Unstable brain metastases; however, participants with known brain metastases may be enrolled in this clinical study if they are clinically stable (without evidence of progression by imaging for at least 2 weeks prior to the first study intervention dose and any neurologic symptoms have returned to baseline), have no evidence of new brain metastases, and are on a stable or decreasing dose of steroids for at least 14 days prior to study intervention Participants with carcinomatous meningitis are excluded regardless of clinical stability. Screening central nervous system imaging is not mandatory * Prior malignant disease within the last 3 years. Exceptions include fully resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, in situ cervical cancer, fully resected ductal carcinoma in situ of the breast, superficial or noninvasive bladder cancer, and Stage IA, Grade I endometrioid endometrial cancer with no myometrial invasion, that has undergone curative therapy. Participants with other localized malignancies treated with curative intent need to be discussed with the Medical Monitor * Participants not recovered from adverse events (AEs) Grade \> 1 from prior anticancer therapies, including surgeries. Exception: Grade 2 AEs not constituting a safety risk (for example \[e.g.\], alopecia), based on the Investigator's judgment; must consult with the medical Monitor prior to enrollment. * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Main Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC) | Time from first administration of study treatment up to 27.7 months | 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. |
| Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs) | Up to Cycle 1 Day 21 (each cycle is of 21 days) | 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. |
| Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Time from first administration of study treatment up to 27.7 months | 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. |
| Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Time from first administration of study treatment up to 27.7 months | 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. |
| Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | Time from first administration of study treatment up to 27.7 months | 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. |
| Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Time from first administration of study treatment up to 27.7 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Main Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Time from first administration of study treatment up to 27.7 months | 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. |
| Main Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Time from first administration of study treatment up to 27.7 months | 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. |
| Main Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | Time from first administration of study treatment up to 27.7 months | 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. |
| Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Time from first administration of study treatment up to 27.7 months | 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. |
| Safety Run-in Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator | Time from first administration of study treatment up to 27.7 months | 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. |
| Safety Run-in Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator | 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. |
| Safety Run-in Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator | 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 | 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. |
| Safety Run-in Part: Overall Survival (OS) | Time from first administration of study treatment to the date of death, assessed up to 27.7 months | Overall survival is defined as the time from first administration of study treatment to the date of death. |
| 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) | Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days | 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. |
| 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) | Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days | 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). |
| 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) | Baseline (Cycle 1 Day 1), end of treatment (up to 64 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. |
| Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast) of Berzosertib | 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 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. |
| 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 | 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). |
| Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Berzosertib | 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. |
| Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of Berzosertib | 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. |
| Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h) of Berzosertib | 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 |
| Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h/Dose) of Berzosertib | 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. |
| Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h) of Berzosertib | 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 |
| Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h/Dose) of Berzosertib | 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. |
| 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) | From first documented objective response to PD or death due to any cause, assessed 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. |
| Safety Run-in Part: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of Berzosertib | 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). |
| Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib | 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. |
| Safety Run-in Part: Plasma Observed Concentration Immediately Before Next Dosing (Ctrough) of Berzosertib | Pre-dose on Cycle 1 Day 5 (each cycle is of 21 days) | Ctrough was the plasma concentration observed immediately before next dosing. |
| Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib | 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. |
| Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib | 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. |
| Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Berzosertib | 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. |
| Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib | 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. |
| Safety Run-in Part: Last Sampling Time (Tlast) of Berzosertib | 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. |
| Safety Run-in Part: Apparent Volume of Distribution During Terminal Phase (Vz) of Berzosertib | 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. |
| Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Berzosertib | 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. |
| 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) | 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 | 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. |
| Main Part: Overall Survival (OS) | Time from first administration of study treatment to the date of death, assessed up to 27.7 months | Overall survival is defined as the time from first administration of study treatment to the date of death. |
| 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) | Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days | 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. |
| 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) | 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. |
| 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) | 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. |
Countries
Belgium, China, France, Italy, Japan, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3 |
| 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. | 73 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | STOP LONG-TERM FOLLOW-UP AS PER SPONSOR'S DECISION | 1 | 7 |
Baseline characteristics
| Characteristic | Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Total | Safety run-in Part (Dose Level 1 [DL 1]): Berzosertib 105 mg/m^2 + Topotecan 1.25 mg/m^2 |
|---|---|---|---|
| Age, Continuous | 63 Years STANDARD_DEVIATION 7.8 | 62 Years STANDARD_DEVIATION 8 | 51 Years STANDARD_DEVIATION 4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 66 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 9 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 22 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 10 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 42 Participants | 0 Participants |
| Sex: Female, Male Female | 16 Participants | 17 Participants | 1 Participants |
| Sex: Female, Male Male | 57 Participants | 59 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 63 / 73 |
| other Total, other adverse events | 3 / 3 | 70 / 73 |
| serious Total, serious adverse events | 0 / 3 | 31 / 73 |
Outcome results
Primary
Main Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)
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
Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
Primary
Safety Run-in 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 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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Hematology | 0 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Biochemistry | 0 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Hematology | 3 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Biochemistry | 0 Participants |
Primary
Safety Run-in 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
Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
Primary
Safety Run-in 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
Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
Primary
Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs)
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
Safety Run-in 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
Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | TEAEs | 3 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Treatment Related TEAEs | 3 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | TEAEs | 3 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Treatment Related TEAEs | 3 Participants |
Secondary
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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
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
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
Secondary
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
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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
Secondary
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
Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Anemia | 18 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Lymphocyte count decreased | 17 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Neutrophil count decreased | 28 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Platelet count decreased | 26 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Alanine aminotransferase increased | 2 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Alkaline phosphatase increased | 1 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Aspartate transaminase increased | 1 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Blood bilirnbin increased | 3 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Hypokalemia | 8 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Hyponatremia | 4 Participants |
Secondary
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
Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
Secondary
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
Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
Secondary
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
Population: Safety (SAF) Analysis Set included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | TEAEs | 73 Participants |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Treatment Related TEAEs | 67 Participants |
Secondary
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
Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Main Part: Overall Survival (OS) | 6.4 months |
Secondary
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
Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib | 1.32 ratio | Geometric Coefficient of Variation 16.3 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib | 1.12 ratio | Geometric Coefficient of Variation 24.9 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib | 17.6 hours | Geometric Coefficient of Variation 10.1 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib | 17.0 hours | Geometric Coefficient of Variation 13.5 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib | 77.8 liter per hour | Geometric Coefficient of Variation 11 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib | 85.4 liter per hour | Geometric Coefficient of Variation 11.4 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Apparent Volume of Distribution During Terminal Phase (Vz) of Berzosertib | 1980 liters | Geometric Coefficient of Variation 4.2 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Apparent Volume of Distribution During Terminal Phase (Vz) of Berzosertib | 2100 liters | Geometric Coefficient of Variation 5.8 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Berzosertib | 4310 h*ng/mL | Geometric Coefficient of Variation 8.8 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h) of Berzosertib | 3790 h*ng/mL | Geometric Coefficient of Variation 5.6 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h) of Berzosertib | 4110 h*ng/mL | Geometric Coefficient of Variation 7.1 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast) of Berzosertib | 2330 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 0.8 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast) of Berzosertib | 4090 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 7.1 |
Secondary
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
Population: As per changes in planned analysis, the outcome measure related to quality of life for safety run-in part was not assessed.
Secondary
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
Population: As per changes in planned analysis, the outcome measure related to quality of life for safety run-in part was not assessed.
Secondary
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
Population: As per changes in planned analysis, the outcome measure related to quality of life for safety run-in part was not assessed.
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of Berzosertib | 11.7 h*ng/mL/mg | Geometric Coefficient of Variation 11.4 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h/Dose) of Berzosertib | 10.3 h*ng/mL/mg | Geometric Coefficient of Variation 8.7 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h/Dose) of Berzosertib | 11.2 h*ng/mL/mg | Geometric Coefficient of Variation 9.9 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 | 11.1 h*ng/mL/mg | Geometric Coefficient of Variation 9.8 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of Berzosertib | 1.21 ng/mL/mg | Geometric Coefficient of Variation 24.9 |
Secondary
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Last Sampling Time (Tlast) of Berzosertib | 70.4 hours | Geometric Coefficient of Variation 0.3 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Last Sampling Time (Tlast) of Berzosertib | 70.6 hours | Geometric Coefficient of Variation 0.7 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Berzosertib | 259 ng/mL | Geometric Coefficient of Variation 23.5 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Berzosertib | 446 ng/mL | Geometric Coefficient of Variation 17.7 |
Secondary
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
Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator | 0.0 percentage of participants |
Secondary
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
Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Overall Survival (OS) | NA months |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Overall Survival (OS) | 15.3 months |
Secondary
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)
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib | Cycle 1 Day 2 | 446 ng/mL | Geometric Coefficient of Variation 17.7 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib | Cycle 1 Day 5 | 500 ng/mL | Geometric Coefficient of Variation 42.7 |
Secondary
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Plasma Observed Concentration Immediately Before Next Dosing (Ctrough) of Berzosertib | 4.84 ng/mL | Geometric Coefficient of Variation 22.3 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Plasma Observed Concentration Immediately Before Next Dosing (Ctrough) of Berzosertib | 8.57 ng/mL | Geometric Coefficient of Variation 23.6 |
Secondary
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
Population: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | 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 |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator | 3.3 months |
Secondary
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)
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Berzosertib | 1.17 hours |
| Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2 | Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Berzosertib | 1.20 hours |