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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Small-cell Lung Cancer

Intervention / Treatment
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* Drug: Berzosertib
* Drug: Berzosertib
* Drug: Topotecan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Berzosertib + Topotecan<br>In Japan, a Safety Run-in Part will be conducted. In case safety and tolerability is confirmed in the Safety Run-in part, Japanese participants will enroll in the Main Part of the Phase 2. Both in the Safety Run-in and Main Part of the Phase 2, participants will receive berzosertib and topotecan until disease progression or other criteria for study intervention discontinuation are met. | Drug: Berzosertib<br>* Participants with advanced solid tumors, for which no effective standard therapy exists, or standard therapy has failed will receive 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 DL1 of safety run-in part.<br>* Other names: M6620;Drug: Berzosertib<br>* Participants with relapsed, platinum-resistant SCLC will receive 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.<br>* Other names: M6620;Drug: Topotecan<br>* Participants who have advanced solid tumors, for which no effective standard therapy exists, or standard therapy has failed or who have relapsed, platinum-resistant SCLC will receive 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Part: Objective Response (OR) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 as assessed by Independent Review Committee (IRC) |  | From first administration of study intervention up to 15 months | 
| Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs) |  | 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), Serious TEAEs and Treatment-Related TEAEs |  | From first administration of study intervention up to 15 months | 
| Safety Run-in Part: Number of Participants with Clinically Significant Changes From Baseline in Vital Signs, 12-Lead Electrocardiogram (ECG) Findings and Laboratory Parameters |  | From first administration of study intervention up to 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Part: Duration of Response (DoR) according to RECIST version 1.1 as assessed by IRC |  | From first administration of study intervention up to 15 months | 
| Main Part: Progression-free Survival (PFS) according to RECIST version 1.1 as assessed by IRC |  | From first administration of study intervention up to 15 months | 
| Main Part: Overall Survival (OS) |  | From first administration of study intervention up to 15 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, Safety follow-up (up to 15 months) | 
| Main 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, Safety follow-up (up to 15 months) | 
| 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, Safety follow-up (up to 15 months) | 
| Main Part: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-Related TEAEs |  | From first administration of study intervention up to 15 months | 
| Main Part: Number of Participants with Clinically Significant Changes From Baseline in Vital Signs, 12-Lead Electrocardiogram (ECG) Findings and Laboratory Parameters |  | From first administration of study intervention up to 15 months | 
| Safety Run-in Part: Objective response according to RECIST version 1.1 as assessed by the Investigator |  | From first administration of study intervention up to 15 months | 
| Safety Run-in Part: Duration of Response (DoR) according to RECIST version 1.1 as assessed by the Investigator |  | From first administration of study intervention up to 15 months | 
| Safety Run-in Part: Progression-free Survival (PFS) according to RECIST version 1.1 as assessed by the Investigator |  | From first administration of study intervention up to 15 months | 
| Safety Run-in Part: Overall Survival (OS) |  | From first administration of study intervention up to 15 months | 
| 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, Safety follow-up (up to 15 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, Safety follow-up (up to 15 months) | 
| 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, Safety follow-up (up to 15 months) | 
| Safety Run-in Part: Area Under the Plasma Concentration-Time Curve from Time Zero to the Last Sampling Time (AUC0-tlast) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (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 |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (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 |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (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 |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (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 |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (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 |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (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 |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (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 |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Plasma Observed Concentration at the End of the Infusion (Ceoi) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Plasma Observed Concentration Immediately Before Next Dosing (Ctrough) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Apparent Total Body Clearance (CL) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Metabolic Ratio of Maximum Observed Plasma Concentration (MR[Cmax]) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Metabolic Ratio of Area Under the Plasma Concentration-Time Curve from Time Zero to the Last Sampling Time (MR[AUC0-tlast]) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Metabolic Ratio Area Under the Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (MR[AUC0-inf]) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Accumulation Ratio for Maximum Observed Plasma Concentration [Racc(Cmax)] of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Time to Reach the Maximum Observed Plasma Concentration (tmax) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Apparent Terminal Half-life (t1/2) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Last Sampling Time (tlast) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 
| Safety Run-in Part: Apparent Volume of Distribution (Vz) of Berzosertib |  | 23 hours post-dose on Cycle 1 Day 3 and 47 hours post-dose on Cycle 1 Day 4 (each cycle is of 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M6620, Berzosertib, Solid Tumor, DDRiver, Topotecan, Ataxia telangiectasia mutated and Rad3-related, Platinum-resistant Small-Cell Lung Cancer