TPS3653 Background: Ataxia telangiectasia and Rad3-related (ATR) is an essential kinase that senses stressed replication forks and orchestrates the multifaceted replication stress response. Cancer cells under replication stress are particularly susceptible to ATR inhibition. Small-cell neuroendocrine cancers (SCNCs) are highly aggressive and arise in multiple tissues, most commonly lung (SCLC). We hypothesized that SCNCs are under replication stress and that exacerbating this stress could selectively kill SCNC by replicative damage. Based on promising data from a single-arm study, this study seeks to evaluate the improvement of progression free survival (PFS) by adding M6620 to topotecan in patients with SCNC. Methods: This study is an investigator-initiated, multicenter, open-label randomized phase 2 clinical trial. Key inclusion criterion are patients at age ≥18 with SCNCs that had relapsed after at least one prior chemotherapy, ECOG PS ≤ 2, and adequate organ function. Patents with asymptomatic brain metastasis, irrespective sensitivity with prior platinum-based chemotherapy, and previously treated with immune checkpoint inhibitors are eligible. The primary cohort consists of 54 patients with SCLC randomized 2:1 to receive either topotecan in combination with M6620 or topotecan alone. Topotecan is administered 1.25 mg/m2 intravenously over 30 minutes every 23 hours on day 1 through 5, pegfilgrastim 6 mg subcutaneously on day 6 and M6620 is administered at 210 mg/m2 intravenously over 60 minutes on day 2 and day 5 if the patient is randomized to the combination arm, in 21-day cycles. Patients randomized to the topotecan alone arm can cross-over to the combination arm at disease progression. An exploratory cohort will enroll 20 patients with SCNC. Primary endpoint is PFS improvement with the combination compared with topotecan alone. Secondary endpoints are ORR and overall survival. To evaluate the genomic features associated with clinical outcomes and to gain insight into the underlying mechanisms of ATR inhibitor response, we require mandatory biopsy before starting treatment. Clinical trial information: NCT03896503 .
725. Seneca Valley Virus, a Novel Systemically Deliverable Oncolytic Virus for the Treatment of Small Cell Lung Cancer and Other Neuroendocrine Cancers
