P2.15-013 Doxorubicin and Topotecan for Relapsed/Refractory Small Cell Lung Cancer (SCLC): A FPBCC Clinical Trials Network Phase I Study

Relapsed or refractory small cell lung cancer (SCLC) has a poor prognosis, with no good therapeutic options. Topotecan, a topoisomerase I inhibitor, and doxorubicin, a topoisomerase II inhibitor, are both active drugs in SCLC. We evaluated the safety and efficacy of a novel combination of oral topotecan and weekly doxorubicin, providing sequential topoisomerase I and II inhibition, in this setting. Adult patients (>19 years) with relapsed or refractory SCLC who had received at least one prior chemotherapy regimen were included in the study. Patients received escalating doses of oral topotecan for five days (Days 1-5 of each cycle) every three weeks for a maximum of 5 cycles. The dosing cohorts were: DL1: 0.85 mg/m2, DL2: 1.05 mg/m2, DL3: 1.35 mg/m2, DL4: 1.65 mg/m2 and DL5: 2.30 mg/m2. All patients received weekly doxorubicin 20 mg/m2intravenously starting Day 6 of the first cycle and continued weekly for the duration of the study (maximum 15 weeks). The study design involved a standard 3+3 approach. In the absence of pre-specified criteria for dose limiting toxicities (DLT), patients were enrolled serially to escalated dose level cohorts. Patients received therapy until disease progression, undue toxicity or completion of the study. Primary objectives were safety and efficacy, dose limiting toxicity and response rate. A total of 22 patients were enrolled in the study, of which 18 were evaluable for toxicity. Median age was 60.5 years, 72% were male and 95% were Caucasian. Most common adverse events observed were hematological toxicities. Grade 3/4 adverse events included: anemia (44%), thrombocytopenia (50%), neutropenia (44%), lymphopenia (33%), leucopenia (39%), transaminitis (17%), hypokalemia (11%), hypotension (5%) and dehydration (5%). There were no therapy-related Grade 5 toxicities. Incidence of DLT based on cohorts were: DL1: 0/3, DL2: 1/6 (Grade 4 Thrombocytopenia), DL3: 1/6 (AST Elevation) and DL4: 2/4 (Grade 4 Thrombocytopenia). Response rate was 16.6% (3/18) and disease control rate (SD + PR) was 33%. The median progression free and overall survival was 3.4 months and 5.8 months, respectively. The novel combination of oral topotecan and weekly doxorubicin was safe and showed promising efficacy in relapsed/refractory SCLC. The maximum tolerated dose of oral topotecan was 1.35 mg/m2 when given concurrently with weekly doxorubicin. A phase 2 trial using this regimen is being developed.