Pharmacokinetic samples in this phase I study were available for INO, anti-CD22 antibody, and free and total calicheamicin derivatives. The data indicated that disposition was nonlinear with the number of dose or increasing dose. Nonlinearity is seen commonly with other antibodies as well [18]. It is due to target-mediated drug disposition, in which elimination and distribution are affected by the antibody and target cell interaction [19]. Mean end of infusion peak concentrations for 2.4 mg/m² once every 3 weeks and 1.8 mg/m² once every 3 weeks could not be distinguished from each other. For the INO and total calicheamicin, increases in area under the curve extrapolated over dosing interval (AUCT) with period and increases in AUCT with dose were observed. Anti-CD22 mAb and total calicheamicin exhibited similar trends of elimination but with a longer half-life than that of INO, suggesting that the acetyl butyrate linker is noticeably stable in plasma [14].

Phase I study of INO in Japan was conducted for patients with follicular lymphoma pretreated with rituximab-based therapy [15]. Based upon this study, safety and efficacy of INO 1.8 mg/m² q-4weeks for 13 Japanese patients were similar to phase I study in the USA/EU, but efficacy was better (Table 7.1).

Adverse events of INO 1.8 mg/m² q-4 weeks for patients with relapsed/refractory B-cell NHL observed in phase I studies of both the EU/USA and Japan are listed in Table 7.2 [14, 15]. The most common adverse events were thrombocytopenia, neutropenia, asthenia, and increase of aspartate transaminase (AST)/alanine aminotransferase (ALT). Thrombocytopenia and neutropenia were the most common reason for dose modification.