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

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)

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

Study Overview

• Status: Completed
• Conditions: Small-cell Lung Cancer
• Intervention / Treatment: Drug: Berzosertib; Drug: Berzosertib; Drug: Topotecan

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Arlon, Belgium
    • Centre Hospitalier de l'Ardenne
  • Brussels, Belgium
    • Institut Jules Bordet - Department of Institut Jules Bordet
  • Gent, Belgium
    • Universitair Ziekenhuis Gent
  • Roeselare, Belgium
    • AZ Delta
  • Yvoir, Belgium
    • CHU UCL Namur - Mont-Godinne
• China
  • Beijing, China
    • Beijing Cancer Hospital
  • Changchun, China
    • Jilin Cancer Hospital
  • Chengdu, China
    • West China Hospital, Sichuan University
  • Chengdu, China
    • Sichuan Cancer Hospital
  • Nanjing, China
    • Jiangsu Province Hospital
  • Shenyang, China
    • Liaoning Cancer Hospital & Institute
  • Wuhan, China
    • Union Hospital of Tongji Medical College, Huazhong University of Science and Technology
  • Xi'an, China
    • The First Affiliated Hospital Of Xi'an Jiaotong University
  • Zhejiang, China
    • The First Affiliated Hospital of Zhejiang University School of Medicine
• France
  • Bordeaux cedex, France
    • Institut Bergonie
  • Créteil, France
    • Centre Hospitalier Intercommunal de Créteil - Service de Pneumologie
  • Lille, France
    • Hopital Albert Calmette - CHU Lille - service de pneumologie et immuno allergologie
  • Poitiers, France
    • CHU Poitiers - Hôpital la Milétrie - service d'oncologie médicale
  • Saint-Herblain, France
    • CHU Nantes - Hôpital Guillaume et René Laënnec - Service de Pneumologie
  • Strasbourg, France
    • CHU de Strasbourg - Nouvel Hôpital Civil - Service de Pneumologie
• Italy
  • Meldola, Italy
    • IRCCS Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori "Dino Amadori" - IRST
  • Milano, Italy
    • Azienda Socio Sanitaria Territoriale Niguarda (Grande Ospedale Metropolitano Niguarda)
  • Pisa, Italy, 56124
    • Azienda Ospedaliero Universitaria Pisana (Presidio di Cisanello)
  • Roma, Italy, 00144
    • Istituto Nazionale Tumori Regina Elena Irccs
  • Rome, Italy
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS - UOC Oncologia Medica
• Japan
  • Chuo-ku, Japan
    • National Cancer Center Hospital
  • Hirakata-shi, Japan
    • Kansai Medical University Hospital
  • Kashiwa-shi, Japan
    • National Cancer Center Hospital East
  • Koto-ku, Japan
    • Cancer Institute Hospital of JFCR
  • Osaka, Japan
    • Kindai University Hospital
  • Osaka, Japan
    • Kurume University Hospital
  • Takatsuki-shi, Japan
    • Osaka Medical and Pharmaceutical University Hospital
• Spain
  • Barcelona, Spain
    • Hospital Clinic de Barcelona
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital Universitario La Paz
  • Malaga, Spain
    • Hospital Universitario Virgen de la Victoria
  • Malaga, Spain
    • Hospital Clinico Universitario Virgen de la Victoria - Oncology Service
  • Sevilla, Spain
    • Hospital Universitario Virgen Macarena
• United States
  • California
    • Santa Rosa, California, United States, 95403
      • St Joseph Heritage Healthcare
    • Santa Rosa, California, United States, 95403
      • Providence Medical Foundation
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Cotton-O'Neil Clinical Research Center, Hematology and Oncology
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Cancer Institute
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • Cancer & Hematology Centers of Western Michigan
  • Missouri
    • Kansas City, Missouri, United States, 64114
      • MidAmerica Cancer Care
  • New Jersey
    • Brick, New Jersey, United States, 08724
      • NJ Center for Cancer Research
  • North Carolina
    • Goldsboro, North Carolina, United States, 27534
      • Southeastern Medical Oncology Center
    • Pinehurst, North Carolina, United States, 28374
      • FirstHealth of the Carolinas, Inc.
  • Ohio
    • Akron, Ohio, United States, 44304
      • Summa Health
    • Toledo, Ohio, United States, 43623
      • Toledo Clinic
  • Texas
    • Houston, Texas, United States, 77090
      • Millennium Physicians Association, Llp

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Dose level 1 participants with histologically proven advanced solid tumors, for which no effective standard therapy exists, or standard therapy has failed or cannot be tolerated
• Dose level 1 participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) less than or equal to (<=) 1 and Karnofsky Scale greater than or equal to (>=) 70 percent (%)
• Dose level 2 and main part participants with ECOG PS <= 2 and Karnofsky Scale >= 60%
• Dose level 2 and main part participants with histologically confirmed SCLC
• Dose level 2 and main part participants with radiologically confirmed progression after first-line or chemoradiation platinum-based treatment (carboplatin or cisplatin), with or without immunotherapy, for treatment of limited or extensive stage SCLC, with a Platinum-free interval (PFI) less than (<) 90 days. The PFI is measured by the elapsed time from the last day of the regimen of a platinum-based treatment until the first day of documented disease progression
• Dose level 2 and main part participants with measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (RECISTv1.1) at Screening. Evidence of measurable disease must be confirmed by the IRC prior to start of treatment
• Tumor tissue provision: archival (collected within 12 months before date of informed consent form [ICF]) signature for Screening) or fresh biopsy specimen, if medically feasible
• Have adequate hematologic and renal function
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Clinically relevant (that is [i.e.], active), uncontrolled intercurrent illness including, but not limited to, severe active infection including, severe acute respiratory syndrome coronavirus-2 infection/coronavirus disease 2019, immune deficiencies, uncontrolled diabetes, uncontrolled arterial hypertension, symptomatic congestive heart failure (New York Heart Association Classification greater than or equal to [>=] Class III), unstable angina pectoris, myocardial infarction, uncontrolled cardiac arrhythmia, cerebral vascular accident/stroke. Calculated corrected QT interval (QTc) average (using the Fridericia correction calculation) of greater than [>] 450 millisecond (msec) for males and > 470 msec for females. Any psychiatric illness/social situations that would limit compliance with study requirements
• Unstable brain metastases; however, participants with known brain metastases may be enrolled in this clinical study if they are clinically stable (without evidence of progression by imaging for at least 2 weeks prior to the first study intervention dose and any neurologic symptoms have returned to baseline), have no evidence of new brain metastases, and are on a stable or decreasing dose of steroids for at least 14 days prior to study intervention Participants with carcinomatous meningitis are excluded regardless of clinical stability. Screening central nervous system imaging is not mandatory
• Prior malignant disease within the last 3 years. Exceptions include fully resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, in situ cervical cancer, fully resected ductal carcinoma in situ of the breast, superficial or noninvasive bladder cancer, and Stage IA, Grade I endometrioid endometrial cancer with no myometrial invasion, that has undergone curative therapy. Participants with other localized malignancies treated with curative intent need to be discussed with the Medical Monitor
• Participants not recovered from adverse events (AEs) Grade > 1 from prior anticancer therapies, including surgeries. Exception: Grade 2 AEs not constituting a safety risk (for example [e.g.], alopecia), based on the Investigator's judgment; must consult with the medical Monitor prior to enrollment.
• Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety run-in Part (Dose Level1 [DL 1]): Berzosertib 105 mg/m^2 + Topotecan 1.25 mg/m^2; Participants received Berzosertib at a dose of 105 milligrams per square meter (mg/m^2 ) intravenously on Day 2 and Day 5 of each 21-daycycle in combination with Topotecan at a dose of 1.25mg/m^2 intravenously on Days1 through 5 of each 21-day cycle in DL1 of safety run-in part until disease progression or other criteria for study intervention discontinuation are met.	Drug: Berzosertib; Participants received Berzosertib at a dose of 105 milligrams per square meter (mg/m^2 ) intravenously on Day 2 and Day 5 of each 21-day cycle until disease progression or other criteria for study intervention discontinuation are met.; Other Names: M6620; Drug: Berzosertib; Participants received Berzosertib at a dose of 210 mg/m^2 intravenously on Day 2 and Day 5 of each 21-day cycle in DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.; Other Names: M6620; Drug: Topotecan; Participants received Topotecan at a dose of 1.25 mg/m^2 intravenously on Days 1 through 5 of each 21-day cycle in DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.
Experimental: Safety run-in Part (DL2) +Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2; Participants received Berzosertib at a dose of 210 mg/m^2 intravenously on Day 2 and Day 5 of each 21-day cycle in combination with Topotecan at a dose of 1.25 mg/m^2 intravenously on Days 1 through 5 of each 21-day cycle in DL 1 and DL 2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.	Drug: Berzosertib; Participants received Berzosertib at a dose of 105 milligrams per square meter (mg/m^2 ) intravenously on Day 2 and Day 5 of each 21-day cycle until disease progression or other criteria for study intervention discontinuation are met.; Other Names: M6620; Drug: Berzosertib; Participants received Berzosertib at a dose of 210 mg/m^2 intravenously on Day 2 and Day 5 of each 21-day cycle in DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.; Other Names: M6620; Drug: Topotecan; Participants received Topotecan at a dose of 1.25 mg/m^2 intravenously on Days 1 through 5 of each 21-day cycle in DL1 and DL2 of safety run-in part and main part until disease progression or other criteria for study intervention discontinuation are met.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Main Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)	Objective response rate was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD). CR: Disappearance of all target and non-target lesions. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of their diameters, and no unequivocal progression of non-target lesions. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, or unequivocal progression of non-target lesions, or appearance of any new lesion.	Time from first administration of study treatment up to 27.7 months
Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs)	DLT is defined as drug-related: Neutropenia Grade 4 for greater than (>) 7 days' duration; Febrile neutropenia (that is [i.e.] absolute neutrophil count less than (< ) 1000 per millimeter cube (mm^3) with single temperature of > 38.3°degree Celsius or a sustained temperature of greater than or equal to (>=) 38 degree Celsius for more than 1 hour; Infection (documented clinically or microbiologically) with Grades 3 or 4 neutropenia; Thrombocytopenia >= Grade 3; Grade >= 3 non-hematological AEs.	Up to Cycle 1 Day 21 (each cycle is of 21 days)
Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs	An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.	Time from first administration of study treatment up to 27.7 months
Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs	Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically significant changes from baseline in vital signs were reported. Clinical significance was decided by Investigator.	Time from first administration of study treatment up to 27.7 months
Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings	ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was decided by investigator. Number of participants with clinically significant changes from baseline in 12-Lead ECGs were reported.	Time from first administration of study treatment up to 27.7 months
Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)	The laboratory measurements included hematology and biochemistry. Number of participants with clinically significant abnormalities with Grade greater than or equals to (>=) 3 in laboratory values reported as TEAEs as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Clinically Significance was decided by investigator.	Time from first administration of study treatment up to 27.7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Main Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)	DoR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all target and non-target lesions. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of their diameters, and no unequivocal progression of non-target lesions. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, or unequivocal progression of non-target lesions, or appearance of any new lesion.	From first documented objective response to PD or death due to any cause, assessed up to 27.7 months
Main Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)	PFS was defined as the time is defined as the time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, or unequivocal progression of non-target lesions, or appearance of any new lesion.	Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed up to 27.7 months
Main Part: Overall Survival (OS)	Overall survival is defined as the time from first administration of study treatment to the date of death.	Time from first administration of study treatment to the date of death, assessed up to 27.7 months
Main Part: Change From Baseline in Physical Functioning Measured by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	The EORTC QLQ-C30 is a participant completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. For the physical functioning scale, subjects self-rated levels of difficulty in doing strenuous activities, taking a walk, how much they needed to stay in bed or a chair, or needed help with eating, dressing, bathing, using the toilet. The physical functioning scale had 4 possible scores (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. A positive change from baseline indicates improvement in physical functioning.	Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days
Main Part: Number of Participants Who Improved, Worsened or Remained Stable in European Organization for the Research and Treatment of Cancer Quality of Life and Lung Cancer Specific Questionnaire (EORTC QLQ-LC13)	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.	Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days
Main Part: Change From Baseline in Health State as Measured by Visual Analogue Scale (VAS) Component of European Quality of Life 5-dimensions 5 Level Scale (EQ-5D-5L)	EQ-5D-5L is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100, where 0 is the worst health you can imagine and 100 is the best health you can imagine.	Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days
Main Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs	An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.	Time from first administration of study treatment up to 27.7 months
Main Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs	Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically significant changes from baseline in vital signs were reported. Clinical significance was decided by Investigator.	Time from first administration of study treatment up to 27.7 months
Main Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings	ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was decided by investigator. Number of participants with clinically significant changes from baseline in 12-Lead ECGs were reported.	Time from first administration of study treatment up to 27.7 months
Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)	The laboratory measurements included hematology and biochemistry. Number of participants with clinically significant abnormalities with Grade greater than or equals to (>=) 3 in laboratory values reported as TEAEs as per NCI-CTCAE, v5.0 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Clinically Significance was decided by investigator. The laboratory assessments were graded according to NCI-CTCAE version 5.0 and data for individual clinically significant abnormalities (Grade >= 3) was extracted using data source (ADLBHEMA). The data categorized here may not necessarily be considered as TEAE by the investigator during the reporting of TEAEs and there is no correlation between the grade >=3 treatment related TEAEs hematology parameters and the TEAEs in the AE module.	Time from first administration of study treatment up to 27.7 months
Safety Run-in Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator	Objective response rate was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD). CR: Disappearance of all target and non-target lesions. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of their diameters, and no unequivocal progression of non-target lesions. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, or unequivocal progression of non-target lesions, or appearance of any new lesion.	Time from first administration of study treatment up to 27.7 months
Safety Run-in Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator	DOR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all target and non-target lesions. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of their diameters, and no unequivocal progression of non-target lesions. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, or unequivocal progression of non-target lesions, or appearance of any new lesion.	Time from first administration of study treatment up to 27.7 months
Safety Run-in Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator	PFS was defined as the time is defined as the time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, or unequivocal progression of non-target lesions, or appearance of any new lesion.	Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed up to 27.7 months
Safety Run-in Part: Overall Survival (OS)	Overall survival is defined as the time from first administration of study treatment to the date of death.	Time from first administration of study treatment to the date of death, assessed up to 27.7 months
Safety Run-in Part: Change From Baseline in Physical Functioning Measured by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	The EORTC QLQ-C30 is a participant completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. For the physical functioning scale, subjects self-rated levels of difficulty in doing strenuous activities, taking a walk, how much they needed to stay in bed or a chair, or needed help with eating, dressing, bathing, using the toilet. The physical functioning scale had 4 possible scores (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. A positive change from baseline indicates improvement in physical functioning.	Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days
Safety Run-in Part: Change From Baseline in Cough, Dyspnea and Chest Pain Measured by European Organization for the Research and Treatment of Cancer Quality of Life and Lung Cancer Specific Questionnaire (EORTC QLQ-LC13)	EORTC QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The EORTC QLQ-LC13 module generated one multiple-item score assessing dyspnea and a series of single item scores assessing coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arms or shoulder and pain in other parts. Score range: 0 (no burden of symptom domain or single symptom item) to 100 (highest burden of symptoms for symptom domains and single items).	Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days
Safety Run-in Part: Change From Baseline in Health State as Measured by Visual Analogue Scale (VAS) Component of European Quality of Life 5-dimensions 5 Level Scale (EQ-5D-5L)	EQ-5D-5L is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100, where 0 is the worst health you can imagine and 100 is the best health you can imagine.	Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days
Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast) of Berzosertib	Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast/Dose) of Berzosertib	AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose. AUC0-t/dose was measured in hour*nanogram per milliliter per milligram (h*ng/mL/mg).	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Berzosertib	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of Berzosertib	AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h) of Berzosertib	Area under the concentration-time curve from pre-dose (time 0) to 48 hours post-dose calculated using the linear-log trapezoidal rule	Pre-dose, 1, 2, 3, 4, 8, 24 and 48 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h/Dose) of Berzosertib	AUC0-48 hour/Dose was defined as AUC from time of dosing to 48 hours divided by dose.	Pre-dose, 1, 2, 3, 4, 8, 24 and 48 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h) of Berzosertib	Area under the concentration-time curve from pre-dose (time 0) to 72 hours post-dose calculated using the linear-log trapezoidal rule	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h/Dose) of Berzosertib	AUC0-72 hour/Dose was defined as AUC from time of dosing to 72 hours divided by dose.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Berzosertib	Cmax was obtained directly from the plasma concentration versus time curve.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of Berzosertib	Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg).	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib	Ceoi was the observed concentration at the end of the infusion period. This was taken directly from the observed Berzosetib concentration-time data.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2; Pre-dose, 1 and 1.5 hours after dose on Cycle 1 Day 5 (each cycle is of 21 days)
Safety Run-in Part: Plasma Observed Concentration Immediately Before Next Dosing (Ctrough) of Berzosertib	Ctrough was the plasma concentration observed immediately before next dosing.	Pre-dose on Cycle 1 Day 5 (each cycle is of 21 days)
Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib	CL was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib	Accumulation ratio of Cmax was calculated as Cmax after dosing on Day 5 divided by Cmax after dosing on Day 2 of Cycle 1.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2; Pre-dose, 1 and 1.5 hours after dose on Cycle 1 Day 5 (each cycle is of 21 days)
Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Berzosertib	Tmax was obtained directly from the plasma concentration versus time curve.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib	T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Last Sampling Time (Tlast) of Berzosertib	tlast is defined as the last sampling time at which the concentration is at or above the lower limit of quantification.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
Safety Run-in Part: Apparent Volume of Distribution During Terminal Phase (Vz) of Berzosertib	Vz: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz = Dose/(AUC0-inf*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.	Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2021
• Primary Completion (Actual): July 21, 2023
• Study Completion (Actual): July 21, 2023

Study Registration Dates

• First Submitted: February 19, 2021
• First Submitted That Met QC Criteria: February 19, 2021
• First Posted (Actual): February 24, 2021

Study Record Updates

• Last Update Posted (Actual): September 26, 2024
• Last Update Submitted That Met QC Criteria: September 3, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Topotecan; Solid Tumor; M6620; Berzosertib; Ataxia telangiectasia mutated and Rad3-related; Platinum-resistant Small-Cell Lung Cancer; DDRiver
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Topotecan
• Other Study ID Numbers: MS201923_0050; 2020-004231-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
• IPD Sharing Time Frame: Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union
• IPD Sharing Access Criteria: Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researchers' qualification and legitimacy of the research proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No