Randomized Trial of Topotecan With M6620, an ATR Kinase Inhibitor, in Small Cell Lung Cancers and Small Cell Cancers Outside of the Lungs

PRIMARY OBJECTIVE: I. To determine if the combination of berzosertib (M6620) with topotecan hydrochloride (topotecan) will result in an improvement in progression-free survival (PFS) compared to topotecan alone in patients with relapsed small cell lung cancer (SCLC). SECONDARY OBJECTIVE: I. To determine the objective response rate (ORR) and overall survival (OS) with the combination of M6220 and topotecan in patients with relapsed SCLC and extrapulmonary small cell cancers. EXPLORATORY OBJECTIVES: I. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to ribonucleic acid (RNA) sequencing (RNA-Seq): Ia. To assess expression of genes Schlafen family member 11 (SLFN11), MYC, and ataxia-telangiectasia mutated (ATM) among others. Ib. To identify potential predictive biomarkers of response to a combination of M6620 with topotecan. Ic. Identify mechanisms of drug sensitivity and resistance using deoxyribonucleic acid (DNA)- and RNA-based assessment platforms. II. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome. III. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the Early-Phase and Experimental Clinical Trials (EET) Biobank at Nationwide Children's Hospital. IV. To characterize circulating cell-free DNA (cfDNA) and circulating tumor cells in patients with relapsed SCLC and extrapulmonary small cell cancers. V. To identify potential predictive biomarkers of response to a combination of M6620 with topotecan in patients with extrapulmonary small cell cancers. OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT I: Patients with SCLC are randomized to 1 of 2 arms. ARM I: Participants receive topotecan hydrochloride intravenously (IV) over 30 minutes on days 1-5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants may crossover to Arm II at disease progression. Participants undergo a computed tomography (CT) scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study. ARM II: Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study. COHORT II (Patients with extrapulmonary small cell cancer): Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study. After completion of study treatment, patients are followed up at 4 weeks and then every 12 weeks thereafter.