Clinical trial NCT04768296: Berzosertib + Topotecan in Relapsed Platinum-Resistant Small-Cell Lung Cancer (DDRiver SCLC 250)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Small-cell Lung Cancer
Keywords: M6620
Berzosertib
Solid Tumor
Topotecan
Ataxia telangiectasia mutated and Rad3-related
Platinum-resistant Small-Cell Lung Cancer
DDRiver
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2021-02-24
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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


Eligibility criteria: 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

Primary outcomes:
measure: Main Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to Cycle 1 Day 21 (each cycle is of 21 days)
measure: Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: Time from first administration of study treatment up to 27.7 months
Secondary outcomes:
measure: 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)
timeFrame: From first documented objective response to PD or death due to any cause, assessed up to 27.7 months
measure: 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)
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
measure: Main Part: Overall Survival (OS)
timeFrame: Time from first administration of study treatment to the date of death, assessed up to 27.7 months
measure: 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)
timeFrame: Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days
measure: 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)
timeFrame: Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days
measure: 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)
timeFrame: Baseline (Cycle 1 Day 1), end of treatment (up to 62 weeks). Each cycle is of 21 days
measure: Main Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Main Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Main Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Main Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Safety Run-in Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Safety Run-in Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator
timeFrame: Time from first administration of study treatment up to 27.7 months
measure: Safety Run-in Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator
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
measure: Safety Run-in Part: Overall Survival (OS)
timeFrame: Time from first administration of study treatment to the date of death, assessed up to 27.7 months
measure: 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)
timeFrame: Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days
measure: 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)
timeFrame: Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days
measure: 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)
timeFrame: Baseline (Cycle 1 Day 1), end of treatment (up to 64 weeks). Each cycle is of 21 days
measure: Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast) of Berzosertib
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h) of Berzosertib
timeFrame: Pre-dose, 1, 2, 3, 4, 8, 24 and 48 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
measure: Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48h/Dose) of Berzosertib
timeFrame: Pre-dose, 1, 2, 3, 4, 8, 24 and 48 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days)
measure: Safety Run-in Part: Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72h/Dose) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Plasma Observed Concentration Immediately Before Next Dosing (Ctrough) of Berzosertib
timeFrame: Pre-dose on Cycle 1 Day 5 (each cycle is of 21 days)
measure: Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Last Sampling Time (Tlast) of Berzosertib
timeFrame: 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)
measure: Safety Run-in Part: Apparent Volume of Distribution During Terminal Phase (Vz) of Berzosertib
timeFrame: 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)
Other outcomes:
Locations:
city: Santa Rosa
country: United States
facility: Providence Medical Foundation
state: California
city: Santa Rosa
country: United States
facility: St Joseph Heritage Healthcare
state: California
city: Topeka
country: United States
facility: Cotton-O'Neil Clinical Research Center, Hematology and Oncology
state: Kansas
city: Bethesda
country: United States
facility: National Cancer Institute
state: Maryland
city: Grand Rapids
country: United States
facility: Cancer & Hematology Centers of Western Michigan
state: Michigan
city: Kansas City
country: United States
facility: MidAmerica Cancer Care
state: Missouri
city: Brick
country: United States
facility: NJ Center for Cancer Research
state: New Jersey
city: Goldsboro
country: United States
facility: Southeastern Medical Oncology Center
state: North Carolina
city: Pinehurst
country: United States
facility: FirstHealth of the Carolinas, Inc.
state: North Carolina
city: Akron
country: United States
facility: Summa Health
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic
state: Ohio
city: Houston
country: United States
facility: Millennium Physicians Association, LLP
state: Texas
city: Arlon
country: Belgium
facility: Centre Hospitalier de l'Ardenne
city: Brussels
country: Belgium
facility: Institut Jules Bordet - Department of Institut Jules Bordet
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Roeselare
country: Belgium
facility: AZ Delta
city: Yvoir
country: Belgium
facility: CHU UCL Namur - Mont-Godinne
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Changchun
country: China
facility: Jilin Cancer Hospital
city: Chengdu
country: China
facility: Sichuan Cancer Hospital
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
city: Nanjing
country: China
facility: Jiangsu Province Hospital
city: Shenyang
country: China
facility: Liaoning Cancer Hospital & Institute
city: Wuhan
country: China
facility: Union Hospital of Tongji Medical College, Huazhong University of Science and Technology
city: Xi'an
country: China
facility: The First Affiliated Hospital of Xi'an Jiaotong University
city: Zhejiang
country: China
facility: The First Affiliated Hospital of Zhejiang University school of medicine
city: Bordeaux cedex
country: France
facility: Institut Bergonié
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil - Service de Pneumologie
city: Lille
country: France
facility: Hopital Albert Calmette - CHU Lille - service de pneumologie et immuno allergologie
city: Poitiers
country: France
facility: CHU Poitiers - Hôpital la Milétrie - service d'oncologie médicale
city: Saint-Herblain
country: France
facility: CHU Nantes - Hôpital Guillaume et René Laënnec - Service de Pneumologie
city: Strasbourg
country: France
facility: CHU de Strasbourg - Nouvel Hôpital Civil - Service de Pneumologie
city: Meldola
country: Italy
facility: IRCCS Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori "Dino Amadori" - IRST
city: Milano
country: Italy
facility: Azienda Socio Sanitaria Territoriale Niguarda (Grande Ospedale Metropolitano Niguarda)
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana (Presidio di Cisanello)
city: Roma
country: Italy
facility: Istituto Nazionale Tumori Regina Elena IRCCS
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS - UOC Oncologia Medica
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Hirakata-shi
country: Japan
facility: Kansai Medical University Hospital
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
city: Koto-ku
country: Japan
facility: Cancer Institute Hospital of JFCR
city: Osaka
country: Japan
facility: Kindai University Hospital
city: Osaka
country: Japan
facility: Kurume University Hospital
city: Takatsuki-shi
country: Japan
facility: Osaka Medical and Pharmaceutical University Hospital
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Malaga
country: Spain
facility: Hospital Clinico Universitario Virgen de la Victoria - Oncology Service
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: