17001 Background: Tumors with multidrug resistance (MDR) frequently show upregulation of efflux proteins MDR protein (MRP-1) and P-glycoprotein (Pgp). MDR represents a major obstacle to successful chemotherapy treatment and can be reversed in Pgp or MRP1-expressing cells by the MDR inhibitor VX-710. A phase II study was designed to evaluate the safety/tolerability and efficacy of VX-710 combined with doxorubicin (D) and vincristine (V) in patients (pts) with relapsed SCLC. Methods: Eligible pts had progressive, measurable disease and a PS <2 after response to 1st-line chemotherapy. Stage I safety evaluation was done with planned expansion to a second stage if 9 responses were confirmed in the first 35 pts. Pts were treated with VX-710 (120 mg/m2/h) for 72 hours with D (45 mg/m2) and V (1.4 mg/m2) given 4 hours after the start of VX-710. Pts were treated q 21 days until progression or intolerable adverse events (AEs). Severe neutropenia was noted in the first 15 pts, so the protocol was amended to include prophylactic G-CSF or ciprofloxacin. Interim analysis was performed after 36 pts were treated. Results: 36 pts were enrolled from 12/98 to 12/00. Neutropenia was the major toxicity, occurring in 25/36 (69%) pts. This was more severe (30% vs. 20% grade 4) and occurred earlier (58% vs. 38% in cycle 1) among the 15 pts enrolled prior to an amendment requiring neutropenia prophylaxis vs. those enrolled afterward. Other common treatment-related AE’s: asthenia (53%), nausea (50%), constipation (44%), alopecia (42%), dyspnea (42%), anemia (42%). 67% were grade 1 or 2 in severity. Four pts died on study or within 30 days of termination: 2 from infections likely related to therapy and 2 from disease progression. Among 32 evaluable pts, 7 (22%) had partial responses; 6 of these sustained responses through 6 cycles (with one response lasting 3 years). Three additional pts had unconfirmed responses. Median survival was 6 months (95% CI 4–7 months). Conclusions: The addition of VX-710 to D and V therapy did not improve anti-tumor activity or survival. Hematologic toxicity was severe, causing 2 pt deaths from neutopenic fever. Although there were some durable responses, response criteria were not met to proceed with stage 2. Further development with VX-710 has since stopped. [Table: see text]