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)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 76
- 试验地点
- 51
- 主要终点
- Main Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Berzosertib (Drug)
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.
干预措施: Topotecan (Drug)
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.
干预措施: Berzosertib (Drug)
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.
干预措施: Topotecan (Drug)
结局指标
主要结局
Main Part: Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)
时间窗: Time from first administration of study treatment up to 27.7 months
Objective response rate was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD). CR: Disappearance of all target and non-target lesions. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of their diameters, and no unequivocal progression of non-target lesions. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, or unequivocal progression of non-target lesions, or appearance of any new lesion.
Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Up to Cycle 1 Day 21 (each cycle is of 21 days)
DLT is defined as drug-related: Neutropenia Grade 4 for greater than (\>) 7 days' duration; Febrile neutropenia (that is \[i.e.\] absolute neutrophil count less than (\< ) 1000 per millimeter cube (mm\^3) with single temperature of \> 38.3°degree Celsius or a sustained temperature of greater than or equal to (\>=) 38 degree Celsius for more than 1 hour; Infection (documented clinically or microbiologically) with Grades 3 or 4 neutropenia; Thrombocytopenia \>= Grade 3; Grade \>= 3 non-hematological AEs.
Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
时间窗: Time from first administration of study treatment up to 27.7 months
An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.
Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
时间窗: Time from first administration of study treatment up to 27.7 months
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically significant changes from baseline in vital signs were reported. Clinical significance was decided by Investigator.
Safety Run-in Part: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings
时间窗: Time from first administration of study treatment up to 27.7 months
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was decided by investigator. Number of participants with clinically significant changes from baseline in 12-Lead ECGs were reported.
Safety Run-in Part: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)
时间窗: Time from first administration of study treatment up to 27.7 months
The laboratory measurements included hematology and biochemistry. Number of participants with clinically significant abnormalities with Grade greater than or equals to (\>=) 3 in laboratory values reported as TEAEs as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Clinically Significance was decided by investigator.
次要结局
- Main Part: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)(From first documented objective response to PD or death due to any cause, assessed up to 27.7 months)
- Main Part: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Independent Review Committee (IRC)(Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed up to 27.7 months)
- Main Part: Overall Survival (OS)(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)(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)(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)(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(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(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(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)(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(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(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(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)(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)(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)(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)(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(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(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(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(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(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(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(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(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(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(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(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(Pre-dose on Cycle 1 Day 5 (each cycle is of 21 days))
- Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib(Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days))
- Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib(Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2; Pre-dose, 1 and 1.5 hours after dose on Cycle 1 Day 5 (each cycle is of 21 days))
- Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Berzosertib(Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days))
- Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib(Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days))
- Safety Run-in Part: Last Sampling Time (Tlast) of Berzosertib(Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days))
- Safety Run-in Part: Apparent Volume of Distribution During Terminal Phase (Vz) of Berzosertib(Pre-dose, 1, 2, 3, 4, 8, 24, 48 and 72 hours after dose on Cycle 1 Day 2 (each cycle is of 21 days))