Phase I study to assess pharmacokinetics (PK), QT/QTc effect, and safety of amrubicin in patients (pts) with advanced solid tumors.

7073 Background: Amrubicin (AMR), a 3rd-generation synthetic anthracycline has shown promising activity in solid tumors, including small cell lung cancer (SCLC) without cardiotoxicity. This intensive PK and safety study also investigated the effect of AMR on QT interval. METHODS Pts with solid tumors and an ECOG PS score ≤ 1 were eligible. AMR 40 mg/m2 IV was given on days 1-3 of a 21-day cycle. Serial blood samples and time-matched triplicate ECG were collected on days 1-9, including an 11 h continuous ECG within 5 days prior to study initiation, and on days 1 and 3 of cycle 1. Urine was also collected for PK analyses. RESULTS 24 pts with different primary cancers (most common SCLC [5 pts]), median age 55 yrs; 46% male; 71% Caucasian) were enrolled. All received the intended AMR dose. AMR concentrations followed biphasic elimination with an initial 80% reduction within 10 min and a T1/2 of 4 h. The active metabolite of AMR, amrubicinol (AMROL), reached a peak concentration at 2-4 h. Blood AMROL had a terminal half-life of 51 h and an accumulation ratio of 1.7 after 3 doses. The AMROL to AMR molar ratio for AUC24 after 3 doses averaged 0.64. Mean urinary excretion of AMR or AMROL over 24 h was < 8% of the AMR dose. The upper 1-sided 95% CI for the time-matched, baseline-adjusted mean difference in QT interval (QTcF) on days 1 and 3 relative to the off-drug day (ΔΔQTcF) was below 10 ms at 20/21 time points, and was marginally above 10 ms at a single time point (day 1, 10 h). No correlation was observed between blood AMR or AMROL levels and ΔΔQTcF. No patients exceeded the clinically relevant thresholds of 480 ms for absolute QTcF or 60 ms for QTcF increase from the time-matched value on the off-drug day. There were no clinically significant findings in QTcF changes from baseline beyond day 3. The most common Gr 3/4 adverse events were neutropenia (45.8%), leukopenia (37.5%) and thrombocytopenia (37.5%). Gr 3/4 infections occurred in 16.7% of patients. CONCLUSIONS The full AMR PK profile was defined for US patients. Therapeutic doses of AMR did not cause clinically significant prolongation of QTc interval in pts with solid tumors. The safety profile of AMR is consistent with earlier findings in SCLC.