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Clinical Trial Results:
A Phase II, Open-label, Single-arm Study of Berzosertib (M6620) in Combination With Topotecan in Participants With Relapsed Platinum-resistant Small-Cell Lung Cancer (DDRiver SCLC 250)

Summary
EudraCT number	2020-004231-25
Trial protocol	FR IT ES
Global end of trial date	21 Jul 2023

Results information
Results version number	v1(current)
This version publication date	03 Aug 2024
First version publication date	03 Aug 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

MS201923_0050

ISRCTN number

US NCT number

NCT04768296

WHO universal trial number (UTN)

Sponsor organisation name

Merck Healthcare KGaA, Darmstadt, Germany

Sponsor organisation address

Frankfurter Strasse 250, Darmstadt, Germany, 64293

Public contact

Communication Centre, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com

Scientific contact

Communication Centre, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

21 Jul 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

21 Jul 2023

Was the trial ended prematurely?

Main objective of the trial

The main purpose of this trial was to assess efficacy, safety, tolerability and pharmacokinetics (PK) of Berzosertib in combination with Topotecan in subjects with relapsed, platinum-resistant small-cell lung cancer (SCLC). This trial was conducted in two parts: safety run-in part and main part. The safety run-in part was conducted in Japan.

Protection of trial subjects

Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Mar 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

Italy: 4

Country: Number of subjects enrolled

Spain: 23

Country: Number of subjects enrolled

United States: 10

Country: Number of subjects enrolled

China: 17

Country: Number of subjects enrolled

Japan: 6

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

First Subject Forst Visit: 29-Mar-2021; Last Subject Last Visit: 21-Jul-2023

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Safety run-in Part (DL 1): Berzosertib + Topotecan

Arm description

Subjects 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 safety run-in part until disease progression or other criteria for study intervention discontinuation are met.

Arm type

Experimental

Investigational medicinal product name

Berzosertib

Investigational medicinal product code

M6620

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Berzosertib was administered at a dose of 105 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.

Investigational medicinal product name

Topotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Topotecan was administered at a dose of 1.25 mg/m^2 intravenously on Days 1 through 5 of each 21-day cycle until disease progression or other criteria for study intervention discontinuation are met.

Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan

Arm description

Subjects 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 safety run-in part until disease progression or other criteria for study intervention discontinuation are met.

Arm type

Experimental

Investigational medicinal product name

Topotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Topotecan was administered at a dose of 1.25 mg/m^2 intravenously on Days 1 through 5 of each 21-day cycle until disease progression or other criteria for study intervention discontinuation are met.

Investigational medicinal product name

Berzosertib

Investigational medicinal product code

M6620

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Berzosertib was administered at a dose of 210 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.

Number of subjects in period 1	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Started	3	73
Completed	2	66
Not completed	1	7
STOP LONG-TERM FOLLOW-UP AS PER SPONSOR'S DECISION	1	7

Baseline characteristics

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Reporting group title

Safety run-in Part (DL 1): Berzosertib + Topotecan

Reporting group description

Reporting group title

Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan

Reporting group description

Reporting group values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan	Total
Number of subjects	3	73	76
Age categorical
Units: Subjects
Age Continuous
Units: Years
arithmetic mean (standard deviation)	51 ( 4 )	63 ( 7.8 )	-
Sex: Female, Male
Units: subjects
Female	1	16	17
Male	2	57	59
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	3	19	22
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	1	1
White	0	42	42
More than one race	0	1	1
Unknown or Not Reported	0	10	10
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	1	1
Not Hispanic or Latino	3	63	66
Unknown or Not Reported	0	9	9

Subject analysis set title

Safety run-in Part (DL 2): Berzosertib + Topotecan

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis sets values	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects	3
Age categorical
Units: Subjects
Age Continuous
Units: Years
arithmetic mean (standard deviation)	0 ( )
Sex: Female, Male
Units: subjects
Female
Male
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native
Asian
Native Hawaiian or Other Pacific Islander
Black or African American
White
More than one race
Unknown or Not Reported
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino
Not Hispanic or Latino
Unknown or Not Reported

End points

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Reporting group title

Safety run-in Part (DL 1): Berzosertib + Topotecan

Reporting group description

Reporting group title

Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan

Reporting group description

Subject analysis set title

Safety run-in Part (DL 2): Berzosertib + Topotecan

Subject analysis set type

Full analysis

Subject analysis set description

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)

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End point title

Main Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as assessed by Independent Review Committee (IRC) ^[1] ^[2]

End point description

Objective response rate was defined as percentage of subjects 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. Full Analysis Set (FAS) included all subjects who were administered at least 1 dose of berzosertib.

End point type

Primary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	73
Units: percentage of subjects
number (confidence interval 95%)	5.5 (1.5 to 13.4)

No statistical analyses for this end point

Primary: Safety Run-in Part: Number of Subjects With Dose Limiting Toxicities (DLTs)

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End point title

Safety Run-in Part: Number of Subjects With Dose Limiting Toxicities (DLTs) ^[3] ^[4]

End point description

DLT is defined as drug-related: Neutropenia Grade 4 for greater than (>) 7 days’ duration; Febrile neutropenia (that is 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. DLT analysis set: all subjects 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.

End point type

Primary

End point timeframe

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

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: subjects	0	0

No statistical analyses for this end point

Primary: Safety Run-in Part: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

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End point title

Safety Run-in Part: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs ^[5] ^[6]

End point description

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 (SAF) Analysis Set included all subjects who were administered at least 1 dose of berzosertib.

End point type

Primary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: subjects
TEAEs	3	3
Treatment Related TEAEs	3	3

No statistical analyses for this end point

Primary: Safety Run-in Part: Number of Subjects with Clinically Significant Changes From Baseline in Vital Signs

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End point title

Safety Run-in Part: Number of Subjects with Clinically Significant Changes From Baseline in Vital Signs ^[7] ^[8]

End point description

Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of subjects with clinically significant changes from baseline in vital signs were reported. Clinical significance was decided by Investigator. Safety (SAF) Analysis Set included all subjects who were administered at least 1 dose of berzosertib.

End point type

Primary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: subjects	0	0

No statistical analyses for this end point

Primary: Safety Run-in Part: Number of Subjects with Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

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End point title

Safety Run-in Part: Number of Subjects with Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings ^[9] ^[10]

End point description

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 subject in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was decided by investigator. Number of subjects with clinically significant changes from baseline in 12-Lead ECGs were reported. Safety (SAF) Analysis Set included all subjects who were administered at least 1 dose of berzosertib.

End point type

Primary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: subjects	0	0

No statistical analyses for this end point

Primary: Safety Run-in Part: Number of Subjects With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)

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End point title

Safety Run-in Part: Number of Subjects With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) ^[11] ^[12]

End point description

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

End point type

Primary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: subjects
Hematology	0	3
Biochemistry	0	0

No statistical analyses for this end point

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)

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End point title

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) ^[13]

End point description

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

End point type

Secondary

End point timeframe

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

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	73
Units: months
median (confidence interval 95%)	2.2 (1.5 to 2.7)

No statistical analyses for this end point

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)

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End point title

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) ^[14]

End point description

DOR: 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. FAS was used. Due to small number of subjects with a response, data was not summarized; however, individual subject data is reported for this endpoint. Here, "Number of Subjects Analyzed" = subjects who were evaluable for this endpoint and "n" = specific subjects evaluated in the arm.

End point type

Secondary

End point timeframe

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

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	4
Units: months
number (not applicable)
Subject 1: n = 1	8.5
Subject 2: n = 1	2.8
Subject 3: n = 1	2.6
Subject 4: n = 1	2.1

No statistical analyses for this end point

Secondary: Main Part: Overall Survival (OS)

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End point title

Main Part: Overall Survival (OS) ^[15]

End point description

End point type

Secondary

End point timeframe

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

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	73
Units: months
median (confidence interval 95%)	6.4 (4.2 to 7.6)

No statistical analyses for this end point

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)

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End point title

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) ^[16]

End point description

The EORTC QLQ-C30 is a subject 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. Full Analysis Set (FAS) included all subjects who were administered at least 1 dose of berzosertib. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

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

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	33
Units: score on a scale
arithmetic mean (standard deviation)	-4.0 ( 20.67 )

No statistical analyses for this end point

Secondary: Main Part: Number of Subjects 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)

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End point title

Main Part: Number of Subjects 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) ^[17]

End point description

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. Full Analysis Set (FAS) included all subjects who were administered at least 1 dose of berzosertib. Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

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

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	33
Units: subjects
Improvement in Cough	6
Stable in Cough	20
Worsened in Cough	7
Improvement in Chest Pain	7
Stable in Chest Pain	22
Worsened in Chest Pain	4

No statistical analyses for this end point

Secondary: Main Part: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

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End point title

Main Part: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs ^[18]

End point description

An adverse event (AE) is defined as any untoward medical occurrence in a subject 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 (SAF) Analysis Set included all subjects who were administered at least 1 dose of berzosertib.

End point type

Secondary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	73
Units: subjects
TEAEs	73
Treatment Related TEAEs	67

No statistical analyses for this end point

Secondary: Main Part: Number of Subjects with Clinically Significant Changes From Baseline in Vital Signs

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End point title

Main Part: Number of Subjects with Clinically Significant Changes From Baseline in Vital Signs ^[19]

End point description

End point type

Secondary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	73
Units: subjects	0

No statistical analyses for this end point

Secondary: Main Part: Number of Subjects with Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

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End point title

Main Part: Number of Subjects with Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings ^[20]

End point description

End point type

Secondary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	73
Units: subjects	0

No statistical analyses for this end point

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

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End point title

Main Part: Number of Subjects With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) ^[21]

End point description

The laboratory measurements included hematology and biochemistry. Number of subjects 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. Safety (SAF) Analysis Set included all subjects who were administered at least 1 dose of berzosertib.

End point type

Secondary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	73
Units: subjects
Anemia	18
Lymphocyte count decreased	17
Neutrophil count decreased	28
Platelet count decreased	26
White blood cell decreased	19
Alanine aminotransferase increased	2
Alkaline phosphatase increased	1
Aspartate transaminase increased	1
Blood Bilirubin increased	3
Hypokalemia	8
Hyponatremia	4

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator ^[22]

End point description

End point type

Secondary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: percentage of subjects
number (confidence interval 95%)	33.3 (0.8 to 90.6)	0.0 (0.0 to 70.8)

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Duration of Response (DoR) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator ^[23]

End point description

DOR was defined for subjects 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. Full Analysis Set (FAS) included all subjects who were administered at least 1 dose of berzosertib. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Time from first administration of study treatment up to 27.7 months

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	1	0 ^[24]
Units: months
number (not applicable)	7.2

Notes
[24] - None of the subjects have objective response.

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator ^[25]

End point description

End point type

Secondary

End point timeframe

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

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: months
median (full range (min-max))	14.3 (4.0 to 14.3)	3.3 (1.2 to 8.1)

No statistical analyses for this end point

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)

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End point title

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) ^[26]

End point description

The EORTC QLQ-C30 is a subject 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. As per changes in planned analysis, the endpoint related to quality of life for safety run-in part was not assessed.

End point type

Secondary

End point timeframe

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

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	0 ^[27]	0 ^[28]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )

Notes
[27] - Data was not assessed.
[28] - Data was not assessed.

No statistical analyses for this end point

Secondary: Safety Run-in Part: Overall Survival (OS)

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End point title

Safety Run-in Part: Overall Survival (OS) ^[29]

End point description

Overall survival is defined as the time from first administration of study treatment to the date of death. Full Analysis Set (FAS) included all subjects who were administered at least 1 dose of berzosertib and "999" signifies that due to small number of events, median and upper limit of 95% Confidence Interval from Kaplan-Meier survival curves could not be derived.

End point type

Secondary

End point timeframe

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

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: months
median (confidence interval 95%)	999 (8.0 to 999)	15.3 (10.0 to 999)

No statistical analyses for this end point

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)

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End point title

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) ^[30]

End point description

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). As per changes in planned analysis, the endpoint related to quality of life for safety run-in part was not assessed.

End point type

Secondary

End point timeframe

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

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	0 ^[31]	0 ^[32]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )

Notes
[31] - Data was not assessed.
[32] - Data was not assessed.

No statistical analyses for this end point

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)

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End point title

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) ^[33]

End point description

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. Full Analysis Set (FAS) included all subjects who were administered at least 1 dose of berzosertib. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

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

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for main part only.

End point values	Safety run-in Part (DL2)+Main Part: Berzosertib + Topotecan
Number of subjects analysed	31
Units: score on a scale
arithmetic mean (standard deviation)	-6.3 ( 19.67 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Area Under the Plasma Concentration-Time Curve from Time Zero to the Last Sampling Time (AUC0-tlast) of Berzosertib ^[34]

End point description

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. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: hournanogram per milliliter (hng/mL)
geometric mean (geometric coefficient of variation)	2330 ( 0.8 )	4090 ( 7.1 )

No statistical analyses for this end point

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

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End point title

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 ^[35]

End point description

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). Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: h*ng/mL/mg
geometric mean (geometric coefficient of variation)	12.2 ( 9.9 )	11.1 ( 9.8 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Area Under the Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf) of Berzosertib ^[36]

End point description

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. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	2460 ( 1.4 )	4310 ( 8.8 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of Berzosertib ^[37]

End point description

AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: h*ng/mL/mg
geometric mean (geometric coefficient of variation)	12.8 ( 11.0 )	11.7 ( 11.4 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Area Under the Plasma Concentration-Time Curve from Time Zero to 48 Hours (AUC0-48h) of Berzosertib ^[38]

End point description

Area under the concentration-time curve from pre-dose (time 0) to 48 hours post-dose calculated using the linear-log trapezoidal rule. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	2160 ( 2.0 )	3790 ( 5.6 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve from Time Zero to 48 Hours (AUC0-48h/Dose) of Berzosertib ^[39]

End point description

AUC0-48 hour/Dose was defined as AUC from time of dosing to 48 hours divided by dose. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: h*ng/mL/mg
geometric mean (geometric coefficient of variation)	11.3 ( 9.7 )	10.3 ( 8.7 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Area Under the Plasma Concentration-Time Curve from Time Zero to 72 Hours (AUC0-72h) of Berzosertib ^[40]

End point description

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

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	2340 ( 0.8 )	4110 ( 7.1 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve from Time Zero to 72 Hours (AUC0-72h/Dose) of Berzosertib ^[41]

End point description

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

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: h*ng/mL/mg
geometric mean (geometric coefficient of variation)	12.2 ( 9.9 )	11.2 ( 9.9 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Berzosertib ^[42]

End point description

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

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: ng/mL
geometric mean (geometric coefficient of variation)	259 ( 23.5 )	446 ( 17.7 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib ^[43]

End point description

Ceoi was the observed concentration at the end of the infusion period. This was taken directly from the observed Berzosetib concentration-time data. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 and Cycle 1 Day 5 (each cycle is of 21 days)

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 2	259 ( 23.5 )	446 ( 17.7 )
Cycle 1 Day 5	341 ( 23.1 )	500 ( 42.7 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of Berzosertib ^[44]

End point description

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).

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: ng/mL/mg
geometric mean (geometric coefficient of variation)	1.35 ( 27.5 )	1.21 ( 24.9 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Plasma Observed Concentration Immediately Before Next Dosing (Ctrough) of Berzosertib ^[45]

End point description

Ctrough was the plasma concentration observed immediately before next dosing. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 5 (each cycle is of 21 days)

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: ng/mL
geometric mean (geometric coefficient of variation)	4.84 ( 22.3 )	8.57 ( 23.6 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib ^[46]

End point description

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. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: liter per hour
geometric mean (geometric coefficient of variation)	77.8 ( 11.0 )	85.4 ( 11.4 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib ^[47]

End point description

The accumulation ratio is to assess the increase in maximum concentration with multiple dosing. Racc(Cmax) = (Cmax after multiple dose)/ (Cmax after single dose). Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: ratio
geometric mean (geometric coefficient of variation)	1.32 ( 16.3 )	1.12 ( 24.9 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (tmax) of Berzosertib ^[48]

End point description

Tmax was obtained directly from the plasma concentration versus time curve. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: hours
median (full range (min-max))	1.17 (1.13 to 1.2)	1.20 (1.17 to 1.23)

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib ^[49]

End point description

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. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: hours
geometric mean (geometric coefficient of variation)	17.6 ( 10.1 )	17.0 ( 13.5 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Apparent Volume of Distribution During Terminal Phase (Vz) of Berzosertib ^[50]

End point description

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. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: liters
geometric mean (geometric coefficient of variation)	1980 ( 4.2 )	2100 ( 5.8 )

No statistical analyses for this end point

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

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End point title

Safety Run-in Part: Last Sampling Time (tlast) of Berzosertib ^[51]

End point description

tlast is defined as the last sampling time at which the concentration is at or above the lower limit of quantification. Pharmacokinetic Analysis Set (PKS) included all subjects 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.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 3 and 7 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	3	3
Units: hours
geometric mean (geometric coefficient of variation)	70.4 ( 0.3 )	70.6 ( 0.7 )

No statistical analyses for this end point

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)

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End point title

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) ^[52]

End point description

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

End point type

Secondary

End point timeframe

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

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be reported for safety run-in part only.

End point values	Safety run-in Part (DL 1): Berzosertib + Topotecan	Safety run-in Part (DL 2): Berzosertib + Topotecan
Number of subjects analysed	0 ^[53]	0 ^[54]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )

Notes
[53] - Data was not assessed.
[54] - Data was not assessed.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Time from first administration of study treatment up to 27.7 months

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Safety run-in Part (DL2) + Main Part: Berzosertib + Topotecan

Reporting group description

Reporting group title

Safety run-in Part (DL 1): Berzosertib + Topotecan

Reporting group description

Serious adverse events	Safety run-in Part (DL2) + Main Part: Berzosertib + Topotecan	Safety run-in Part (DL 1): Berzosertib + Topotecan
Total subjects affected by serious adverse events
subjects affected / exposed	31 / 73 (42.47%)	0 / 3 (0.00%)
number of deaths (all causes)	63	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
General physical health deterioration
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Asthenia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	6 / 73 (8.22%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Acute respiratory distress syndrome
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Haemoptysis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Neutrophil count decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Spinal compression fracture
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Seizure
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myelosuppression
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	4 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vestibular disorder
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Liver injury
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
COVID-19
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
COVID-19 pneumonia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Lung abscess
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal sepsis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Serratia sepsis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pneumonia pneumococcal
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pneumonia bacterial
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Safety run-in Part (DL2) + Main Part: Berzosertib + Topotecan	Safety run-in Part (DL 1): Berzosertib + Topotecan
Total subjects affected by non serious adverse events
subjects affected / exposed	70 / 73 (95.89%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Cancer pain
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Metastases to central nervous system
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Vascular disorders
Orthostatic hypotension
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Hypertension
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences all number	4	0
Hypotension
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	3	0
Deep vein thrombosis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Pallor
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Phlebitis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	6	0
General disorders and administration site conditions
Gait disturbance
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Asthenia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	18 / 73 (24.66%)	0 / 3 (0.00%)
occurrences all number	31	0
Chest discomfort
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Chest pain
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	2	0
Chills
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Face oedema
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Fatigue
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	10 / 73 (13.70%)	1 / 3 (33.33%)
occurrences all number	12	1
Generalised oedema
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	2	0
Influenza like illness
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Injection site pruritus
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Localised oedema
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Malaise
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences all number	4	0
Mucosal inflammation
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences all number	4	0
Oedema peripheral
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences all number	3	0
Pain
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Pyrexia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	5 / 73 (6.85%)	0 / 3 (0.00%)
occurrences all number	9	0
Secretion discharge
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Swelling face
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Hyperthermia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Immune system disorders
Hypersensitivity
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Pleuritic pain
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Pleural effusion
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Pneumothorax
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Aphonia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Cough
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	7 / 73 (9.59%)	0 / 3 (0.00%)
occurrences all number	8	0
Dysphonia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Dyspnoea
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	11 / 73 (15.07%)	0 / 3 (0.00%)
occurrences all number	14	0
Dyspnoea exertional
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences all number	3	0
Dyspnoea paroxysmal nocturnal
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Epistaxis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	6 / 73 (8.22%)	0 / 3 (0.00%)
occurrences all number	6	0
Haemoptysis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences all number	4	0
Hypoxia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Nasal congestion
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Productive cough
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Pulmonary embolism
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Sputum discoloured
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Wheezing
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Anxiety
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Confusional state
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Depression
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Insomnia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	5 / 73 (6.85%)	0 / 3 (0.00%)
occurrences all number	5	0
Product issues
Device malfunction
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Investigations
Activated partial thromboplastin time prolonged
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	4	0
Alanine aminotransferase increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	7 / 73 (9.59%)	0 / 3 (0.00%)
occurrences all number	7	0
C-reactive protein increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Aspartate aminotransferase decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Aspartate aminotransferase increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	7 / 73 (9.59%)	0 / 3 (0.00%)
occurrences all number	7	0
Blood albumin decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Blood alkaline phosphatase increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	6 / 73 (8.22%)	0 / 3 (0.00%)
occurrences all number	8	0
Blood bilirubin increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Blood cholesterol increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Blood creatinine increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences all number	4	0
Blood glucose increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	2	0
Blood lactate dehydrogenase increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Blood lactic acid increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Blood magnesium decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Blood phosphorus decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	2	0
Blood sodium decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Blood urea increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Amylase increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	4	0
CD4/CD8 ratio decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Electrocardiogram QT prolonged
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	1 / 3 (33.33%)
occurrences all number	1	1
Gamma-glutamyltransferase increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences all number	5	0
Haemoglobin decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Lipase increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	6 / 73 (8.22%)	1 / 3 (33.33%)
occurrences all number	8	1
Lymphocyte count decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	9 / 73 (12.33%)	0 / 3 (0.00%)
occurrences all number	21	0
Neutrophil count decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	12 / 73 (16.44%)	0 / 3 (0.00%)
occurrences all number	18	0
Platelet count decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	22 / 73 (30.14%)	0 / 3 (0.00%)
occurrences all number	45	0
Platelet count increased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Urine output decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Weight decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	6 / 73 (8.22%)	0 / 3 (0.00%)
occurrences all number	8	0
White blood cell count decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	13 / 73 (17.81%)	0 / 3 (0.00%)
occurrences all number	22	0
Creatinine renal clearance decreased
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Compression fracture
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Fall
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Infusion related reaction
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	0 / 73 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1
Radiation oesophagitis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Radiation pneumonitis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Spinal fracture
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Cardiac disorders
Atrial fibrillation
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Arrhythmia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Cardiac failure
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Sinus tachycardia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Tachycardia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences all number	5	0
Nervous system disorders
Disturbance in attention
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Dizziness
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	5 / 73 (6.85%)	0 / 3 (0.00%)
occurrences all number	6	0
Dysgeusia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	1 / 3 (33.33%)
occurrences all number	3	1
Headache
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	7 / 73 (9.59%)	0 / 3 (0.00%)
occurrences all number	8	0
Hemianopia homonymous
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Hemiparesis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Memory impairment
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Neuropathy peripheral
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	1 / 3 (33.33%)
occurrences all number	2	1
Paraesthesia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Presyncope
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Seizure
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Transient aphasia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Tremor
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Blood and lymphatic system disorders
Anaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	48 / 73 (65.75%)	3 / 3 (100.00%)
occurrences all number	89	6
Coagulopathy
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Febrile neutropenia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Leukopenia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	1 / 3 (33.33%)
occurrences all number	2	1
Myelosuppression
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Thrombocytopenia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	26 / 73 (35.62%)	3 / 3 (100.00%)
occurrences all number	45	3
Thrombocytosis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Neutropenia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	23 / 73 (31.51%)	1 / 3 (33.33%)
occurrences all number	37	1
Ear and labyrinth disorders
Vestibular disorder
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Eye disorders
Diplopia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Eye discharge
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Macular oedema
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Conjunctival pallor
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Gastrooesophageal reflux disease
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences all number	5	0
Abdominal discomfort
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	2	0
Abdominal distension
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Abdominal pain
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences all number	3	0
Abdominal pain upper
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Constipation
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	13 / 73 (17.81%)	1 / 3 (33.33%)
occurrences all number	16	1
Diarrhoea
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	11 / 73 (15.07%)	0 / 3 (0.00%)
occurrences all number	12	0
Dry mouth
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Dyspepsia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Dysphagia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Flatulence
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Gingival pain
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Haemorrhoids thrombosed
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Lip dry
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Lower gastrointestinal haemorrhage
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Nausea
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	20 / 73 (27.40%)	1 / 3 (33.33%)
occurrences all number	29	2
Oral disorder
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Tooth loss
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Toothache
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	0 / 73 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	2
Vomiting
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	10 / 73 (13.70%)	0 / 3 (0.00%)
occurrences all number	11	0
Haemorrhoids
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Hepatobiliary disorders
Cholestasis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Hepatic pain
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Hyperbilirubinaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Liver injury
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences all number	3	0
Skin and subcutaneous tissue disorders
Alopecia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	2 / 3 (66.67%)
occurrences all number	3	2
Decubitus ulcer
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Nail disorder
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Night sweats
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Petechiae
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Photosensitivity reaction
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Pruritus
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	3	0
Rash
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Rash pruritic
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Skin lesion
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
Acute kidney injury
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Choluria
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Nephrolithiasis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Renal impairment
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Endocrine disorders
Hypothyroidism
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Immune-mediated hypothyroidism
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Back pain
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Muscle spasms
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	2	0
Muscular weakness
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Pain in extremity
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Infections and infestations
Bronchiolitis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Bronchitis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Candida infection
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Diverticulitis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Gastroenteritis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	5	0
Herpes zoster reactivation
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Pneumonia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	8 / 73 (10.96%)	0 / 3 (0.00%)
occurrences all number	9	0
Respiratory tract infection
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Sinusitis
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Upper respiratory tract infection
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	2 / 73 (2.74%)	0 / 3 (0.00%)
occurrences all number	3	0
Wound infection
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
COVID-19
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	1 / 3 (33.33%)
occurrences all number	4	1
Metabolism and nutrition disorders
Hyperkalaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Decreased appetite
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	18 / 73 (24.66%)	0 / 3 (0.00%)
occurrences all number	22	0
Electrolyte imbalance
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Gout
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Hyperglycaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences all number	4	0
Hypoalbuminaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	7 / 73 (9.59%)	0 / 3 (0.00%)
occurrences all number	8	0
Hypochloraemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Hypokalaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	8 / 73 (10.96%)	0 / 3 (0.00%)
occurrences all number	9	0
Hypomagnesaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	4 / 73 (5.48%)	0 / 3 (0.00%)
occurrences all number	5	0
Hyponatraemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	5 / 73 (6.85%)	0 / 3 (0.00%)
occurrences all number	11	0
Hypophosphataemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	3 / 73 (4.11%)	0 / 3 (0.00%)
occurrences all number	4	0
Malnutrition
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	1 / 73 (1.37%)	0 / 3 (0.00%)
occurrences all number	1	0
Hypocalcaemia
alternative dictionary used: MedDRA 26.0
subjects affected / exposed	6 / 73 (8.22%)	0 / 3 (0.00%)
occurrences all number	8	0

More information

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Were there any global substantial amendments to the protocol? Yes

20 Nov 2020

• To eliminate the potential risk for increased toxicity in participants with such history. • To provide additional instructions for guidance prior to dosing, treatment interruption and resumption. • To provide more specific guidance about premedication and granulocyte colony-stimulating-factor (G-CSF) administration

23 Dec 2020

• The Safety Run-in Part in Japan • Assessments of patient-reported outcomes (PROs) • An additional exclusion criterion for QTc, modification on the exclusion criterion regarding New York Heart Association Classification and the wash-out period for previous anticancer antibody or antibody drug conjugates • Additional minor Sponsor modifications

21 Jun 2021

• All country-specific changes into a single global amendment • Clarification of weak DDI potential of berzosertib via CYP3A4 inhibition and recommendations on precautions for coadministration of certain CYP3A4 substrates • Merck standards updates.

08 Feb 2022

• To increase the scientific value of the study, enabling the assessment of the effect size between the combination of berzosertib and topotecan and single agent topotecan • Berzosertib in combination with topotecan is potentially effective in relapsed SCLC, not only in platinum resistant SCLC • Randomized design part added to increase the scientific value of the study, enabling the assessment of the effect size between the combination of berzosertib and topotecan and single agent topotecan • Berzosertib in combination with topotecan is potentially effective in relapsed SCLC, not only in platinum resistant SCLC

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase II, Open-label, Single-arm Study of Berzosertib (M6620) in Combination With Topotecan in Participants With Relapsed Platinum-resistant Small-Cell Lung Cancer (DDRiver SCLC 250)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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)

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)

Primary: Safety Run-in Part: Number of Subjects With Dose Limiting Toxicities (DLTs)

Primary: Safety Run-in Part: Number of Subjects With Dose Limiting Toxicities (DLTs)

Primary: Safety Run-in Part: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

Primary: Safety Run-in Part: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

Primary: Safety Run-in Part: Number of Subjects with Clinically Significant Changes From Baseline in Vital Signs

Primary: Safety Run-in Part: Number of Subjects with Clinically Significant Changes From Baseline in Vital Signs

Primary: Safety Run-in Part: Number of Subjects with Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

Primary: Safety Run-in Part: Number of Subjects with Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

Primary: Safety Run-in Part: Number of Subjects With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)

Primary: Safety Run-in Part: Number of Subjects With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)

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)

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)

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)

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)

Secondary: Main Part: Overall Survival (OS)

Secondary: Main Part: Overall Survival (OS)

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)

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)

Secondary: Main Part: Number of Subjects 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)

Secondary: Main Part: Number of Subjects 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)

Secondary: Main Part: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

Secondary: Main Part: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

Secondary: Main Part: Number of Subjects with Clinically Significant Changes From Baseline in Vital Signs

Secondary: Main Part: Number of Subjects with Clinically Significant Changes From Baseline in Vital Signs

Secondary: Main Part: Number of Subjects with Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

Secondary: Main Part: Number of Subjects with Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

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

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

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

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

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

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

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

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

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)

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)

Secondary: Safety Run-in Part: Overall Survival (OS)

Secondary: Safety Run-in Part: Overall Survival (OS)

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)

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)

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)

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Clinical Trial Results:
A Phase II, Open-label, Single-arm Study of Berzosertib (M6620) in Combination With Topotecan in Participants With Relapsed Platinum-resistant Small-Cell Lung Cancer (DDRiver SCLC 250)