Background: SCLC is a high-grade neuroendocrine malignancy with overall response rates (ORR) to second-line chemotherapy generally ranging from 10-30%. The poly(ADP-ribose) polymerase (PARP) inhibitor O has activity in SCLC in preclinical studies and may synergize with the alkylating agent T. Methods: We performed a single-arm phase 1/2 study of combination O/T in adults with SCLC. Eligibility criteria included histologically/cytologically confirmed incurable SCLC which had progressed following ≥ 1 platinum-based chemotherapy. O (tablet formulation) and T were administered orally on days 1-7 of 21-day cycles at escalating doses using a 3+3 design in the phase 1 portion, followed by a phase 2 expansion at the recommended phase 2 dose (RP2D). Response assessments were performed every 6 weeks. The primary endpoint of the phase 2 portion was ORR. We present data at a planned interim analysis after enrollment of 20 patients at the RP2D. Patient-derived xenografts (PDXs) were generated from a subset of patients prior to O/T and at progression. O/T activity was assessed in vivo in PDXs in a co-clinical trial. Results: 13 patients were enrolled to 4 escalating dose levels in the phase 1 portion, and 17 additional patients were enrolled at the RP2D, O 200 mg BID and T 75 mg/m2 QD. The median (m) age was 62.0 years (range 39.2-85.2) and m prior lines of therapy was 2 (range 1-7). The most common treatment emergent adverse events (AEs) related to study drugs across dose levels were thrombocytopenia (67%; 23% grade (g) 3-4), anemia (63%; 23% g 3-4), and neutropenia (50%; 47% g 3-4). There was one related g 5 AE due to pneumonia and neutropenia. Among 29 evaluable patients at all dose levels, ORR was 41.4% (95% CI 23.5-59.3), with responses seen in 10/19 and 2/9 platinum-sensitive and -resistant patients, respectively. The mPFS was 87 days (95% CI 48-159), the mOS was 220 days (95% CI 140-308), and the mDOR was 103 days. In PDX models, responses to O/T mirrored those in donor patients, and basal total PARylation was a strong predictive biomarker for sensitivity. Conclusions: O/T shows promising clinical activity in SCLC. Further exploration of dosing strategies and biomarkers in patients and PDXs is underway. Clinical trial information: NCT02446704