Aims: Amrubicin, a 3rd gen. anthracycline and potent topoisomerase II inhibitor, has shown activity in SCLC. ACT-1 compared the safety and efficacy of amr vs. topo for 2nd line treatment of SCLC. Methods: 637 pts were random. 2:1 amr 40mg/m2 IV d 1–3 (n=424) vs. topo 1.5mg/m2 IV d 1–5 (n=213) with proph. WBC growth factors and antibiotics required in last 1/3 of trial. Endpoints: OS (primary), RR, PFS, and safety. Subgroup analyses used protocol-defined definitions: refract. pts had PD as best response to 1st line therapy or progressed <90 days. QoL was assessed by mean change in LCSS, Symptom Burden (LCSS SB) score, and EQ –5D. Results: Baseline characteristics were similar in both groups: med. age 62 vs. 61 years; pts <65 years 60% vs. 65%; men 58% vs. 60%; PS sens. 30% vs. 34%; refractory 47% vs. 45%. Covariates in the Cox model are PS 0 (yes, no), age, response to 1st line platinum-based therapy (refr., sens.), and disease stage (lim., ext.). Pts treated with amr had better symptom control and QoL: LCSS 0.2 vs. 5.6 and LCSS-SB -0.1 vs. 5.2 for amr and topo, respectively, all P<0.05. Grade ¾ AEs in amr and topo groups, respectively, were: neutropenia (41% vs. 53%), thrombocytopenia (21% vs. 54%), anemia (16% vs. 30%), infections (16% vs. 10%), febrile neutropenia (10% vs. 4%), all P<0.05, and cardiac disorders (5% vs. 5%; P=0.84). Conclusions: Amrubicin is active in 2nd treatment of SCLC with significantly improved RR and PFS versus topotecan. While the primary endpoint was not met, survival trended in favor of amrubicin (HR 0.88), especially in refractory patients (HR 0.77). Preliminary QoL results favored amrubicin.