Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers

Background: Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Although highly responsive to chemotherapy initially, SCLC typically relapses quickly and becomes refractory to treatment within a few months. There is only one Food and Drug Administration (FDA) approved treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand deoxyribonucleic acid (DNA) breaks leading to lethal double-strand DNA breaks. The survival of some SCLC cells despite initial tumor sensitivity to chemotherapy suggests the existence of a highly effective DNA damage response network. SCLC is characterized by high replication stress (RB transcriptional corepressor 1 (RB1) inactivation, MYC and cyclin E1 (CCNE1) activation) and defective ataxia-telangiectasia mutated tumor protein p53 (ATM-p53) signaling pathway, which cause an excessive reliance on ataxia-telangiectasia rad 3-related (ATR) for survival following DNA damage. We hypothesize that a combination of ATR kinase inhibition with DNA damaging agents such as topotecan will provide an attractive synthetically lethal therapeutic option for SCLC. VX-970 is a potent and selective kinase inhibitor of ATR, and in vitro data support the hypothesis that ATR inhibition can improve SCLC responses to DNA damaging agents. Primary objectives: Phase 1: To identify the maximum tolerated dose (MTD) of topotecan in combination with VX-970. Phase 2: To assess the efficacy with respect to clinical response rate of a combination of topotecan and VX-970 in the second-line treatment of patients with SCLC. Eligibility: Both Phase 1 and 2: Subjects must be greater than or equal to 18 years of age and have a performance status (Eastern Cooperative Oncology Group (ECOG) less than or equal to 2. Subjects must not have received chemotherapy or undergone major surgery within 4 weeks and radiotherapy within 24 hours prior to enrollment. Phase 1: Subjects with histologically confirmed SCLC, non-small cell cancer (NSCLC), ovarian cancer, cervical cancer, and neuroendocrine cancers, and at least one prior chemotherapy. Patients with other histologies will be allowed if no standard treatment options exist. Patients with evaluable, but not measurable disease will be eligible for Phase I. Phase 2: Subjects with histological confirmation of SCLC and one prior platinum-based chemotherapy. Patients with both platinum-sensitive and platinum-refractory disease will be eligible. Patients must have measurable disease to be eligible for Phase II. Design: Participants meeting inclusion and exclusion criteria will receive topotecan and VX-970 administered every 21 days (1 cycle), until disease progression or development of intolerable side effects. Blood and hair samples will be collected at multiple time points during cycle 1 (pre-treatment on day 1, post treatment on days 2, and 3) for pharmacodynamic (PD) analyses. Tumor biopsies, which are optional, will be obtained at baseline, during the first treatment cycle (approximately 15 hours after the first dose of VX-970 on day 3) and at disease progression except for subjects at the first dose level. Participants at the first dose level will undergo biopsies on day 3 prior to third dose of topotecan. Participants will be monitored weekly during the first cycle by clinic visit and basic labs. Toxicity will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and tumor assessments will be made using computed tomography (CT) scans (chest, abdomen and pelvis) at baseline and after every 2 cycles according to Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1. Follow-up for survival will be carried out every 3 months.