T-DM1 is an antibody-drug conjugate composed of DM1 conjugated to trastuzumab. T-DM1 combines the antitumor properties of trastuzumab with the antimicrotubule activity of DM1. Nonclinical data suggest synergy for the combination of T-DM1 and taxanes. T-DM1 is expected to undergo proteolytic degradation with no significant involvement of cytochrome P450 isoenzymes (CYPs). DM1 is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. T is metabolized primarily by CYP2C8 and to minor metabolites by CYP3A4. Neither DM1 nor T inhibit or induce CYPs at clinically relevant concentrations. Since T and DM1 are substrates of CYPs, their PK may be altered by interaction with other compounds that are substrates, inhibitors or inducers of CYPs. Given these metabolic pathways, it is important to evaluate if a PK-based drug-drug interaction potential exists when T-DM1 and T are administered together. Methods

The tolerability, PK and dose-limiting toxicities of T-DM1 (q3w and qw) and T (qw) (and pertuzumab in subsequent cohorts) in patients with HER2- positive MBC previously treated with a trastuzumab-containing regimen were investigated in this 3+3 phase Ib study, TDM4652g. In Part 1, patients received T-DM1 (2.4 mg/kg or 2.0 mg/kg q3w) and T (65 mg/m2 or 80 mg/m2 qw). In Cycle 1 of all cohorts there was a planned 1-day delay between T and T-DM1 administration; in later cycles, T was administered immediately after T-DM1, allowing within study PK comparisons of T ± T-DM1. Study patients were evaluated for serum concentrations of T-DM1, total trastuzumab (conjugated and unconjugated to DM1), and plasma concentrations of DM1 and T, at prespecified time points. PK of T-DM1 and related analytes were compared to historical monotherapy data by population analysis and/or noncompartmental analysis (NCA). Whether combination with T was a significant covariate of T-DM1 clearance (CL) and central volume of distribution (V1) was tested. PK parameters of T at Cycle 1 (without T-DM1) and Cycle 2 (with T-DM1) were estimated and compared by NCA. Results from 14 patients enrolled in Part 1 are reported here. Results

The maximal concentration (Cmax) and area under the concentration-time curve (AUC) values (days 0-7) of T-DM1 in combination treatment were comparable with historical monotherapy data (Table 1) as was the PK of total trastuzumab and DM1. Maximum DM1 level was <5 ng/mL. Combination with T was not a significant covariate of T-DM1 CL and V1 (p>.05, by log likelihood ratio test).

The PK for T was comparable from Cycle 1 (without T-DM1) and Cycle 2 (with T-DM1) for Cmax, AUC, half-life, CL and steady-state volume of distribution. Conclusions

This assessment suggests a low potential for PK-based T-DM1 T interaction when these drugs are given in combination therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-22.