Phase I trials of PS-341 (bortezomib, B) in combination with topotecan (T) in advanced solid tumors: A potential pharmacokinetic (PK) interaction.

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3108 Background: Preclinical data has demonstrated that B when combined with camptothecins enhances apoptotic effects which may be independent of NF-κB status and dependent on the sequence of exposure to the proteasome inhibitor. Other data suggests PK interactions of B with some chemotherapeutic agents. It is hypothesized that B will act synergistically with T and enhance the apoptotic effects of T. Conflicting data exists regarding schedule dependent synergistic cytotoxicity of the combination. This study examined both sequences of administration and determined the PK of each sequence. Methods: A standard 3 + 3 schedule was used in both sequences (S). The dose of B was fixed with escalating doses of T. S1: B 1.3 mg/m2 on days 1, 4, 8, and 11. T 2 to 3.5 mg/m2 on days 1 and 8 was given 6 h before B. S2: B 1.3 mg/m2 on days 1, 4, 8, 11 followed by T 2 to 3 mg/m2 given 6 h after B. Cycle length was q28 days. PK sampling for both sequences was performed. Results: 54 pts (S1: 27, S2: 27) received a median of 2 cycles (range 1-7) of therapy. Pts were heavily pre-treated. For S1, the maximum tolerated dose (MTD) of B and T were 1.3 and 3 mg/m2 respectively. For S2, the MTD of B and T were 1.3 and 2.5 mg/m2 respectively. Dose-limiting toxicities (2 pt in each sequence) were gr 3 thrombocytopenia in S1, and gr 4 thrombocytopenia in S2. Stable disease was seen in 6/27 pts in S1, and 6/27 in S2. PK results for S2 show no significant difference between the day 1 and day 8 PKs. However, the mean AUC (454±150 mg/Lxhr) and Cmax (123±51 mg/L) at the MTD of 2.5 mg/m2 reached on this trial is similar to those reported with single agent doses of 4 mg/m2 given over 30 minutes weekly x 3. As a result, the estimated topotecan clearance (11.3±5 L/hr) when given following bortezomib is approximately one half of the reported clearance for the single agent. (Curtis et al, J Clin Pharmacol, 50:268, 2010). Conclusions: The tolerability and toxicity of both sequences was similar. MTD differs with S2 having a lower tolerated dose of T. PK results suggest a possible drug-drug interaction with decreased clearance of T with S2. PK results for S1 are pending. Supported by CCSG CA62505.